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Purpose: MALT1 deficiency is a combined immune deficiency characterized by recurrent infections, eczema, chronic diarrhea, and failure to thrive. Clinical and immunological characterizations of the disease have not been previously reported in large cohorts. We sought to determine the clinical, immunological, genetic features, and the natural history of MALT-1 deficiency. Methods: The clinical findings and treatment outcomes were evaluated in nine new MALT1-deficient patients. Peripheral lymphocyte subset analyses, cytokine secretion, and proliferation assays were performed. We also analyzed ten previously reported patients to comprehensively evaluate genotype/phenotype correlation. Results: The mean age of patients and disease onset were 33 ± 17 and 1.6 ± 0.7months, respectively. The main clinical findings of the disease were recurrent infections (100%), skin involvement (100%), failure to thrive (100%), oral lesions (67%), chronic diarrhea (56%), and autoimmunity (44%). Eosinophilia and high IgE were observed in six (67%) and two (22%) patients, respectively. The majority of patients had normal T and NK cells, while eight (89%) exhibited reduced B cells. Immunoglobulin replacement and antibiotics prophylaxis were mostly ineffective in reducing the frequency of infections and other complications. One patient received hematopoietic stem cell transplantation (HSCT) and five patients died as a complication of life-threatening infections. Analyzing this cohort with reported patients revealed overall survival in 58% (11/19), which was higher in patients who underwent HSCT (P = 0.03). Conclusion: This cohort provides the largest analysis for clinical and immunological features of MALT1 deficiency. HSCT should be offered as a curative therapeutic option for all patients at the early stage of life.

Glioblastoma (GBM) is the most lethal type of brain cancer. An increasing number of studies suggest that long non-coding RNAs (lncRNAs) are implicated in tumor progression. LncRNA HOXD‐AS2 was reported to be highly expressed in glioma and associated with glioma grade and poor prognosis. However, the molecular mechanism remains to be elucidated. In this study, we first analyzed differentially expressed lncRNAs in glioblastoma using RNA-seq dataset (156 GBM samples and 5 adjacent normal samples in TCGA (Cancer Genome Atlas) and GTEx (Genotype-Tissue Expression) database). HOXD-AS2 was found to be significantly up-regulated in GBM tissues, which was further confirmed in GBM patient tumor samples and GBM cell lines. Silencing HOXD-AS2 inhibited cell proliferation, migration and invasion, and promoted cell apoptosis. We further identified and validated miR-3681-5p as a target of HOXD-AS2, and miR-3681-5p was negatively regulated by HOXD-AS2. By negatively affecting miR-3681-5p, HOXD-AS2 could promote the expression of MALT1 to augment the aggressiveness of GBM cells. miR-3681-5p overexpression or MALT1 knockdown attenuated aggressiveness of GBM cells. Importantly, silencing HOXD-AS2 suppressed tumorigenesis of GBM cells in the xenograft mouse model. Collectively, our study clarified the role of miR-3681-5p/MALT1 axis underlying the oncogenic function of lncRNA HOXD-AS2 in GBM. Future work is required to study the mechanism by which HOXD-AS2 is upregulated in GBM cells, which can provide novel insights into therapeutic intervention for GBM treatment.

The activated B-cell (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) has an aggressive course and is associated with poor prognosis in the relapsed or refractory setting. ABC-DLBCL is characterized by chronic active signaling of NF-κB, which is dependent on the CARD11-BCL10-MALT1 (CBM) complex. MALT1 is a key effector of the CBM complex and activates canonical NF-κB and AP-1 among other transcription factors via distinct protease and scaffold functions. There is therefore growing interest in therapeutic targeting of MALT1 for B-cell malignancies. Here, we review recent advances in therapeutic targeting of MALT1 for ABC-DLBCL. Covalent and allosteric MALT1 protease inhibitors have been developed which inhibit growth of ABC-DLBCL in preclinical models, and two clinical MALT1 protease inhibitors are being developed in phase I clinical trials. Importantly, these compounds can overcome resistance to BTK inhibitors in preclinical models. Alternative compounds blocking the scaffold effect of MALT1 are also in early preclinical development. Blockade of MALT1 protease activity may have important implications for anti-lymphoma immunity by increasing immunogenicity of ABC-DLBCL cells and also by potentiating anti-lymphoma activity of other immune cells in the lymphoma microenvironment. Together, early data suggest that MALT1 is a promising target for ABC-DLBCL and possibly other B-cell malignancies, and can have lymphoma cell-intrinsic as well as immune-mediated therapeutic effects.

Regulatory T cells (Tregs) are essential for the inhibition of immunity and the maintenance of tissue homeostasis. Signals from the T-cell antigen receptor (TCR) are critical for early Treg development, their expansion, and inhibitory activity. Although TCR-engaged activation of the paracaspase MALT1 is important for these Treg activities, the MALT1 effector pathways in Tregs remain ill-defined. Here, we demonstrate that MALT1 protease activity controls the TCR-induced upregulation of the transcription factor MYC and the subsequent expression of MYC target genes in Tregs. These mechanisms are important for Treg-intrinsic mitochondrial function, optimal respiratory capacity, and homeostatic Treg proliferation. Consistently, conditional deletion of Myc in Tregs results similar to MALT1 inactivation in a lethal autoimmune inflammatory syndrome. Together, these results identify a MALT1 protease-mediated link between TCR signaling in Tregs and MYC control that coordinates metabolism and Treg expansion for the maintenance of immune homeostasis.

Human germline MALT1 deficiency is an inborn error of immunity characterized by recurrent bacterial, viral, and fungal infections, periodontal disease, enteropathy, dermatitis, and failure to thrive. The number of identified MALT1-deficient patients have greatly increased in the past two years, which has significantly improved our understanding of the clinical features of this disorder. Patients frequently experience infections affecting the respiratory, skin, gastrointestinal, and blood systems. The most frequently detected pathogens are Staphylococcus aureus, Candida albicans, and cytomegalovirus. Enhanced susceptibility to S. aureus and C. albicans is likely due to impaired Th17 immunity, similar to STAT3 and IL-17 pathway deficiencies.

Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) regulates T helper/regulatory T cell balance, autoimmunity development, and leukemia pathogenesis. As a result, this study aimed to investigate the clinical role of MALT1 in patients with acute myeloid leukemia (AML).MALT1 expressions were measured in peripheral blood mononuclear cell (PBMC) from 90 newly diagnosed AML patients before and after induction treatment using RT-qPCR. Moreover, MALT1 expressions were also determined in 50 disease controls (DCs) and 50 healthy controls (HCs).MALT1 expression was reduced in AML patients compared to HCs and DCs (both adjustedPBMC MALT1 deficiency is common and relates to unfavorable induction therapy response and survival profile in AML patients.

Alternative splicing plays key roles for cell type-specific regulation of protein function. It is controlled by cis-regulatory RNA elements that are recognized by RNA binding proteins (RBPs). The MALT1 paracaspase is a key factor of signaling pathways that mediate innate and adaptive immune responses. Alternative splicing of

Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) mediates the immunity and inflammatory response in multiple ways to be intimately involved in the progression of autoimmune diseases. This study intended to explore the linkage of MALT1 with inflammation, disease activity, and its change with infliximab treatment response in Crohn's disease (CD) patients.MALT1 in peripheral blood mononuclear cell samples from 72 active CD patients (at baseline, 2 weeks [W2], W6, and W12 after infliximab treatment), 20 remissive CD patients (after enrollment), and 20 healthy controls (after enrollment) were detected by RT-qPCR.MALT1 was highest in active CD patients, followed by remissive CD patients, and lowest in healthy controls (p 0.001). MALT1 was positively linked with C-reactive protein (p = 0.001), erythrocyte sedimentation rate (p = 0.014), clinical disease activity index (p = 0.003), tumor necrosis factor (TNF)-α (p = 0.006), interleukin (IL)-1β (p = 0.049), and IL-17A (p = 0.004), but not other clinical characteristics (all p 0.05) in active CD patients. After infliximab treatment, MALT1 was decreased from baseline to W12 in active CD patients (p 0.001), especially in responders (p 0.001), but not in nonresponders (p = 0.053). The reduction of MALT1 at W6 (p = 0.049) and W12 (p = 0.004) was associated with a good treatment response to infliximab in active CD patients. Moreover, the response rate or MALT1 at any time point was not different between active CD patients with and without TNFi history (all p 0.05).MALT1 reflects aggravated inflammation and disease activity. Meanwhile, the decrement of MALT1 from baseline to W12 could reflect infliximab treatment response in CD patients.

Development of mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) inhibitors is of great value and significance in the treatment of neoplastic disorders and inflammatory and autoimmune diseases. However, there is a lack of effective MALT1 inhibitors in clinic. Herein, a novel class of potent 5-oxo-1-thioxo-4,5-dihydro-1H-thiazolo[3,4-a]quinazoline-based MALT1 inhibitors and their covalent derivatives were first identified and designed through high-throughput screening. We demonstrated that compounds 15c, 15e, and 20c effectively inhibited the MALT1 protease and displayed selective cytotoxicity to activated B cell-like diffuse large B cell lymphoma with low single-digit micromolar potency. Furthermore, compound 20c specifically repressed NF-κB signaling and induced cell apoptosis in MALT1-dependent TMD8 cells in a dose-dependent manner. More importantly, 20c showed good pharmacokinetic properties and antitumor efficacy with no significant toxicity in the TMD8 xenograft tumor model. Collectively, this study provides valuable lead compounds of MALT1 inhibitors for further structural optimization and antitumor mechanism study.

MALT1 forms part of a central signaling node downstream of immunoreceptor tyrosine-based activation motif (ITAM)-containing receptors, across a broad range of immune cell subsets, and regulates NF-κB driven transcriptional responses via dual scaffolding-protease activity. Allosteric inhibition of MALT1 activity has demonstrated benefit in animal models of inflammation. However, development of MALT1 inhibitors to treat autoimmune and inflammatory diseases (A&ID) has been hindered by reports linking MALT1 inhibition and genetic loss-of-function to reductions in regulatory T-cell (Treg) numbers and development of auto-inflammatory syndromes. Using an allosteric MALT1 inhibitor, we investigated the consequence of pharmacological inhibition of MALT1 on proinflammatory cells compared to regulatory T-cells. Consistent with its known role in ITAM-driven responses, MALT1 inhibition suppressed proinflammatory cytokine production from activated human T-cells and monocyte-derived macrophages, and attenuated B-cell proliferation. Oral administration of a MALT1 inhibitor reduced disease severity and synovial cytokine production in a rat collagen-induced arthritis model. Interestingly, reduction in splenic Treg numbers was less pronounced in the context of inflammation compared with naïve animals. Additionally, in the context of the disease model, we observed an uncoupling of anti-inflammatory effects of MALT1 inhibition from Treg reduction, with lower systemic concentrations of inhibitor needed to reduce disease severity compared to that required to reduce Treg numbers. MALT1 inhibition did not affect suppressive function of human Tregs in vitro. These data indicate that anti-inflammatory efficacy can be achieved with MALT1 inhibition without impacting the number or function of Tregs, further supporting the potential of MALT1 inhibition in the treatment of autoimmune disease.

Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) facilitates CD4This study recruited 73 AS patients underwent adalimumab treatment. Peripheral blood mononuclear cell (PBMC) was obtained at Week (W) 0, W4, W8, and W12 after treatment initiation; then, MALT1 was measured using RT-qPCR. Furthermore, PBMC and serum at W0 were proposed to flow cytometry and ELISA for Th1 cells, Th17 cells, IFN-γ, and IL-17A levels measurement. Besides, 20 osteoarthritis patients and 20 healthy controls (HCs) were enrolled to detect MALT1.Mucosa-associated lymphoid tissue lymphoma translocation protein 1 expression was higher in AS patients compared with HCs (p 0.001) and osteoarthritis patients (p 0.001). Besides, MALT1 expression was positively linked with CRP (p = 0.002), BASDAI (p = 0.026), PGADA (p = 0.040), ASDASMucosa-associated lymphoid tissue lymphoma translocation protein 1 positively correlates with Th17 cells, inflammatory, and activity degree; meanwhile, its decrement along with treatment reflects the response to TNF inhibitor in AS patients.

MALT1 regulates immunity and inflammation in multiple ways, while its role in rheumatoid arthritis (RA) is obscure. This study aimed to investigate the relationship of MALT1 with disease features, treatment outcome, as well as its effect on Th1/2/17 cell differentiation and underlying molecule mechanism in RA.Totally 147 RA patients were enrolled. Then their blood Th1, Th2, and Th17 cells were detected by flow cytometry. Besides, PBMC MALT1 expression was detected before treatment (baseline), at week (W) 6, W12, and W24. PBMC MALT1 in 30 osteoarthritis patients and 30 health controls were also detected. Then, blood CD4MALT1 was increased in RA patients compared to osteoarthritis patients and healthy controls. Meanwhile, MALT1 positively related to CRP, ESR, DAS28 score, Th17 cells, negatively linked with Th2 cells, but did not link with other features or Th1 cells in RA patients. Notably, MALT1 decreased longitudinally during treatment, whose decrement correlated with RA treatment outcome (treatment response, low disease activity, or disease remission). In addition, MALT1 overexpression promoted Th17 differentiation, inhibited Th2 differentiation, less affected Th1 differentiation, activated NF-κB and JNK pathways in RA CD4MALT1 regulates Th2 and Th17 differentiation

The caspase activation and recruitment domain-coiled-coil (CARD-CC) family of proteins-CARD9, CARD10, CARD11, and CARD14-is collectively expressed across nearly all tissues of the body and is a crucial mediator of immunologic signaling as part of the CARD-B-cell lymphoma/leukemia 10-mucosa-associated lymphoid tissue lymphoma translocation protein 1 (CBM) complex. Dysfunction or dysregulation of CBM proteins has been linked to numerous clinical manifestations known as "CBM-opathies." The CBM-opathy spectrum encompasses diseases ranging from mucocutaneous fungal infections and psoriasis to combined immunodeficiency and lymphoproliferative diseases; however, there is accumulating evidence that the CARD-CC family members also contribute to the pathogenesis and progression of allergic inflammation and allergic diseases. Here, we review the 4 CARD-CC paralogs, as well as B-cell lymphoma/leukemia 10 and mucosa-associated lymphoid tissue lymphoma translocation protein 1, and their individual and collective roles in the pathogenesis and progression of allergic inflammation and 4 major allergic diseases (allergic asthma, atopic dermatitis, food allergy, and allergic rhinitis).

Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is a key adaptor protein that regulates the NF-κB pathway, in which MALT1 functions as a scaffold protein and protease to trigger downstream signals. The abnormal expression of MALT1 is closely associated with lymphomagenesis and other diseases, including solid tumors and autoimmune diseases. MALT1 is the only protease in the underlying pathogenesis of these diseases, and its proteolytic activity can be pharmacologically regulated. Therefore, MALT1 is a potential and promising target for anti-lymphoma and other MALT1-related disease treatments. Currently, the development of MALT1 inhibitors is still in its early stages. This review presents an overview of MALT1, particularly its X-ray structures and biological functions, and elaborates on the pathogenesis of diseases associated with its dysregulation. We then summarize previously reported MALT1 inhibitors, focusing on their molecular structure, biological activity, structure-activity relationship, and limitations. Finally, we propose future research directions to accelerate the discovery of novel MALT1 inhibitors with clinical applications. Overall, this review provides a comprehensive and systematic overview of MALT1-related research advances and serves as a theoretical basis for drug discovery and research.

Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) participates in the immune-related allergic response and inflammation flare, while its clinical role in asthma children is still unknown. Herein, this study aimed to investigate MALT1 expression, and its correlation with exacerbation risk, T helper (Th)1, Th2 cells (and their secreted cytokines), as well as inflammatory cytokines in asthma children.Sixty children with asthma exacerbation and 60 children with remission asthma were enrolled in this study; then their blood MALT1, Th1, Th2 cells, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interferon-gamma (IFN-γ), and interleukin-4 (IL-4) were detected. Besides, blood MALT1 in another 20 health controls was also determined.Mucosa-associated lymphoid tissue lymphoma translocation protein 1 was highest in children with asthma exacerbation, followed by children with remission asthma, and lowest in health controls (p 0.001). MALT1 could distinguish children with asthma exacerbation from children with remission asthma (area under the curve (AUC): 0.757, 95% CI: 0.670-0.843). In children with asthma exacerbation, MALT1 was negatively linked with IFN-γ (p = 0.002) and Th1 cells (p = 0.050), but positively related to Th2 cells (p = 0.027) and exhibited a positive correlation trend (without statistical significance) with IL-4 (p = 0.066); meanwhile, MALT1 was positively correlated with exacerbation severity (p = 0.010) and TNF-α (p = 0.003), but not linked with IL-6 (p = 0.096). In children with remission asthma, MALT1 only was negatively associated with Th1 cells (p = 0.023), but positively linked with TNF-α (p = 0.023).Mucosa-associated lymphoid tissue lymphoma translocation protein 1 serves as a potential biomarker for monitoring exacerbation risk and Th1/Th2 imbalance-mediated inflammation of asthma children.

CARD11 acts as a gatekeeper for adaptive immune responses after T cell or B cell antigen receptor (TCR/BCR) ligation on lymphocytes. PKCθ/β-catalyzed phosphorylation of CARD11 promotes the assembly of the CARD11-BCL10-MALT1 (CBM) complex and lymphocyte activation. Here, we demonstrated that PKCθ/β-dependent CARD11 phosphorylation also suppressed CARD11 functions in T or B cells. Through mass spectrometry–based proteomics analysis, we identified multiple constitutive and inducible CARD11 phosphorylation sites in T cells. We demonstrated that a single TCR- or BCR-inducible phosphorylation on Ser 893 in the carboxyl terminus of CARD11 prevented the activation of the transcription factor NF-κB, the kinase JNK, and the protease MALT1. Moreover, CARD11 Ser 893 phosphorylation sensitized BCR-addicted lymphoma cells to toxicity induced by Bruton’s tyrosine kinase (BTK) inhibitors. Phosphorylation of Ser 893 in CARD11 by PKCθ controlled the strength of CARD11 scaffolding by impairing the formation of the CBM complex. Thus, PKCθ simultaneously catalyzes both stimulatory and inhibitory CARD11 phosphorylation events, which shape the strength of CARD11 signaling in lymphocytes.

MALT1 is linked with multiple organic dysfunctions, inflammatory storm, and T helper (Th) cell differentiation. Herein, the current study aimed to investigate the correlation of peripheral blood mononuclear cell (PBMC) MALT1 with Th1 cells, Th17 cells, and prognosis of sepsis patients.In general, 78 sepsis patients and 40 health controls (HCs) were enrolled. MALT1 expression was detected in PBMCs from all subjects by RT-qPCR. Besides, Th1 and Th17 cells were measured in PBMCs from sepsis patients by flow cytometry; interleukin 17A (IL-17A) and interferon gamma (IFN-γ) were determined in serum from sepsis patients by ELISA.MALT1 expression was higher in sepsis patients than HCs (p 0.001). MALT1 expression was positively correlated with Th17 cells (rPBMC MALT1 is highly expressed in sepsis patients with its overexpression associated with multiple organic dysfunctions, elevated Th17 cells, and increased mortality risk.

T cell activation initiates protective adaptive immunity, but counterbalancing mechanisms are critical to prevent overshooting responses and to maintain immune homeostasis. The CARD11-BCL10-MALT1 (CBM) complex bridges T cell receptor engagement to NF-κB signaling and MALT1 protease activation. Here, we show that ABIN-1 is modulating the suppressive function of A20 in T cells. Using quantitative mass spectrometry, we identified ABIN-1 as an interactor of the CBM signalosome in activated T cells. A20 and ABIN-1 counteract inducible activation of human primary CD4 and Jurkat T cells. While A20 overexpression is able to silence CBM complex-triggered NF-κB and MALT1 protease activation independent of ABIN-1, the negative regulatory function of ABIN-1 depends on A20. The suppressive function of A20 in T cells relies on ubiquitin binding through the C-terminal zinc finger (ZnF)4/7 motifs, but does not involve the deubiquitinating activity of the OTU domain. Our mechanistic studies reveal that the A20/ABIN-1 module is recruited to the CBM complex via A20 ZnF4/7 and that proteasomal degradation of A20 and ABIN-1 releases the CBM complex from the negative impact of both regulators. Ubiquitin binding to A20 ZnF4/7 promotes destructive K48-polyubiquitination to itself and to ABIN-1. Further, after prolonged T cell stimulation, ABIN-1 antagonizes MALT1-catalyzed cleavage of re-synthesized A20 and thereby diminishes sustained CBM complex signaling. Taken together, interdependent post-translational mechanisms are tightly controlling expression and activity of the A20/ABIN-1 silencing module and the cooperative action of both negative regulators is critical to balance CBM complex signaling and T cell activation. Supplementary Information The online version contains supplementary material available at 10.1007/s00018-022-04154-z.

Immune cells activate in binary, switch-like fashion via large protein assemblies known as signalosomes, but the molecular mechanism of the switch is not yet understood. Here, we employed an in-cell biophysical approach to dissect the assembly mechanism of the CARD-BCL10-MALT1 (CBM) signalosome, which governs nuclear transcription factor-κB activation in both innate and adaptive immunity. We found that the switch consists of a sequence-encoded and deeply conserved nucleation barrier to ordered polymerization by the adaptor protein BCL10. The particular structure of the BCL10 polymers did not matter for activity. Using optogenetic tools and single-cell transcriptional reporters, we discovered that endogenous BCL10 is functionally supersaturated even in unstimulated human cells, and this results in a predetermined response to stimulation upon nucleation by activated CARD multimers. Our findings may inform on the progressive nature of age-associated inflammation, and suggest that signalosome structure has evolved via selection for kinetic rather than equilibrium properties of the proteins.The innate immune system is the body’s first line of defence against pathogens. Although innate immune cells do not recognize specific disease-causing agents, they can detect extremely low levels of harmful organisms or substances. In response, they activate signals that lead to inflammation, which tells other cells that there is an infection. Innate immune cells are turned on in a switch-like fashion, becoming active very quickly after interacting with a pathogen. This is due to the action of signalosomes, large complexes made up of several proteins that clump together to form long chains that activate the cell. But how do these large protein complexes assemble quick enough to create the switch-like activation observed in innate immune cells? To answer this question, Rodríguez Gama et al. focused on the CBM signalosome, which is involved in triggering inflammation through the activation of a protein called NF-kB. First, Rodríguez Gama et al. used genetic tools to determine that activating the CBM signalosome drives a switch-like activation of NF-kB in cells. This means that individual cells in a population either become fully activated or not at all in response to minute amounts of harmful substances. Once they had established this, Rodríguez Gama et al. wanted to know which protein in the CBM signalosome was responsible for the switch. They found that one of the proteins in the signalosome, called BCL10, has a ‘nucleation barrier’ encoded in its sequence. This means that it is very hard for BCL10 to start clumping together, but once it does, the clumps grow on their own. The nucleation barrier describes exactly how hard it is for these clumps to get started, and is determined by how disorganized the protein is. When a pathogen ‘stimulates’ an immune cell, a tiny template is formed that lowers the nucleation barrier so that BCL10 can then aggregate itself together, leading to the switch-like behaviour observed. The nucleation barrier allows there to be more than enough BCL10 present in the cell at all times – ready to clump together at a moment’s notice – and this permits the cell to detect very low levels of a pathogen. Rodríguez Gama et al. then tested whether BCL10 from other animals also has a nucleation barrier. They found that this feature is conserved from cnidarians, such as corals or jellyfish, to mammals, including humans. This suggests that the use of nucleation barriers to regulate innate immune signalling has existed for a long time throughout evolution. The work by Rodríguez Gama et al. broadens our understanding of how the innate immune system senses and responds to extremely low levels of pathogens. That BCL10 is always ready to clump together suggests it may be a driving force for chronic and age-associated inflammation. Additionally, the findings of Rodríguez Gama et al. also offer insights into how other signalosomes may become activated, and offer the possibility of new drugs aimed at modifying nucleation barriers.

Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is a multifunctional protein. MALT1 functions as an adaptor protein to assemble and recruit proteins such as B-cell lymphoma 10 (BCL10) and caspase-recruitment domain (CARD)-containing coiled-coil protein 11 (CARD11). Conversely it also acts as a paracaspase to cleave specified substrates. Because of its involvement in immunity, inflammation and cancer through its dual functions of scaffolding and catalytic activity, MALT1 is becoming a promising therapeutic target in B cell- and T cell-related diseases. There is growing evidence that the function of MALT1 is subtly modulated via post-translational modifications. This review summarized recent progress in relevant studies regarding the physiological and pathophysiological functions of MALT1, post-translational modifications of MALT1 and its role in B cell- and T cell- related diseases. In addition, the current available MALT1 inhibitors were also discussed.

MALT1 is the effector protein of the CARMA/Bcl10/MALT1 (CBM) signalosome, a multiprotein complex that drives pro-inflammatory signaling pathways downstream of a diverse set of receptors. Although CBM activity is best known for its role in immune cells, emerging evidence suggests that it plays a key role in the pathogenesis of solid tumors, where it can be activated by selected G protein–coupled receptors (GPCR). Here, we demonstrated that overexpression of GPCRs implicated in breast cancer pathogenesis, specifically the receptors for Angiotensin II and thrombin (AT1R and PAR1), drove a strong epithelial-to-mesenchymal transition (EMT) program in breast cancer cells that is characteristic of claudin-low, triple-negative breast cancer (TNBC). In concert, MALT1 was activated in these cells and contributed to the dramatic EMT phenotypic changes through regulation of master EMT transcription factors including Snail and ZEB1. Importantly, blocking MALT1 signaling, through either siRNA-mediated depletion of MALT1 protein or pharmacologic inhibition of its activity, was effective at partially reversing the molecular and phenotypic indicators of EMT. Treatment of mice with mepazine, a pharmacologic MALT1 inhibitor, reduced growth of PAR1+, MDA-MB-231 xenografts and had an even more dramatic effect in reducing the burden of metastatic disease. These findings highlight MALT1 as an attractive therapeutic target for claudin-low TNBCs harboring overexpression of one or more selected GPCRs. Implications: This study nominates a GPCR/MALT1 signaling axis as a pathway that can be pharmaceutically targeted to abrogate EMT and metastatic progression in TNBC, an aggressive form of breast cancer that currently lacks targeted therapies.

An innovative strategy for cancer therapy is to combine the inhibition of cancer cell-intrinsic oncogenic signaling with cancer cell-extrinsic immunological activation of the tumor microenvironment (TME). In general, such approaches will focus on two or more distinct molecular targets in the malignant cells and in cells of the surrounding TME. In contrast, the protease Mucosa-associated lymphoid tissue protein 1 (MALT1) represents a candidate to enable such a dual approach by engaging only a single target. Originally identified and now in clinical trials as a lymphoma drug target based on its role in the survival and proliferation of malignant lymphomas addicted to chronic B cell receptor signaling, MALT1 proteolytic activity has recently gained additional attention through reports describing its tumor-promoting roles in several types of non-hematological solid cancer, such as breast cancer and glioblastoma. Besides cancer cells, regulatory T (Treg) cells in the TME are particularly dependent on MALT1 to sustain their immune-suppressive functions, and MALT1 inhibition can selectively reprogram tumor-infiltrating Treg cells into Foxp3-expressing proinflammatory antitumor effector cells. Thereby, MALT1 inhibition induces local inflammation in the TME and synergizes with anti-PD-1 checkpoint blockade to induce antitumor immunity and facilitate tumor control or rejection. This new concept of boosting tumor immunotherapy in solid cancer by MALT1 precision targeting in the TME has now entered clinical evaluation. The dual effects of MALT1 inhibitors on cancer cells and immune cells therefore offer a unique opportunity for combining precision oncology and immunotherapy to simultaneously impair cancer cell growth and neutralize immunosuppression in the TME. Further, MALT1 targeting may provide a proof of concept that modulation of Treg cell function in the TME represents a feasible strategy to augment the efficacy of cancer immunotherapy. Here, we review the role of MALT1 protease in physiological and oncogenic signaling, summarize the landscape of tumor indications for which MALT1 is emerging as a therapeutic target, and consider strategies to increase the chances for safe and successful use of MALT1 inhibitors in cancer therapy.

Signal transduction typically displays a so-called bow-tie topology: Multiple receptors lead to multiple cellular responses but the signals all pass through a narrow waist of central signaling nodes. One such signaling node for several inflammatory and oncogenic signaling pathways is the CARD-CC/BCL10/MALT1 (CBM) complexes, which get activated by protein kinase C (PKC)-mediated phosphorylation of the caspase activation and recruitment domain (CARD)-coiled-coil domain (CC) component. In humans, there are four CARD-CC family proteins (CARD9, CARD10, CARD11, and CARD14) and 9 true PKC isozymes (α to ι). At this moment, less than a handful of PKC::CARD-CC relationships are known. In order to explore the biologically relevant combinatorial space out of all 36 potential permutations in this two-component signaling event, we made use of CARD10-deficient human embryonic kidney 293T cells for subsequent pairwise cotransfections of all CARD-CC family members and all activated PKCs. Upon analysis of NF-κB-dependent reporter gene expression, we could define specific PKC::CARD-CC relationships. Surprisingly, as many as 21 PKC::CARD-CC functional combinations were identified. CARD10 was responsive to most PKCs, while CARD14 was mainly activated by PKCδ. The CARD11 activation profile was most similar to that of CARD9. We also discovered the existence of mixed protein complexes between different CARD-CC proteins, which was shown to influence their PKC response profile. Finally, multiple PKCs were found to use a common phosphorylation site to activate CARD9, while additional phosphorylation sites contribute to CARD14 activation. Together, these data reveal the combinatorial space of PKC::CARD-CC signal transduction nodes, which will be valuable for future studies on the regulation of CBM signaling.

Psoriasis is a severe disease associated with the disturbance of metabolism and inflammation, but the molecular mechanisms underlying these aspects of psoriasis pathology are poorly understood. Here, we report that glutaminase 1–mediated (GLS1-mediated) glutaminolysis was aberrantly activated in patients with psoriasis and in psoriasis-like mouse models, which promoted Th17 and γδ T17 (IL-17A–producing γδ T) cell differentiation through enhancement of histone H3 acetylation of the Il17a promoter, thereby contributing to the immune imbalance and development of psoriasis. We further demonstrate that mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) protease was constitutively active in psoriatic CD4(+) and γδ T cells, thereby supporting GLS1 expression by stabilizing c-Jun, which directly binds to the GLS1 promoter region. Blocking the activity of either GLS1 or MALT1 protease resolved Th17 and γδ T17 cell differentiation and epidermal hyperplasia in the psoriasis-like mouse models. Finally, IL-17A enhanced GLS1 expression via the MALT1/cJun pathway in keratinocytes, resulting in hyperproliferation of and chemokine production by keratinocytes. Our findings identify the role of the MALT1/cJun/GLS1/glutaminolysis/H3 acetylation/T17 axis in psoriasis pathogenesis and reveal potential therapeutic targets for this disease.

Objectives T-cell receptor (TCR) signaling-induced activation of NF-κB requires assembly of the CARD11-BCL10-MALT-1 complex and IκB kinase (IKK). Gain-of-function alterations in this component of the TCR/NF-κB pathway are associated with the development of HTLV-1-driven adult T-cell leukemia (ATL). We aimed to determine whether inhibition of MALT-1-mediated NF-κB activation could have anti-ATL activity. Methods RT-PCR, immunoblotting, and electrophoretic mobility shift assays were performed to assess expression levels of MALT-1 and the intracellular signaling cascades. Cell proliferation, cell cycle progression, and apoptotic events were examined using WST-8 assays, flow cytometry, and Hoechst 33342 staining. Results MALT-1 expression was upregulated in ATL-derived T-cell lines compared to that in normal PBMCs and uninfected or HTLV-1-transformed T-cell lines. Targeting MALT-1 with siRNA decreased cell proliferation. A MALT-1 inhibitor (MI-2) suppressed cleavage of the MALT-1-target protein, CYLD, and inhibited proliferation via G1 phase arrest. MI-2 induced apoptosis through caspase-3/8/9 activation and inhibited the phosphorylation of IKKα/β and IκBα, resulting in the accumulation of IκBα and suppression of NF-κB-DNA binding. Additionally, MI-2 inhibited the expression of apoptosis- and cell cycle-related proteins regulated by NF-κB. Conclusions MALT-1 plays an important regulatory role in NF-κB signaling during ATL-genesis, and targeting MALT-1 is a promising therapeutic strategy for this disease.

Glioblastoma multiforme (GBM) is the most common malignant tumour in the adult brain and hard to treat. Nuclear factor κB (NF‐κB) signalling has a crucial role in the tumorigenesis of GBM. EGFR signalling is an important driver of NF‐κB activation in GBM; however, the correlation between EGFR and the NF‐κB pathway remains unclear. In this study, we investigated the role of mucosa‐associated lymphoma antigen 1 (MALT1) in glioma progression and evaluated the anti‐tumour activity and effectiveness of MI‐2, a MALT1 inhibitor in a pre‐clinical GBM model. We identified a paracaspase MALT1 that is involved in EGFR‐induced NF‐kB activation in GBM. MALT1 deficiency or inhibition significantly affected the proliferation, survival, migration and invasion of GBM cells both in vitro and in vivo. Moreover, MALT1 inhibition caused G1 cell cycle arrest by regulating multiple cell cycle–associated proteins. Mechanistically, MALTI inhibition blocks the degradation of IκBα and prevents the nuclear accumulation of the NF‐κB p65 subunit in GBM cells. This study found that MALT1, a key signal transduction cascade, can mediate EGFR‐induced NF‐kB activation in GBM and may be potentially used as a novel therapeutic target for GBM.

The signaling protein MALT1 plays a key role in promoting NF-κB activation in Ag-stimulated lymphocytes. In this capacity, MALT1 has two functions, acting as a scaffolding protein and as a substrate-specific protease. MALT1 is also required for NF-κB–dependent induction of proinflammatory cytokines after FcεR1 stimulation in mast cells, implicating a role in allergy. Because MALT1 remains understudied in this context, we sought to investigate how MALT1 proteolytic activity contributes to the overall allergic response. We compared bone marrow–derived mast cells from MALT1 knockout (MALT1−/−) and MALT1 protease-deficient (MALTPD/PD) mice to wild-type cells. We found that MALT1−/− and MALT1PD/PD mast cells are equally impaired in cytokine production following FcεRI stimulation, indicating that MALT1 scaffolding activity is insufficient to drive the cytokine response and that MALT1 protease activity is essential. In addition to cytokine production, acute mast cell degranulation is a critical component of allergic response. Intriguingly, whereas degranulation is MALT1-independent, MALT1PD/PD mice are protected from vascular edema induced by either passive cutaneous anaphylaxis or direct challenge with histamine, a major granule component. This suggests a role for MALT1 protease activity in endothelial cells targeted by mast cell–derived vasoactive substances. Indeed, we find that in human endothelial cells, MALT1 protease is activated following histamine treatment and is required for histamine-induced permeability. We thus propose a dual role for MALT1 protease in allergic response, mediating 1) IgE-dependent mast cell cytokine production, and 2) histamine-induced endothelial permeability. This dual role indicates that therapeutic inhibitors of MALT1 protease could work synergistically to control IgE-mediated allergic disease.

Objective Fcγ receptors (FcγR) play important roles in both protective and pathogenic immune responses. The assembly of the CBM signalosome encompassing caspase recruitment domain-containing protein 9, B cell CLL/lymphoma 10, and mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT-1) is required for optimal FcγR-induced canonical NF-κB activation and proinflammatory cytokine release. This study was undertaken to clarify the relevance of MALT-1 protease activity in FcγR-driven events and evaluate the therapeutic potential of selective MALT-1 protease inhibitors in FcγR-mediated diseases. Methods Using genetic and pharmacologic disruption of MALT-1 scaffolding and enzymatic activity, we assessed the relevance of MALT-1 function in murine and human primary myeloid cells upon stimulation with immune complexes (ICs) and in murine models of autoantibody-driven arthritis and immune thrombocytopenic purpura (ITP). Results MALT-1 protease function is essential for optimal FcγR-induced production of proinflammatory cytokines by various murine and human myeloid cells stimulated with ICs. In contrast, MALT-1 protease inhibition did not affect the Syk-dependent, FcγR-mediated production of reactive oxygen species or leukotriene B4 . Notably, pharmacologic MALT-1 protease inhibition in vivo reduced joint inflammation in the murine K/BxN serum-induced arthritis model (mean area under the curve for paw swelling of 45.42% versus 100% in control mice; P = 0.0007) but did not affect platelet depletion in a passive model of ITP. Conclusion Our findings indicate a specific contribution of MALT-1 protease activity to FcγR-mediated events and suggest that MALT-1 protease inhibitors have therapeutic potential in a subset of FcγR-driven inflammatory disorders.

Constitutive proteolytic activity of MALT1 is associated with highly aggressive B-cell lymphomas. Chemical tools that detect active MALT1 have been reported, but suffer from poor cell permeability and/or cross-reactivity with the cysteine protease cathepsin B. Here, we report that the non-natural amino acid pipecolinic acid in the P2 position of substrates and chemical probes leads to improved selectivity toward MALT1 and results in cell-permeable fluorescent probes.

Antigen receptor–dependent (AgR-dependent) stimulation of the NF-κB transcription factor in lymphocytes is a required event during adaptive immune response, but dysregulated activation of this signaling pathway can lead to lymphoma. AgR stimulation promotes assembly of the CARMA1-BCL10-MALT1 complex, wherein MALT1 acts as (a) a scaffold to recruit components of the canonical NF-κB machinery and (b) a protease to cleave and inactivate specific substrates, including negative regulators of NF-κB. In multiple lymphoma subtypes, malignant B cells hijack AgR signaling pathways to promote their own growth and survival, and inhibiting MALT1 reduces the viability and growth of these tumors. As such, MALT1 has emerged as a potential pharmaceutical target. Here, we identified G protein–coupled receptor kinase 2 (GRK2) as a new MALT1-interacting protein. We demonstrated that GRK2 binds the death domain of MALT1 and inhibits MALT1 scaffolding and proteolytic activities. We found that lower GRK2 levels in activated B cell–type diffuse large B cell lymphoma (ABC-DLBCL) are associated with reduced survival, and that GRK2 knockdown enhances ABC-DLBCL tumor growth in vitro and in vivo. Together, our findings suggest that GRK2 can function as a tumor suppressor by inhibiting MALT1 and provide a roadmap for developing new strategies to inhibit MALT1-dependent lymphomagenesis.

Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) lymphoma of the stomach is mainly associated with Helicobacter pylori infection, and H. pylori eradication therapy is often effective. However, 20-30% of the cases of MALT lymphoma are resistant to the eradication therapy, and translocation of the API2-MALT1 gene is often found in these cases. Most cases without translocation of API2-MALT1 are localized to the stomach, whereas some cases with this translocation are a more advanced stage of MALT lymphoma that spreads to other organs. The c-Met receptor is a prognostic factor involved in infiltration and metastasis in many malignant tumors, including gastric, pancreatic, lung, and kidney cancer. In the present study, the expression of c-Met in 43 cases of gastric MALT lymphomas was immunohistochemically examined and compared with clinicopathological factors. To elucidate the significance of c-Met in MALT lymphoma, the expression intensity of c-Met in 22 API2-MALT1 translocation-positive and 21 API2-MALT1 translocation-negative cases was scored, compared, and examined. The immunohistochemistry analysis revealed strong staining for c-Met in 21 API2-MALT1 translocation-positive cases and in 1 translocation-negative case (P = 0.00). This result indicates the relationship between strong expression of c-Met and the progression of MALT lymphoma with API2-MALT1 gene translocation.

Rationale: Constitutive activation of the NF-κB signalling pathway plays a pivotal role in the pathogenesis of activated B cell-like diffuse large B-cell lymphomas (ABC-DLBCLs), the most aggressive and chemoresistant form of DLBCL. In ABC-DLBCLs, the CARMA1-BCL10 (CB) complex forms a filamentous structure and functions as a supramolecular organizing centre (CB-SMOC) that is required for constitutive NF-κB activation, making it an attractive drug target for ABC-DLBCL treatment. However, a pharmaceutical approach targeting CB-SMOC has been lacking. Here, we developed Bcl10 peptide inhibitors (BPIs) that specifically target the BCL10 filamentation process. Methods: Electron microscopy and immunofluorescence imaging were used to visualize the effect of the BPIs on the BCL10 filamentation process. The cytotoxicity of the tested BPIs was evaluated in DLBCL cell lines according to cell proliferation assays. Different in vitro experiments (pharmacokinetics, immunoprecipitation, western blotting, annexin V and PI staining) were conducted to determine the functional mechanisms of the BPIs. The in vivo therapeutic effect of the BPIs was examined in different xenograft DLBCL mouse models. Finally, Ki67 and TUNEL staining and histopathology analysis were used to evaluate the antineoplastic mechanisms and systemic toxicity of the BPIs. Results: We showed that these BPIs can effectively disrupt the BCL10 filamentation process, destabilize BCL10 and suppress NF-κB signalling in ABC-DLBCL cells. By examining a panel of DLBCL cell lines, we found that these BPIs selectively repressed the growth of CB-SMOC-dependent DLBCL cells by inducing apoptosis and cell cycle arrest. Moreover, by converting the BPIs to acquire a D-retro inverso (DRI) configuration, we developed DRI-BPIs with significantly improved intracellular stability and unimpaired BPI activity. These DRI-BPIs selectively repressed the growth of CB-SMOC-dependent DLBCL tumors in mouse xenograft models without eliciting discernible adverse effects. Conclusion: We developed novel BPIs to target the BCL10 filamentation process and demonstrated that targeting BCL10 by BPIs is a potentially safe and effective pharmaceutical approach for the treatment of ABC-DLBCL and other CB-SMOC-dependent malignancies.

Objective: Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT-1) plays a crucial role in innate and adaptive immune signaling by modulating the threshold for activation of immune cells, including Treg cells. Therefore, MALT-1 is regarded to be an interesting therapeutic target in several immune-mediated diseases. The goal of this study was to examine the role of MALT-1 in experimental animal models of rheumatoid arthritis (RA). Methods: MALT-1 activation was assessed by measuring cleavage of the deubiquitinase CYLD in lymphocytes from mice with collagen-induced arthritis (CIA). Furthermore, the impact of MALT-1 deficiency on arthritis was evaluated in Malt1(KO) mice with CIA or with collagen antibody-induced arthritis (CAIA). T cell-specific MALT-1 deficiency was measured in mice with deletion of T cell-specific MALT-1 (Malt1(TcellKO) ), and the time-dependent effects of MALT-1 deficiency were assessed in mice with deletion of tamoxifen-inducible T cell-specific MALT-1 (Malt1(iTcellKO)). Bone density was determined in MALT-1-deficient mice using micro-computed tomography and femur-bending tests. Reconstitution of Treg cells was performed using adoptive transfer experiments. Results: MALT-1 activation was observed in the lymphocytes of mice with CIA. T cell-specific MALT-1 deletion in the induction phase of arthritis (incidence of arthritis, 25% in control mice versus 0% in Malt1(iTcellKO) mice; P < 0.05), but not in the effector phase of arthritis, completely protected mice against the development of CIA. Consistent with this finding, MALT-1 deficiency had no impact on CAIA, an effector phase model of RA. Finally, mice with MALT-1 deficiency showed a spontaneous decrease in bone density (mean SEM trabecular thickness, 46.3 +/- 0.7 mu m in control mice versus 40 +/- 1.1 mu m in Malt1(KO) mice; P < 0.001), which was linked to the loss of Treg cells in these mice. Conclusion: Overall, these data in murine models of RA highlight MALT-1 as a master regulator of T cell activation, which is relevant to the pathogenesis of autoimmune arthritis. Furthermore, these findings show that MALT-1 deficiency can lead to spontaneous osteoporosis, which is associated with impaired Treg cell numbers.

The activation of key signaling pathways downstream of antigen receptor engagement is critically required for normal lymphocyte activation during the adaptive immune response. CARD11 is a multidomain signaling scaffold protein required for antigen receptor signaling to NF-κB, c-Jun N-terminal kinase, and mTOR. Germline mutations in the CARD11 gene result in at least four types of primary immunodeficiency, and somatic CARD11 gain-of-function mutations drive constitutive NF-κB activity in diffuse large B cell lymphoma and other lymphoid cancers. In response to antigen receptor triggering, CARD11 transitions from a closed, inactive state to an open, active scaffold that recruits multiple signaling partners into a complex to relay downstream signaling. However, how this signal-induced CARD11 conversion occurs remains poorly understood. Here we investigate the role of Inducible Element 1 (IE1), a short regulatory element in the CARD11 Inhibitory Domain, in the CARD11 signaling cycle. We find that IE1 controls the signal-dependent Opening Step that makes CARD11 accessible to the binding of cofactors, including Bcl10, MALT1, and the HOIP catalytic subunit of the linear ubiquitin chain assembly complex. Surprisingly, we find that IE1 is also required at an independent step for the maximal activation of HOIP and MALT1 enzymatic activity after cofactor recruitment to CARD11. This role of IE1 reveals that there is an Enzymatic Activation Step in the CARD11 signaling cycle that is distinct from the Cofactor Association Step. Our results indicate that CARD11 has evolved to actively coordinate scaffold opening and the induction of enzymatic activity among recruited cofactors during antigen receptor signaling.

Diagnosis of pulmonary lymphoma using small tissue samples is difficult and often requires surgical procedures; thus, a less invasive sampling method is desirable. We previously showed that pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma can be diagnosed by detecting MALT lymphoma translocation gene 1 (MALT1) translocations in bronchoalveolar lavage fluid (BALF) cells. Analysis of B-cell clonality based on immunoglobulin heavy chain (IGH) gene rearrangements was also reportedly useful for diagnosing pulmonary lymphoma. The aim of this prospective multicenter study was to evaluate the yet unknown diagnostic potential of combined detection of MALT1 translocations and clonality using BALF. We analyzed B- and T-cell clonality based on IGH and T-cell receptor (TCR) rearrangements together with MALT1 translocations using BALF of patients with clinically suspected pulmonary lymphomas. In total, 39 patients were evaluated and categorized into three groups: B-cell lymphoma, lymphoproliferative disorders, and other diseases. IGH rearrangement detection for B-cell lymphoma diagnosis exhibited sensitivity and specificity of 88.9% and 90.0%, respectively. TCR rearrangements were not observed in patients with B-cell lymphomas. The presence of IGH rearrangements together with the absence of TCR rearrangements indicated 96.0% specificity for the diagnosis of B-cell lymphoma. The sensitivity and specificity of MALT1 translocations for diagnosing MALT lymphoma were 28.6% and 100%, respectively. The combined detection of lymphocyte clonality and MALT1 translocations using BALF is suitable for screening and diagnosis of B-cell lymphomas. Analysis of specific genes such as MALT1 should improve the precision of B-cell lymphoma diagnosis.

Activated B cell–like diffuse large B-cell lymphomas (ABC-DLBCL) have unfavorable outcomes and chronic activation of CARD11–BCL10–MALT1 (CBM) signal amplification complexes that form due to polymerization of BCL10 subunits, which is affected by recurrent somatic mutations in ABC-DLBCLs. Herein, we show that BCL10 mutants fall into at least two functionally distinct classes: missense mutations of the BCL10 CARD domain and truncation of its C-terminal tail. Truncating mutations abrogated a motif through which MALT1 inhibits BCL10 polymerization, trapping MALT1 in its activated filament-bound state. CARD missense mutations enhanced BCL10 filament formation, forming glutamine network structures that stabilize BCL10 filaments. Mutant forms of BCL10 were less dependent on upstream CARD11 activation and thus manifested resistance to BTK inhibitors, whereas BCL10 truncating but not CARD mutants were hypersensitive to MALT1 inhibitors. Therefore, BCL10 mutations are potential biomarkers for BTK inhibitor resistance in ABC-DLBCL, and further precision can be achieved by selecting therapy based on specific biochemical effects of distinct mutation classes. Significance: ABC-DLBCLs feature frequent mutations of signaling mediators that converge on the CBM complex. We use structure–function approaches to reveal that BCL10 mutations fall into two distinct biochemical classes. Both classes confer resistance to BTK inhibitors, whereas BCL10 truncations confer hyperresponsiveness to MALT1 inhibitors, providing a road map for precision therapies in ABC-DLBCLs.

Balanced control of T cell signaling is critical for adaptive immunity and protection from autoimmunity. By combining genetically engineered mouse models, biochemical analyses and pharmacological interventions, we describe an unexpected dual role of the tumor necrosis factor receptor–associated factor 6 (TRAF6) E3 ligase as both a positive and negative regulator of mucosa-associated lymphoid tissue 1 (MALT1) paracaspase. Although MALT1-TRAF6 recruitment is indispensable for nuclear factor κB signaling in activated T cells, TRAF6 counteracts basal MALT1 protease activity in resting T cells. In mice, loss of TRAF6-mediated homeostatic suppression of MALT1 protease leads to severe autoimmune inflammation, which is completely reverted by genetic or therapeutic inactivation of MALT1 protease function. Thus, TRAF6 functions as a molecular brake for MALT1 protease in resting T cells and a signaling accelerator for MALT1 scaffolding in activated T cells, revealing that TRAF6 controls T cell activation in a switch-like manner. Our findings have important implications for development and treatment of autoimmune diseases.

Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) regulates adaptive and innate immune responses in several inflammatory disease. However, clinical involvement of MALT1 in inflammatory bowel disease (IBD) patients remains unclear. Hence, this study was intended to investigate the correlation of blood MALT1 with disease activity, inflammation indexes as well as treatment response of IBD patients.Blood MALT1 expression in 100 IBD patients [including 25 active (A)-Crohn's disease (CD) patients, 25 remission (R)-CD patients, 25 A-ulcerative colitis (UC) patients, and 25 R-UC patients] and 25 health controls (HCs) was detected by reverse transcription-quantitative polymerase chain reaction; besides, serum tumor necrosis factor-alpha (TNF-α) and interleukin-17A (IL-17A) in IBD patients were detected by enzyme-linked immunosorbent assay.MALT1 was increased in A-UC patients than in R-UC patients (p = 0.038) and in HCs (p 0.001), and also elevated in A-CD patients than in R-CD patients (p = 0.048) and in HCs (p 0.001). MALT1 was positively related to C-reactive protein (CRP, p = 0.011), TNF-α (p = 0.036), IL-17A (p = 0.023), and Mayo score (p = 0.005) in A-UC patients, CRP (p = 0.017), erythrocyte sedimentation rate (p = 0.033), TNF-α (p = 0.004), and Crohn's disease activity index score (p = 0.028) in A-CD patients. But MALT1 was not correlated with either inflammation indexes or disease activity score in R-UC and R-CD patients. MALT1 gradually declined from baseline to W12 in A-UC and A-CD patients (both p 0.001). Moreover, MALT1 at W4 (p = 0.031) and W12 (p = 0.003) in A-UC patients as well as MALT1 at W12 (p = 0.008) in A-CD patients associated with clinical response.MALT1 serves as a potential biomarker for disease surveillance and treatment response prediction of IBD patients.