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Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the biosynthesis of nicotinamide adenine dinucleotide (NAD+), making it a potential target for cancer therapy. Two challenges hinder its translation in the clinic: targeting the extracellular form of NAMPT (eNAMPT) remains insufficient, and side effects are observed in normal tissues. We previously utilized proteolysis-targeting chimera (PROTAC) to develop two compounds capable of simultaneously degrading iNAMPT and eNAMPT. Unfortunately, the pharmacokinetic properties were inadequate, and toxicities similar to those associated with traditional inhibitors arose. We have developed a next-generation PROTAC molecule 632005 to address these challenges, demonstrating exceptional target selectivity and bioavailability, improved in vivo exposure, extended half-life, and reduced clearance rate. When combined with nicotinic acid, 632005 exhibits safety and robust efficacy in treating NAPRT-deficient pan-cancers, including xenograft models with hematologic malignancy and prostate cancer and patient-derived xenograft (PDX) models with liver cancer. Our findings provide clinical references for patient selection and treatment strategies involving NAMPT-targeting PROTACs. [Display omitted] • Tumor cells with NAPRT deficiency are sensitive to NAMPT-targeting PROTACs • In-depth structure-activity relationship analysis of NAMPT-targeting PROTACs • The toxicity of NAMPT-targeting PROTACs is mitigated with NA supplementation • Treatment with the lead PROTAC and NA is efficacious against NAPRT-deficient pan-cancers Zhu et al. develop and assess a second-generation PROTAC compound that degrades the NAD+ biosynthesis enzyme NAMPT in the salvage pathway. Co-administration with nicotinic acid (NA) effectively mitigates toxicity associated with NAMPT perturbation, demonstrating both efficacy and safety in the treatment of pan-cancers with NAPRT deficiency. [ABSTRACT FROM AUTHOR]

Antibiotic filter residue (AFR) is a typical deep-utilized biomass waste residue with high yield, which is difficult to burn be individually utilized as fuel due to its poor combustion characteristics. The co-combustion of AFR with vegetal biomass is likely to be an effective approach to enhance the combustion performance of AFR, while the co-firing mechanism and kinetics have yet to be fully understood. The present study aimed to investigate the co-combustion characteristics and kinetics of antibiotic filter residue and vegetal biomass (forestall biomass and agricultural biomass) by thermogravimetric experiments and kinetics analysis. The experimental results showed that the co-firing of AFR with peanut shell and poplar improved the combustion characteristics of AFR. Kinetic analysis indicated that the optimal solid-phase reaction models of the blend combustion were diffusion models. The specific form of the reaction function varied with the type and mass fraction of the blends. The present study can provide an improved understanding of the clean and efficient utilization of antibiotic filter residue by co-combustion. [ABSTRACT FROM AUTHOR]

An ever-increasing attention has been paid to the treatment of antibiotic filter residue (AFR) due to its serious hazard and growing production. Duo to the unique features of AFR, the ash properties of AFR are still unclear. The effects of biomass blending on ash characteristics of AFR have yet to be sufficiently understood. In addition, little work has been performed on ash morphology, fusibility and mineral transformation during co-combustion of AFR and biomass. The present study dealt with the ash characteristics of AFR and its blends with biomass at various combustion temperatures and blended ratios. Experimental results indicate that the ash compositions in blended fuel AFR/poplar (PL) are generally identical as those in AFR but nearly independent of PL portion. Nevertheless, the mineral distributions in the blends of AFR and peanut shell (PS) vary greatly with the blended ratio, especially minerals containing calcium and silicon. There are more species of minerals in AFR/PS blends in comparison to individual fuels, but the condition of AFR/PL blends is significantly different. The present study was helpful to understand of ash behaviors of AFR and its blends during co-combustion, and further promoted the safe, clean and efficient utilization of AFR by co-firing technology. Image 1 • Ash properties of antibiotic filter residue and its blends were studied. • The effects of co-combustion on mineral transformation were investigated. • The chemical compositions of blends AFR/PL are almost independent of poplar content. • Mineral species of blends AFR/PS follows the additive rule. • The blends very likely have lower ash fusion temperatures than component samples. [ABSTRACT FROM AUTHOR]

Background: The Late Embryogenesis-Abundant (LEA) gene families, which play significant roles in regulation of tolerance to abiotic stresses, widely exist in higher plants. Poplar is a tree species that has important ecological and economic values. But systematic studies on the gene family have not been reported yet in poplar. Results: On the basis of genome-wide search, we identified 88 LEA genes from Populus trichocarpa and renamed them as PtrLEA. The PtrLEA genes have fewer introns, and their promoters contain more cis-regulatory elements related to abiotic stress tolerance. Our results from comparative genomics indicated that the PtrLEA genes are conserved and homologous to related genes in other species, such as Eucalyptus robusta, Solanum lycopersicum and Arabidopsis. Using RNA-Seq data collected from poplar under two conditions (with and without salt treatment), we detected 24, 22 and 19 differentially expressed genes (DEGs) in roots, stems and leaves, respectively. Then we performed spatiotemporal expression analysis of the four up-regulated DEGs shared by the tissues, constructed gene co-expression-based networks, and investigated gene function annotations. Conclusion: Lines of evidence indicated that the PtrLEA genes play significant roles in poplar growth and development, as well as in responses to salt stress. [ABSTRACT FROM AUTHOR]

Aberrant overexpression of nicotinamide phosphoribosyltransferase (NAMPT) has been reported in a variety of tumor cells and is a poor prognosis factor for patient survival. It plays an important role in tumor cell proliferation, acting concurrently as an nicotinamide adenine dinucleotide (NAD+) synthase and, unexpectedly, as an extracellular signaling molecule for several tumor-promoting pathways. Although previous efforts to modulate NAMPT activity were limited to enzymatic inhibitors with low success in clinical studies, protein degradation offers the possibility to simultaneously disrupt NAMPT's enzyme activity and ligand capabilities. Here we report the development of two highly selective proteolysis-targeting chimeras (PROTACs) that promote NAMPT degradation in a cereblon-dependent manner. Both PROTAC degraders outperform a clinical candidate, FK866, in killing effect on hematological tumor cells. These results emphasize the importance and feasibility of applying PROTACs as a superior strategy for targeting proteins with multiple tumor-promoting functions like NAMPT, which is not easily achieved by conventional enzymatic inhibitors. [Display omitted] • SAR-guided design of two PROTAC degraders against NAD+ synthesis enzyme NAMPT • PROTAC degraders hijack the E3 ubiquitin ligase CRBN for selective degradation of NAMPT • PROTAC degraders outperform FK866 in killing effect by targeting iNAMPT and eNAMPT • PROTAC degraders suppress NF-κB and MAPK-Erk signaling pathways upon eNAMPT degradation Zhu et al. report two NAMPT-targeting PROTAC compounds that were designed to achieve specific clearance of intracellular and extracellular forms of NAMPT in a broad spectrum of tumor cell lines, interfering with the metabolic fitness of tumor cells. [ABSTRACT FROM AUTHOR]

Clinical evidence suggests that poor persistence of chimeric antigen receptor-T cells (CAR-T) in patients limits therapeutic efficacy. Here, we designed a CAR with recyclable capability to promote in vivo persistence and to sustain antitumor activity. We showed that the engagement of tumor antigens induced rapid ubiquitination of CARs, causing CAR downmodulation followed by lysosomal degradation. Blocking CAR ubiquitination by mutating all lysines in the CAR cytoplasmic domain (CARKR) markedly repressed CAR downmodulation by inhibiting lysosomal degradation while enhancing recycling of internalized CARs back to the cell surface. Upon encountering tumor antigens, CARKR-T cells ameliorated the loss of surface CARs, which promoted their long-term killing capacity. Moreover, CARKR-T cells containing 4-1BB signaling domains displayed elevated endosomal 4-1BB signaling that enhanced oxidative phosphorylation and promoted memory T cell differentiation, leading to superior persistence in vivo. Collectively, our study provides a straightforward strategy to optimize CAR-T antitumor efficacy by redirecting CAR trafficking. • Tumor antigen encounter triggers CAR ubiquitination and downmodulation • Tumor antigen-induced CAR ubiquitination targets CARs for lysosomal degradation • CAR signaling in CAR-T cells expressing 4-1BB can be propagated in endosomes • Blocking CAR ubiquitination enhances endosomal CAR signaling and CAR-T persistence Chimeric antigen receptor-T cell therapy offers a promising approach for cancer immunotherapy, but poor CAR-T persistence in patients limits therapeutic efficacy. Li et al. investigated the trafficking of CARs during CAR-T cell activation and designed a recyclable CAR with enhanced persistence and sustained antitumor function. [ABSTRACT FROM AUTHOR]

PARP1 is crucial in DNA damage repair, chromatin remodeling, and transcriptional regulation. The principle of synthetic lethality has effectively guided the application of PARP inhibitors in treating tumors carrying BRCA1/2 mutations. Meanwhile, PARP inhibitors have exhibited efficacy in BRCA-proficient patients, further highlighting the necessity for a deeper understanding of PARP1 function and its inhibition in cancer therapy. Here, we unveil PIN2/TRF1-interacting telomerase inhibitor 1 (PINX1) as an uncharacterized PARP1-interacting protein that synergizes with PARP inhibitors upon its depletion across various cancer cell lines. Loss of PINX1 compromises DNA damage repair capacity upon etoposide treatment. The vulnerability of PINX1-deficient cells to etoposide and PARP inhibitors could be effectively restored by introducing either a full-length or a mutant form of PINX1 lacking telomerase inhibitory activity. Mechanistically, PINX1 is recruited to DNA lesions through binding to the ZnF3-BRCT domain of PARP1, facilitating the downstream recruitment of the DNA repair factor XRCC1. In the absence of DNA damage, PINX1 constitutively binds to PARP1, promoting PARP1-chromatin association and transcription of specific DNA damage repair proteins, including XRCC1, and transcriptional regulators, including GLIS3. Collectively, our findings identify PINX1 as a multifaceted partner of PARP1, crucial for safeguarding cells against genotoxic stress and emerging as a potential candidate for targeted tumor therapy., (© 2024. The Author(s).)

Poplar is an important greening and timber tree species in China, which has great economic and ecological values. However, the spread of Hyphantria cunea has become increasingly serious in recent years, resulting in huge economic loss of poplar production. Exploring the molecular mechanism of poplar reponse to H. cunea stress has significant implications for future development of new insect-resistant poplar varieties using genetic engineering technology. In this study, a total of 1039 differentially expressed genes (DEGs), 106 differentially expressed proteins (DEPs) and 212 differentially expressed metabolites (DEMs) were screened from Populus simonii × P. nigra leaves under H. cunea stress by transcriptome, proteomics and metabolomics analysis, respectively. GO and KEGG analysis showed that the DEGs and DEPs are associated with endopeptidase inhibitor activity, stress response, α-linolenic acid metabolism, phenylpropanoid biosynthesis and metabolic pathways, cysteine and methionine metabolism pathways and MAKP signaling pathway. Metabolomics analysis showed the most of DEMs were lipids and lipid molecules, and the pathways associated with transcriptome mainly include plant hormone signal transduction, α-linolenic acid metabolic pathway, amino sugar and nucleotide sugar metabolism, and phenylpropanoid biosynthesis. In particular, multi-omics analysis showed that several pathways such as α-linolenic acid metabolic, phenylpropanoid biosynthesis and metabolic pathway and cysteine and methionine metabolic pathway were significantly enriched in the three omics, which may play an important role in the resistance to pests in poplar., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Jiang, Fan, Wang, Yao, Zhou and Jiang.)

AMPylation is a post-translational modification in which AMP is added to the amino acid side chains of proteins 1,2 . Here we show that, with ATP as the ligand and actin as the host activator, the effector protein LnaB of Legionella pneumophila exhibits AMPylase activity towards the phosphoryl group of phosphoribose on PR R42 -Ub that is generated by the SidE family of effectors, and deubiquitinases DupA and DupB in an E1- and E2-independent ubiquitination process 3-7 . The product of LnaB is further hydrolysed by an ADP-ribosylhydrolase, MavL, to Ub, thereby preventing the accumulation of PR R42 -Ub and ADPR R42 -Ub and protecting canonical ubiquitination in host cells. LnaB represents a large family of AMPylases that adopt a common structural fold, distinct from those of the previously known AMPylases, and LnaB homologues are found in more than 20 species of bacterial pathogens. Moreover, LnaB also exhibits robust phosphoryl AMPylase activity towards phosphorylated residues and produces unique ADPylation modifications in proteins. During infection, LnaB AMPylates the conserved phosphorylated tyrosine residues in the activation loop of the Src family of kinases 8,9 , which dampens downstream phosphorylation signalling in the host. Structural studies reveal the actin-dependent activation and catalytic mechanisms of the LnaB family of AMPylases. This study identifies, to our knowledge, an unprecedented molecular regulation mechanism in bacterial pathogenesis and protein phosphorylation., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

As global climate change continues, drought episodes have become increasingly frequent. Studying plant stress tolerance is urgently needed to ensure food security. The common ice plant is one of the model halophyte plants for plant stress biology research. This study aimed to investigate the functions of a newly discovered transcription factor, Homeobox 7 (HB7), from the ice plant in response to drought stress. An efficient Agrobacterium -mediated transformation method was established in the ice plant, where ectopic McHB7 expression may be sustained for four weeks. The McHB7 overexpression (OE) plants displayed drought tolerance, and the activities of redox enzymes and chlorophyll content in the OE plants were higher than the wild type. Quantitative proteomics revealed 1910 and 495 proteins significantly changed in the OE leaves compared to the wild type under the control and drought conditions, respectively. Most increased proteins were involved in the tricarboxylic acid cycle, photosynthesis, glycolysis, pyruvate metabolism, and oxidative phosphorylation pathways. Some were found to participate in abscisic acid signaling or response. Furthermore, the abscisic acid levels increased in the OE compared with the wild type. Mc HB7 was revealed to bind to the promoter motifs of Early Responsive to Dehydration genes and abscisic acid-responsive genes, and protein-protein interaction analysis revealed candidate proteins responsive to stresses and hormones (e.g., abscisic acid). To conclude, McHB7 may contribute to enhance plant drought tolerance through abscisic acid signaling.

The dynamic remodeling of the cytoskeletal network of vimentin intermediate filaments network supports various cellular functions, including cell morphology, elasticity, migration, organelle localization, and resistance against mechanical or pathological stress. Currently available chemicals targeting vimentin predominantly induce network reorganization and shrinkage around the nucleus. Effective tools for long-term manipulation of vimentin network dispersion in living cells are still lacking, limiting in-depth studies on vimentin function and potential therapeutic applications. Here, we verified that a commercially available small molecule, Trametinib, is capable of inducing spatial spreading of the cellular vimentin network without affecting its transcriptional or translational regulation. Further evidence confirmed its low cytotoxicity and similar effects on different cell types. Importantly, Trametinib has no impact on the other two cytoskeletal systems, actin filaments and the microtubule network. Moreover, Trametinib regulates vimentin network dispersion rapidly and efficiently, with effects persisting for up to 48 h after drug withdrawal. We also ruled out the possibility that Trametinib directly affects the phosphorylation level of vimentin. In summary, we identified an unprecedented regulator, Trametinib, capable of spreading the vimentin network toward the cell periphery, and thus complemented the existing repertoire of vimentin remodeling drugs in the field of cytoskeletal research., (© The Author(s) 2024. Published by Oxford University Press on behalf of Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences.)