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2 results on '"CARMA1-BCL10-MALT1"'

1. Assembly mechanism of the CARMA1-BCL10-MALT1- TRAF6 signalosome.

Author

David, Liron, Yang Li, Hao Wu, Jun Ma, Xinzheng Zhang, and Garner, Ethan

Subjects
*NATURAL immunity, *GUANYLATE cyclase, *LYMPHOMAS, *B cell receptors, *PROTEIN kinases, *T cells
Abstract

The CARMA1-BCL10-MALT1 (CBM) signalosome is a central mediator of T cell receptor and B cell receptor-induced NF-κB signaling that regulates multiple lymphocyte functions. While caspaserecruitment domain (CARD) membrane-associated guanylate kinase (MAGUK) protein 1 (CARMA1) nucleates B cell lymphoma 10 (BCL10) filament formation through interactions between CARDs, mucosaassociated lymphoid tissue lymphoma translocation protein 1 (MALT1) is a paracaspase with structural similarity to caspases, which recruits TNF receptor-associated factor 6 (TRAF6) for K63-linked polyubiquitination. Here we present cryo-electron microscopy (cryo-EM) structure of the BCL10 CARD filament at 4.0-Å resolution. The structure redefines CARD-CARD interactions compared with the previous EM structure determined from a negatively stained sample. Surprisingly, time-lapse confocal imaging shows that BCL10 polymerizes in a unidirectional manner. CARMA1, the BCL10 nucleator, serves as a hub for formation of star-shaped filamentous networks of BCL10 and significantly decreases the lag period of BCL10 polymerization. Cooperative MALT1 interaction with BCL10 filaments observed under EM suggests immediate dimerization of MALT1 in the BCL10 filamentous scaffold. In addition, TRAF6 cooperatively decorates CBM filaments to form higher-order assemblies, likely resulting in all-ornone activation of the downstream pathway. Collectively, these data reveal biophysical mechanisms in the assembly of the CARMA1-BCL10-MALT1-TRAF6 complex for signal transduction. [ABSTRACT FROM AUTHOR]

Published
2018
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2. Characteristics of CARMA1-BCL10-MALT1-A20-NF-κB expression in T cell-acute lymphocytic leukemia

Author

Xu Wang, Ziwei Liao, Yangqiu Li, Suming Huang, Shaohua Chen, Yi Xu, Fan Zhang, Yu Ma, Ziyun Zhong, Gengxin Luo, Xin Huang, Xiuli Wu, and Lijian Yang

Subjects
Adult, Male, Adolescent, T-Lymphocytes, Biology, medicine.disease_cause, Peripheral blood mononuclear cell, Pathogenesis, immune system diseases, hemic and lymphatic diseases, medicine, Humans, Child, Tumor Necrosis Factor alpha-Induced Protein 3, Adaptor Proteins, Signal Transducing, Aged, Regulation of gene expression, Mutation, Gene Expression Regulation, Leukemic, Intracellular Signaling Peptides and Proteins, NF-kappa B, Nuclear Proteins, General Medicine, Middle Aged, Precursor Cell Lymphoblastic Leukemia-Lymphoma, B-Cell CLL-Lymphoma 10 Protein, medicine.disease, BCL10, Neoplasm Proteins, Lymphoma, CARD Signaling Adaptor Proteins, DNA-Binding Proteins, MALT1, A20, Guanylate Cyclase, Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein, Caspases, Child, Preschool, Immunology, Female, Signal transduction, CARMA1-BCL10-MALT1, T-cell acute lymphoblastic leukemia, Research Article, Signal Transduction
Abstract

Background Knowledge of the oncogenic signaling pathways of T-cell acute lymphoblastic leukemia (T-ALL) remains limited. Constitutive aberrant activation of the nuclear factor kappa B (NF-κB) signaling pathway has been detected in various lymphoid malignancies and plays a key role in the development of these carcinomas. The zinc finger-containing protein, A20, is a central regulator of multiple NF-κB-activating signaling cascades. A20 is frequently inactivated by deletions and/or mutations in several B-and T-cell lymphoma subtypes. However, few A20 mutations and polymorphisms have been reported in T-ALL. Thus, it is of interest to analyze the expression characteristics of A20 and its regulating factors, including upstream regulators and the CBM complex, which includes CARMA1, BCL10, and MALT1. Methods The expression levels of CARMA1, BCL10, MALT1, A20, and NF-κB were detected in peripheral blood mononuclear cells (PBMCs) from 21 patients with newly diagnosed T-ALL using real-time PCR, and correlations between the aberrant expression of these genes in T-ALL was analyzed. Sixteen healthy individuals, including 10 males and 6 females, served as controls. Results Significantly lower A20 expression was found in T-ALL patients (median: 4.853) compared with healthy individuals (median: 8.748; P = 0.017), and significantly increased expression levels of CARMA1 (median: 2.916; P = 0.034), BCL10 (median: 0.285; P = 0.033), and MALT1 (median: 1.201; P = 0.010) were found in T-ALL compared with the healthy individuals (median: 1.379, 0.169, and 0.677, respectively). In contrast, overexpression of NF-κB (median: 0.714) was found in T-ALL compared with healthy individuals (median: 0.335; P = 0.001). A negative correlation between the MALT1 and A20 expression levels and a positive correlation between CARMA1 and BCL10 were found in T-ALL and healthy individuals. However, no negative correlation was found between A20 and NF-κB and the MALT1 and NF-κB expression level in the T-ALL group. Conclusions We characterized the expression of the CARMA-BCL10-MALT1-A20-NF-κB pathway genes in T-ALL. Overexpression of CARMA-BCL10-MALT in T-ALL may contribute to the constitutive cleavage and inactivation of A20, which enhances NF-κB signaling and may be related to T-ALL pathogenesis.

Published
2014
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