USP12 promotes CD4+ T cell responses through deubiquitinating and stabilizing BCL10

• Published in: Cell death and differentiation Vol. 28; no. 10; pp. 2857 - 2870
• Main Authors: Fu, Yuling, Wang, Peng, Zhao, Jingjing, Tan, Yunke, Sheng, Junli, He, Shitong, Du, Xialin, Huang, Yulan, Yang, Yalong, Li, Jinling, Cai, Yuxiong, Liu, Yuxuan, Hu, Shengfeng
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.10.2021; Nature Publishing Group
• Subjects: 13/21; 13/31; 38/77; 631/250/1619/554; 631/45/612/645; 82/80; Adaptive immunity; Animals; Apoptosis; Autoimmune diseases; B-Cell CLL-Lymphoma 10 Protein - metabolism; B-cell lymphoma; Bcl-10 protein; Biochemistry; Biomedical and Life Sciences; CD4 antigen; CD4-Positive T-Lymphocytes - metabolism; CD8 antigen; Cell activation; Cell Biology; Cell Cycle Analysis; Cell differentiation; Cell Proliferation; Cell signaling; Deubiquitinating Enzymes - metabolism; Immune response; Inflammatory diseases; Life Sciences; Lymphocytes; Lymphocytes T; Mice; NF-κB protein; Peptidase; Phenotypes; Signal transduction; Stem Cells; T-Lymphocytes - metabolism; Therapeutic applications; Therapeutic targets; Ubiquitin; Ubiquitin Thiolesterase - metabolism
• ISSN: 1350-9047; 1476-5403; 1476-5403
• DOI: 10.1038/s41418-021-00787-y

Deubiquitinases (DUBs) regulate diverse biological processes and represent a novel class of drug targets. However, the biological function of only a small fraction of DUBs, especially in adaptive immune response regulation, is well-defined. In this study, we identified DUB ubiquitin-specific peptidase 12 (USP12) as a critical regulator of CD4 + T cell activation. USP12 plays an intrinsic role in promoting the CD4 + T cell phenotype, including differentiation, activation, and proliferation. Although USP12-deficient CD4 + T cells protected mice from autoimmune diseases, the immune response against bacterial infection was subdued. USP12 stabilized B cell lymphoma/leukemia 10 (BCL10) by deubiquitinating, and thereby activated the NF-κB signaling pathway. Interestingly, this USP12 regulatory mechanism was identified in CD4 + T cells, but not in CD8 + T cells. Our study results showed that USP12 activated CD4 + T cell signaling, and targeting USP12 might help develop therapeutic interventions for treating inflammatory diseases or pathogen infections.