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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Zhang, Jing Shu, Hong-bing Zhang, Yu Huang, Zhe-fu Hu, Ming-ming Zhang, Xiao-dong Zhong, Bo Wang, Yan-yi Yang, Qing Liu, Shi-meng Lin, Heng |
| Description | Author Affiliation: Hu MM ( State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China.); |
| Abstract | TNF and IL-1ß are two proinflammatory cytokines that play critical roles in many diseases, including rheumatoid arthritis and infectious diseases. How TNF - and IL-1ß-mediated signaling is finely tuned is not fully elucidated. Here, we identify tripartite-motif protein 38 (TRIM38) as a critical negative regulator of TNF - and IL-1ß-triggered signaling. Overexpression of TRIM38 inhibited activation of NF-κB and induction of downstream cytokines following TNF and IL-1ß stimulation, whereas knockdown or knockout of TRIM38 had the opposite effects. TRIM38 constitutively interacted with critical components TGF-ß-activated kinase 1 (TAK1)-binding protein 2/3 (TAB2/3) and promoted lysosome-dependent degradation of TAB2/3 independent of its E3 ubiquitin ligase activity. Consistently, deficiency of TRIM38 resulted in abolished translocation of TAB2 to the lysosome, increased level of TAB2 in cells, and enhanced activation of TAK1 after TNF and IL-1ß stimulation. We conclude that TRIM38 negatively regulates TNF - and IL-1ß-induced signaling by mediating lysosome-dependent degradation of TAB2/3, two critical components in TNF - and IL-1ß-induced signaling pathways. Our findings reveal a previously undiscovered mechanism by which cells keep the inflammatory response in check to avoid excessive harmful immune response triggered by TNF and IL-1ß. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 4 |
| Volume Number | 111 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2014-01-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Adaptor Proteins, Signal Transducing Metabolism Carrier Proteins Physiology Interleukin-1beta Intracellular Signaling Peptides And Proteins Lysosomes NF-kappa B Tumor Necrosis Factor-alpha Genetics DNA Primers Proteolysis RNA Interference Signal Transduction Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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