期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2014
卷号：111
期号：4
页码：1509-1514
DOI：10.1073/pnas.1318227111
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：TNF and IL-1{beta} are two proinflammatory cytokines that play critical roles in many diseases, including rheumatoid arthritis and infectious diseases. How TNF- and IL-1{beta}-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-1{beta}-triggered signaling. Overexpression of TRIM38 inhibited activation of NF-{kappa}B and induction of downstream cytokines following TNF and IL-1{beta} stimulation, whereas knockdown or knockout of TRIM38 had the opposite effects. TRIM38 constitutively interacted with critical components TGF-{beta}-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-1{beta} stimulation. We conclude that TRIM38 negatively regulates TNF- and IL-1{beta}-induced signaling by mediating lysosome-dependent degradation of TAB2/3, two critical components in TNF- and IL-1{beta}-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-1{beta}.
