TRIM38 inhibits TNFα- and IL-1β-triggered NF-κB activation by mediating lysosome-dependent degradation of TAB2/3

TNF alpha and IL-1 beta are two proinflammatory cytokines that play critical roles in many diseases, including rheumatoid arthritis and infectious diseases. How TNF alpha- and IL-1 beta-mediated signaling is finely tuned is not fully elucidated. Here, we identify tripartitemotif protein 38 (TRIM38) as a critical negative regulator of TNF alpha- and IL-1 beta-triggered signaling. Overexpression of TRIM38 inhibited activation of NF-kappa B and induction of downstream cytokines following TNF alpha 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 alpha and IL-1 beta stimulation. We conclude that TRIM38 negatively regulates TNF alpha- and IL-1 beta-induced signaling by mediating lysosome-dependent degradation of TAB2/3, two critical components in TNF alpha- 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 alpha and IL-1 beta.