TRIM38 ELISA Kit

Activation of TLR signaling in the innate immune cells is critical for the elimination of invading microorganisms. However, uncontrolled activation may lead to autoimmune and inflammatory diseases. In this article, we report the identification of tripartite motif (TRIM) 38 as a negative feedback regulator in TLR signaling by targeting TNFR-associated factor 6 (TRAF6). TRIM38 was induced by TLR stimulation in an NF-kappa B-dependent manner in macrophages. Knockdown of TRIM38 expression by small interfering RNA resulted in augmented activation of NF-kappa B and MAPKs, and enhanced expression of proinflammatory cytokines, whereas overexpression of TRIM38 has an opposite effect. As an E3 ligase, TRIM38 bound to TRAF6 and promoted K48-linked polyubiquitination, which led to the proteasomal degradation of TRAF6. Consistently, knockdown of TRIM38 expression resulted in higher protein level of TRAF6 in primary macrophages. Our findings defined a novel function for TRIM38 to prevent excessive TLR-induced inflammatory responses through proteasomal degradation of TRAF6. The Journal of Immunology, 2012, 188: 2567-2574.

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.