Tripartite motif 8 (TRIM8) modulates TNFα- and IL-1β-triggered NF-κB activation by targeting TAK1 for K63-linked polyubiquitination

The tripartite motif (TRIM)-containing proteins are a family of proteins that have been known to be involved in divergent biological processes, including important roles in immune responses through regulating various signaling pathways. In this study, we identified a member of the TRIM family, TRIM8, as a positive regulator of tumor necrosis factor-alpha (TNF alpha) and interleukin-1 beta (IL-1 beta)-triggered NF-kappa B activation. Overexpression of TRIM8 activated NF-kappa B and potentiated TNF alpha- and IL-1 beta-induced activation of NF-kappa B, whereas knockdown of TRIM8 had opposite effects. Coimmunoprecipitations indicated that TRIM8 interacted with TGF beta activated kinase 1 (TAK1), a serine/threonine kinase essential for TNF alpha- and IL-beta-induced NF-kappa B activation. Furthermore, we found that TRIM8 mediated K63-linked polyubiquitination of TAK1 triggered by TNF alpha and IL-1 beta. Our findings demonstrate that TRIM8 serves as a critical regulator of TNF alpha- and IL-1 beta-induced NF-kappa B activation by mediating K63-linked polyubiquitination of TAK1.