Ubiquitination is a versatile post-translational modification involved in nuclear factor-κB (NF-κB) activation of Toll-like receptor (TLR) signaling. Here, we demonstrated that Trim13, an E3 ubiquitin ligase, is up-regulated in macrophages upon stimulation with TLR2 ligand. Knockdown of Trim13 attenuated TLR2-mediated production of cytokines/chemokines and formation of foam cells as well as activation of NF-κB. Trim13 interacts with tumor necrosis factor receptor-associated factor 6 (TRAF6) and potentiates NF-κB activity via ubiquitination of TRAF6. Overexpression of inactive mutant (C10/13A) or really interesting new gene (RING) deletion mutant of Trim13 did not potentiate ubiquitination of TRAF6 or activation of NF-κB. These results suggest that the effects of Trim13 are dependent on its E3 ligase activity. Trim13 used K29-linked polyubiquitin chains for TRAF6 ubiquitination to promote NF-κB activity and thus potentiated activation of TLR2-mediated immune responses. Our data identify Trim13 as a positive regulator of NF-κB activation and suggest that K29-linked polyubiquitination is a specific ubiquitin-linked pattern involved in the control of TLR2 signaling.
Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.