title: Trim13 Potentiates Toll-Like Receptor 2-Mediated Nuclear FactorκB Activation via K29-Linked Polyubiquitination of Tumor Necrosis Factor Receptor-Associated Factor 6.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, Yeungnam University, Daegu, South Korea.
authors.forename: Bin
authors.initials: B
authors.lastname: Huang
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, Yeungnam University, Daegu, South Korea sbaek@med.yu.ac.kr.
authors.forename: Suk-Hwan
authors.initials: SH
authors.lastname: Baek
mesh_terms: D000818:Animals; D018925:Chemokines / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008239:Lysine / Q000378:metabolism*; D008262:Macrophage Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D025821:Polyubiquitin / Q000378:metabolism*; D011485:Protein Binding; D000067996:RAW 264.7 Cells; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000378:metabolism*; D000070584:Tripartite Motif Proteins / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination; D015854:Up-Regulation / Q000235:genetics
chemical_list: D018925:Chemokines; D004268:DNA-Binding Proteins; D016328:NF-kappa B; D048029:TNF Receptor-Associated Factor 6; D051195:Toll-Like Receptor 2; D000070584:Tripartite Motif Proteins; D025821:Polyubiquitin; C000594665:TRIM13 protein, mouse; D044767:Ubiquitin-Protein Ligases; D008239:Lysine