title: Helicobacter pylori activates NF-κB by inducing Ubc13-mediated ubiquitination of lysine 158 of TAK1.
abstract: The Helicobacter pylori virulence factor CagA targets a variety of host proteins to alter different cellular responses, including the induction of pro-inflammatory cytokines. We have previously shown that CagA-facilitated lysine 63-linked ubiquitination of TAK1 is essential for the H. pylori-induced NF-κB activation and the expression of proinflammatory cytokines. However, the molecular mechanism for TAK1 ubiquitination and activation in H. pylori-mediated NF-κB activation remains elusive. Here, we identify lysine 158 of TAK1 as the key residue undergoing lysine 63-linked ubiquitination in response to H. pylori infection. Mutation of lysine 158 to arginine prevents the ubiquitination of TAK1 and impairs H. pylori-induced TAK1 and NF-κB activation. Moreover, we demonstrate that E2 ubiquitin conjugating enzyme Ubc13 is involved in H. pylori-mediated TAK1 ubiquitination. Suppressing the activity of Ubc13 by a dominant-negative mutant or siRNA abolishes CagA-facilitated and H. pylori-induced TAK1 and NF-κB activation. These findings further underscore the importance of lysine 63-linked ubiquitination of TAK1 in H. pylori-induced NF-κB activation and NF-κB-mediated inflammatory response.
authors.affiliation: Department of Biochemistry, College of Medicine, Urbana, Illinois 61801, USA.
authors.forename: Acacia
authors.initials: A
authors.lastname: Lamb
authors.forename: JinJing
authors.initials: J
authors.lastname: Chen
authors.forename: Steven R
authors.initials: SR
authors.lastname: Blanke
authors.forename: Lin-Feng
authors.initials: LF
authors.lastname: Chen
mesh_terms: D002460:Cell Line; D045744:Cell Line, Tumor; D016480:Helicobacter pylori / Q000472:pathogenicity*; D054884:Host-Pathogen Interactions; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D008239:Lysine / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000235:genetics / Q000502:physiology*; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D008239:Lysine; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D044763:Ubiquitin-Conjugating Enzymes; D000099151:MAP Kinase Kinase Kinase 7; C471607:UBE2N protein, human
keywords: CagA; NF-κB; TAK1; UBIQUITINATION; Ubc13