title: Site-specific ubiquitination is required for relieving the transcription factor Miz1-mediated suppression on TNF-α-induced JNK activation and inflammation.
abstract: The transcription factor zinc-finger protein Miz1 represses TNF-α-induced JNK activation and the repression is relieved upon TNF-α stimulation. However, the underlying mechanism is incompletely understood. Here we report that Miz1 interferes with the ubiquitin conjugating enzyme (E2) Ubc13 for binding to the RING domain of TNF-receptor associated factor 2 (TRAF2), thereby inhibiting the ubiquitin ligase (E3) activity of TRAF2 and suppressing TNF-α-induced JNK activation. Upon TNF-α stimulation, Miz1 rapidly undergoes K48-linked polyubiquitination at Lys388 and Lys472 residues and subsequent proteasomal degradation in a TRAF2-dependent manner. Replacement of Lysine 388 and Lysine 472 by arginines generates a nondegradable Miz1 mutant, which significantly suppresses TNF-α-induced JNK1 activation and inflammation. Thus, our results reveal a molecular mechanism by which the repression of TNF-α-induced JNK activation by Miz1 is de-repressed by its own site-specific ubiquitination and degradation, which may account for the temporal control of TNF-α-JNK signaling.
authors.affiliation: Ben May Department for Cancer Research, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.forename: Jie
authors.initials: J
authors.lastname: Yan
authors.forename: Shan
authors.initials: S
authors.lastname: Jiang
authors.forename: Jing
authors.initials: J
authors.lastname: Wen
authors.forename: Long
authors.initials: L
authors.lastname: Chen
authors.forename: Yingming
authors.initials: Y
authors.lastname: Zhao
authors.forename: Anning
authors.initials: A
authors.lastname: Lin
mesh_terms: D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D007249:Inflammation / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000172:deficiency / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008954:Models, Biological; D009687:Nuclear Proteins / Q000172:deficiency / Q000378:metabolism*; D025821:Polyubiquitin / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D050828:Protein Inhibitors of Activated STAT / Q000172:deficiency / Q000378:metabolism*; D059748:Proteolysis / Q000187:drug effects; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects*
chemical_list: D018836:Inflammation Mediators; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D050828:Protein Inhibitors of Activated STAT; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha; C107961:ZBTB17 protein, human; D025821:Polyubiquitin; C485521:Miz1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D048031:JNK Mitogen-Activated Protein Kinases; D046988:Proteasome Endopeptidase Complex; D008239:Lysine