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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Enzyme Activation / drug effects
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Gene Expression Regulation / drug effects
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HeLa Cells
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Humans
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Inflammation / enzymology*
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Inflammation / genetics
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Inflammation / pathology
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Inflammation Mediators / metabolism
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JNK Mitogen-Activated Protein Kinases / metabolism*
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Kruppel-Like Transcription Factors / deficiency
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Kruppel-Like Transcription Factors / metabolism*
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Lysine / metabolism
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MAP Kinase Signaling System / drug effects
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Mice
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Models, Biological
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Nuclear Proteins / deficiency
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Nuclear Proteins / metabolism*
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Polyubiquitin / metabolism
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Proteasome Endopeptidase Complex / metabolism
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Protein Binding / drug effects
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Protein Inhibitors of Activated STAT / deficiency
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Protein Inhibitors of Activated STAT / metabolism*
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Proteolysis / drug effects
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TNF Receptor-Associated Factor 2 / metabolism
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Tumor Necrosis Factor-alpha / pharmacology*
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Ubiquitin-Protein Ligases / metabolism
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Ubiquitination / drug effects*
Substances
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Inflammation Mediators
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Kruppel-Like Transcription Factors
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Nuclear Proteins
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Protein Inhibitors of Activated STAT
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TNF Receptor-Associated Factor 2
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Tumor Necrosis Factor-alpha
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ZBTB17 protein, human
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Polyubiquitin
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Miz1 protein, mouse
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Ubiquitin-Protein Ligases
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JNK Mitogen-Activated Protein Kinases
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Proteasome Endopeptidase Complex
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Lysine