期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 109, 期 1, 页码 191-196出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1105176108
关键词
TNF receptor complex; protein kinase
资金
- National Institutes of Health [CA100460, ES015868, GM081603]
- National Basic Research Program of China [2012CB910801]
- National Natural Science Foundation of China [31130035]
The transcription factor zinc-finger protein Miz1 represses TNF-alpha-induced JNK activation and the repression is relieved upon TNF-alpha 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-alpha-induced JNK activation. Upon TNF-alpha 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-alpha-induced JNK1 activation and inflammation. Thus, our results reveal a molecular mechanism by which the repression of TNF-alpha-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-alpha-JNK signaling.
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