| First Author | Liu J | Year | 2012 |
| Journal | Proc Natl Acad Sci U S A | Volume | 109 |
| Issue | 1 | Pages | 191-6 |
| PubMed ID | 22184250 | Mgi Jnum | J:180128 |
| Mgi Id | MGI:5305505 | Doi | 10.1073/pnas.1105176108 |
| Citation | Liu J, et al. (2012) Site-specific ubiquitination is required for relieving the transcription factor Miz1-mediated suppression on TNF-alpha-induced JNK activation and inflammation. Proc Natl Acad Sci U S A 109(1):191-6 |
| abstractText | 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. |
