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

Liu J,Yan J,Jiang S,Wen J,Chen L,Zhao Y,Lin A

doi

10.1073/pnas.1105176108

subject

Has Abstract

pub_date

2012-01-03 00:00:00

pages

191-6

issue

1

eissn

0027-8424

issn

1091-6490

pii

1105176108

journal_volume

109

pub_type

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