期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2010
卷号：107
期号：30
页码：13444-13449
DOI：10.1073/pnas.0913690107
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：The zinc finger transcription factor Miz1 is a negative regulator of TNF{alpha}-induced JNK activation and cell death through inhibition of TRAF2 K63-polyubiquitination in a transcription-independent manner. Upon TNF{alpha} stimulation, Miz1 undergoes K48-linked polyubiquitination and proteasomal degradation, thereby relieving its inhibition. However, the underling regulatory mechanism is not known. Here, we report that HECT-domain-containing Mule is the E3 ligase that catalyzes TNF{alpha}-induced Miz1 polyubiquitination. Mule is a Miz1-associated protein and catalyzes its K48-linked polyubiquitination. TNF{alpha}-induced polyubiquitination and degradation of Miz1 were inhibited by silencing of Mule and were promoted by ectopic expression of Mule. The interaction between Mule and Miz1 was promoted by TNF{alpha} independently of the pox virus and zinc finger domain of Miz1. Silencing of Mule stabilized Miz1, thereby suppressing TNF{alpha}-induced JNK activation and cell death. Thus, our study reveals a molecular mechanism by which Mule regulates TNF{alpha}-induced JNK activation and apoptosis by catalyzing the polyubiquitination of Miz1.
