E3 ubiquitin ligase Mule ubiquitinates Miz1 and is required for TNFalpha-induced JNK activation.

Proceedings of the National Academy of Sciences of the United States of America
Yi YangJing Liu

Abstract

The zinc finger transcription factor Miz1 is a negative regulator of TNFalpha-induced JNK activation and cell death through inhibition of TRAF2 K63-polyubiquitination in a transcription-independent manner. Upon TNFalpha 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 TNFalpha-induced Miz1 polyubiquitination. Mule is a Miz1-associated protein and catalyzes its K48-linked polyubiquitination. TNFalpha-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 TNFalpha independently of the pox virus and zinc finger domain of Miz1. Silencing of Mule stabilized Miz1, thereby suppressing TNFalpha-induced JNK activation and cell death. Thus, our study reveals a molecular mechanism by which Mule regulates TNFalpha-induced JNK activation and apoptosis by catalyzing the polyubiquitination of Miz1.

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Citations

Mar 26, 2013·Nature Immunology·Hanh Chi Do-UmeharaJing Liu
Dec 21, 2011·Proceedings of the National Academy of Sciences of the United States of America·Jing LiuAnning Lin
May 30, 2013·American Journal of Respiratory and Critical Care Medicine·Nathaniel M WeathingtonRama K Mallampalli
Nov 20, 2015·Digestive Diseases and Sciences·Ping ChenYunlin Wu
Apr 18, 2015·Nucleic Acids Research·Juan YiGenze Shao
Jul 6, 2011·FEBS Letters·Svetlana V Khoronenkova, Grigory L Dianov
Sep 5, 2018·Journal of Biomedical Science·Shih-Han KaoKou-Juey Wu
Nov 5, 2014·EMBO Molecular Medicine·Franz X Schaub, John L Cleveland
May 15, 2020·The Journal of Experimental Medicine·Amparo Toboso-NavasaDinis Pedro Calado
Feb 15, 2017·ELife·Bodo SanderSonja Lorenz
Dec 14, 2019·Genes & Diseases·Yingxiao ChenMu-Shui Dai
Feb 20, 2021·Pharmacology & Therapeutics·Sunil SinghJ Sivaraman
Jan 27, 2012·Biochemical and Biophysical Research Communications·Tahel NoyAaron Ciechanover
Feb 6, 2019·Neuropharmacology·Zi-Yang ZhangXiao-Dong Hu

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