期刊
CELL REPORTS
卷 21, 期 2, 页码 442-454出版社
CELL PRESS
DOI: 10.1016/j.celrep.2017.09.052
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类别
资金
- NIGMS [R01GM051923]
- U.S. Israel Binational Science Foundation [2003085]
- Israel Science Foundation (ISF) [1264/06, 822/12]
- INCPM-ISF [2376/15]
- Charles Wolfson Charitable Trust
- Hymen Milgrom Trust
We describe a mechanism by which the antiapoptotic B cell lymphoma 2 (Bcl-2) protein is down-regulated to induce apoptosis. ARTS (Sept4_i2) is a tumor suppressor protein that promotes cell death through specifically antagonizing XIAP (X-linked inhibitor of apoptosis). ARTS and Bcl-2 reside at the outer mitochondrial membrane in living cells. Upon apoptotic induction, ARTS brings XIAP and Bcl-2 into a ternary complex, allowing XIAP to promote ubiquitylation and degradation of Bcl-2. ARTS binding to Bcl-2 involves the BH3 domain of Bcl-2. Lysine 17 in Bcl-2 serves as the main acceptor for ubiquitylation, and a Bcl-2 K17A mutant has increased stability and is more potent in protection against apoptosis. Bcl-2 ubiquitylation is reduced in both XIAP-and Sept4/ARTS-deficient MEFs, demonstrating that XIAP serves as an E3 ligase for Bcl-2 and that ARTS is essential for this process. Collectively, these results suggest a distinct model for the regulation of Bcl-2 by ARTS-mediated degradation.
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