We describe a mechanism by which the anti-apoptotic B cell lymphoma 2 (Bcl-2) protein is downregulated 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. Many cancers avoid cell death (apoptosis) by expressing high levels of apoptosis inhibitors, such as Bcl-2. Thus, Bcl-2 is a major target for cancer therapy. Edison et al. describe a mechanism by which the ARTS protein promotes proteasome-mediated degradation of Bcl-2 and thereby stimulates cell death.
Bibliographical noteFunding Information:
We thank Hermann Steller, Suzanne Cory, David Huang, Binghui Li, Assaf Friedler, and Reuven Stein for generously providing us with the constructs and cell lines used in this manuscript. We thank Hermann Steller for thoughtful discussion of the manuscript and Gal Sevi Karniel for excellent graphical work. H.T.K. was supported by NIGMS Grant R01GM051923 (to A.L.G.), U.S. Israel Binational Science Foundation Grant 2003085 (to S.L.), Israel Science Foundation (ISF) Grants 1264/06 and 822/12 (to S.L.), INCPM-ISF Grant 2376/15 (to S.L.), the Charles Wolfson Charitable Trust , and by a generous grant award from the Hymen Milgrom Trust (to S.L.).
© 2017 The Author(s)
- protein degradation
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology (all)