3 years ago

Degradation of Bcl-2 by XIAP and ARTS Promotes Apoptosis

Degradation of Bcl-2 by XIAP and ARTS Promotes Apoptosis
Sarit Larisch, Nicolas Chorubczyk, Yael Curtz, Hyoung Tae Kim, Nir Kfir, Juliana Kagan, David Morgenstern, Tali Haviv-Reingewertz, Nicole Paland, Natalia Edison, Dana Mamriev, Meital Kupervaser


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.

Publisher URL: http://www.cell.com/cell-reports/fulltext/S2211-1247(17)31342-6

DOI: 10.1016/j.celrep.2017.09.052

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