Degradation of Bcl-2 by XIAP and ARTS Promotes Apoptosis
Natalia Edison,
Yael Curtz,
Nicole Paland,
Dana Mamriev,
Nicolas Chorubczyk,
Tali Haviv-Reingewertz,
Nir Kfir,
David Morgenstern,
Meital Kupervaser,
Juliana Kagan,
Hyoung Tae Kim,
Sarit Larisch
Affiliations
Natalia Edison
Cell Death and Cancer Research Laboratory, Department of Biology, University of Haifa, Haifa 31905, Israel
Yael Curtz
Cell Death and Cancer Research Laboratory, Department of Biology, University of Haifa, Haifa 31905, Israel
Nicole Paland
Cell Death and Cancer Research Laboratory, Department of Biology, University of Haifa, Haifa 31905, Israel
Dana Mamriev
Cell Death and Cancer Research Laboratory, Department of Biology, University of Haifa, Haifa 31905, Israel
Nicolas Chorubczyk
Cell Death and Cancer Research Laboratory, Department of Biology, University of Haifa, Haifa 31905, Israel
Tali Haviv-Reingewertz
Cell Death and Cancer Research Laboratory, Department of Biology, University of Haifa, Haifa 31905, Israel
Nir Kfir
Cell Death and Cancer Research Laboratory, Department of Biology, University of Haifa, Haifa 31905, Israel
David Morgenstern
De Botton Institute for Protein Profiling, Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot 76100, Israel
Meital Kupervaser
De Botton Institute for Protein Profiling, Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot 76100, Israel
Juliana Kagan
Cell Death and Cancer Research Laboratory, Department of Biology, University of Haifa, Haifa 31905, Israel
Hyoung Tae Kim
Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA
Sarit Larisch
Cell Death and Cancer Research Laboratory, Department of Biology, University of Haifa, Haifa 31905, Israel; Corresponding author
Summary: 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. Keywords: apoptosis, mitochondria, ARTS, Bcl-2, caspase, XIAP, ubiquitin, protein degradation, E3-ligase
