2. Academic Validation
  3. Degradation of Bcl-2 by XIAP and ARTS Promotes Apoptosis

Degradation of Bcl-2 by XIAP and ARTS Promotes Apoptosis

  • Cell Rep. 2017 Oct 10;21(2):442-454. doi: 10.1016/j.celrep.2017.09.052.
Natalia Edison 1,  Yael Curtz 1,  Nicole Paland 1,  Dana Mamriev 1,  Nicolas Chorubczyk 1,  Tali Haviv-Reingewertz 1,  Nir Kfir 1,  David Morgenstern 2,  Meital Kupervaser 2,  Juliana Kagan 1,  Hyoung Tae Kim 3,  Sarit Larisch 4
Affiliations

Affiliations

  • 1 Cell Death and Cancer Research Laboratory, Department of Biology, University of Haifa, Haifa 31905, Israel.
  • 2 De Botton Institute for Protein Profiling, Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot 76100, Israel.
  • 3 Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
  • 4 Cell Death and Cancer Research Laboratory, Department of Biology, University of Haifa, Haifa 31905, Israel. Electronic address: [email protected].
PMID: 29020630 DOI: 10.1016/j.celrep.2017.09.052
Abstract

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.

Keywords

ARTS; Bcl-2; E3-ligase; XIAP; apoptosis; caspase; mitochondria; protein degradation; ubiquitin.

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