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

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)442-454
Number of pages13
JournalCell Reports
Issue number2
StatePublished - 10 Oct 2017

Bibliographical note

Publisher Copyright:
© 2017 The Author(s)


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

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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