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Τρίτη 10 Οκτωβρίου 2017

Degradation of Bcl-2 by XIAP and ARTS Promotes Apoptosis

Publication date: 10 October 2017
Source:Cell Reports, Volume 21, Issue 2
Author(s): 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
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.

Graphical abstract

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Teaser

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.


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