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Ku B, Woo JS, Liang C, Lee KH, Hong HS, E X et al.. Structural and biochemical bases for the inhibition of autophagy and apoptosis by viral BCL-2 of murine gamma-herpesvirus 68. PLoS Pathog 4: e25

Oregon Health and Science University, United States of America
PLoS Pathogens (Impact Factor: 7.56). 03/2008; 4(2):e25. DOI: 10.1371/journal.ppat.0040025
Source: PubMed

ABSTRACT

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In higher animals, defective or surplus cells are removed by a process known as apoptosis. On the other hand, defective or damaged cellular components are removed by a process known as autophagy. These two destructive processes are indispensable for the survival and development of an organism. While apoptosis is known as a central host defense mechanism that removes virus-infected cells, the role of autophagy against viral infection has recently emerged. Many viruses express an armory of viral proteins that counteract cell death–mediated innate immune control. One such protein is a homologue of the cellular BCL-2 protein that suppresses apoptosis through inhibitory binding to apoptosis-promoting proteins. Murine γ-herpesvirus 68 also encodes a viral BCL-2, known as M11. In this study, we quantitatively measured the binding affinity of M11 for its potential cellular targets, including ten different proapoptotic proteins and the proautophagic protein Beclin1. We found that M11 neutralizes the proapoptotic proteins broadly rather than selectively to suppress apoptosis. Surprisingly, M11 bound to Beclin1 with the highest affinity, which correlated with its strong antiautophagic activity in cells. These data suggest that M11 suppresses not only apoptosis but also autophagy potently, which ultimately contributes to the viral chronic infection.

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Available from: Xiaofei Ee, Jun 19, 2014
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    • "Overexpression of antiapoptotic Bcl-2 family proteins has been demonstrated to contribute to prolonged cell survival, resistance to apoptosis, cancer development and progression, and decreased sensitivity to chemotherapeutics in cancer cells [11] [12]. The proapoptotic BAD protein interact with the hydrophobic binding groove of Bcl homologs (Bcl-2 and Bcl-xL) [13] and disrupts the integrity of mitochondria to initiate the release of cytochrome C into the cytoplasm to induce apoptosis [14] [15]. Therefore, targeting Bcl- 2/Bcl-xL proteins using small molecules that can interact with their hydrophobic socket may serve as agents with therapeutic potential to induce apoptosis in cancer cells. "
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    • "ICP34.5 binding to Beclin 1 inhibits the formation of autophagosomes in neurons, suggesting that the virus has evolved to actively inhibit autophagy. Other viral proteins inhibiting through Beclin 1 binding include Bcl-2 homologs, such as the KSHV orf16 protein and the MHV-68 M11 protein (Ku et al., 2008; Su et al., 2014). In addition to ICP34.5's "
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    • "However, the utilization of autophagic membranes has not been reported so far for DNA viruses. Indeed, herpes viruses rather seem to encode Bcl-2 homologues that inhibit autophagosome formation via their binding to Atg6/Beclin-1 (E et al., 2009; Ku et al., 2008; Orvedahl et al., 2007; Pattingre et al., 2005 "
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