Structural and Biochemical Bases for the Inhibition of Autophagy and Apoptosis by Viral BCL-2 of Murine γ-Herpesvirus 68 Export

@article{citeulike:3054937, abstract = {All gammaherpesviruses express homologues of antiapoptotic B-cell lymphoma-2 (BCL-2) to counter the clearance of infected cells by host antiviral defense machineries. To gain insights into the action mechanisms of these viral BCL-2 proteins, we carried out structural and biochemical analyses on the interactions of M11, a viral BCL-2 of murine γ-herpesvirus 68, with a fragment of proautophagic Beclin1 and BCL-2 homology 3 (BH3) domain-containing peptides derived from an array of proapoptotic BCL-2 family proteins. Mainly through hydrophobic interactions, M11 bound the BH3-like domain of Beclin1 with a dissociation constant of 40 nanomole, a markedly tighter affinity compared to the 1.7 micromolar binding affinity between cellular BCL-2 and Beclin1. Consistently, M11 inhibited autophagy more efficiently than BCL-2 in NIH3T3 cells. M11 also interacted tightly with a BH3 domain peptide of BAK and those of the upstream BH3-only proteins BIM, BID, BMF, PUMA, and Noxa, but weakly with that of BAX. These results collectively suggest that M11 potently inhibits Beclin1 in addition to broadly neutralizing the proapoptotic BCL-2 family in a similar but distinctive way from cellular BCL-2, and that the Beclin1-mediated autophagy may be a main target of the virus.}, author = {Ku, Bonsu and Woo, Jae-Sung and Liang, Chengyu and Lee, Kwang-Hoon and Hong, Hyang-Suk and Xiaofei and Kim, Key-Sun and Jung, Jae U. and Oh, Byung-Ha}, citeulike-article-id = {3054937}, citeulike-linkout-0 = {http://dx.doi.org/10.1371/journal.ppat.0040025}, day = {1}, doi = {10.1371/journal.ppat.0040025}, journal = {PLoS Pathog}, keywords = {apoptosis, atg6, autophagy, bcl2, beclin1, m11, mhv68, structure}, month = {February}, number = {2}, pages = {e25+}, posted-at = {2008-07-29 00:44:04}, priority = {0}, publisher = {Public Library of Science}, title = {Structural and Biochemical Bases for the Inhibition of Autophagy and Apoptosis by Viral BCL-2 of Murine γ-Herpesvirus 68}, url = {http://dx.doi.org/10.1371/journal.ppat.0040025}, volume = {4}, year = {2008} }

TY - JOUR ID - citeulike:3054937 L3 - citeulike-article-id:3054937 N2 - All gammaherpesviruses express homologues of antiapoptotic B-cell lymphoma-2 (BCL-2) to counter the clearance of infected cells by host antiviral defense machineries. To gain insights into the action mechanisms of these viral BCL-2 proteins, we carried out structural and biochemical analyses on the interactions of M11, a viral BCL-2 of murine γ-herpesvirus 68, with a fragment of proautophagic Beclin1 and BCL-2 homology 3 (BH3) domain-containing peptides derived from an array of proapoptotic BCL-2 family proteins. Mainly through hydrophobic interactions, M11 bound the BH3-like domain of Beclin1 with a dissociation constant of 40 nanomole, a markedly tighter affinity compared to the 1.7 micromolar binding affinity between cellular BCL-2 and Beclin1. Consistently, M11 inhibited autophagy more efficiently than BCL-2 in NIH3T3 cells. M11 also interacted tightly with a BH3 domain peptide of BAK and those of the upstream BH3-only proteins BIM, BID, BMF, PUMA, and Noxa, but weakly with that of BAX. These results collectively suggest that M11 potently inhibits Beclin1 in addition to broadly neutralizing the proapoptotic BCL-2 family in a similar but distinctive way from cellular BCL-2, and that the Beclin1-mediated autophagy may be a main target of the virus. IS - 2 JF - PLoS Pathog TI - Structural and Biochemical Bases for the Inhibition of Autophagy and Apoptosis by Viral BCL-2 of Murine γ-Herpesvirus 68 PB - Public Library of Science VL - 4 SP - e25 KW - apoptosis KW - atg6 KW - autophagy KW - bcl2 KW - beclin1 KW - m11 KW - mhv68 KW - structure AU - Ku, Bonsu AU - Woo, Jae-Sung AU - Liang, Chengyu AU - Lee, Kwang-Hoon AU - Hong, Hyang-Suk AU - Xiaofei AU - Kim, Key-Sun AU - Jung, Jae AU - Oh, Byung-Ha PY - 2008/02/01/ UR - http://dx.doi.org/10.1371/journal.ppat.0040025 ER -