| Structural highlights
Function
ARBH_MHV68 Plays a role in the protection against apoptosis mediated by cytotoxic cells during the immune response to acute and persistent viral infection. Contributes therefore to latency establishment. Plays also a role in the inhibition of host starvation-induced autophagy which ultimately contributes to the viral chronic infection.[1] [2] [3] [4] [5]
Publication Abstract from PubMed
gamma-herpesviruses (gammaHVs) are common human pathogens that encode homologs of the anti-apoptotic cellular Bcl-2 proteins, which are critical to viral reactivation and oncogenic transformation. The murine gammaHV68 provides a tractable in vivo model for understanding general features of these important human pathogens. Bcl-XL, a cellular Bcl-2 homolog, and the murine gammaHV68 Bcl-2 homolog, M11, both bind to a BH3 domain within the key autophagy effector Beclin 1 with comparable affinities, resulting in the down-regulation of Beclin 1-mediated autophagy. Despite this similarity, differences in residues lining the binding site of M11 and Bcl-XL dictate varying affinities for the different BH3 domain-containing proteins. Here we delineate Beclin 1 differential specificity determinants for binding to M11 or Bcl-XL by quantifying autophagy levels in cells expressing different Beclin 1 mutants and either M11 or Bcl-XL, and we show that a G120E/D121A Beclin 1 mutant selectively prevents down-regulation of Beclin 1-mediated autophagy by Bcl-XL, but not by M11. We use isothermal titration calorimetry to identify a Beclin 1 BH3 domain-derived peptide that selectively binds to M11, but not to Bcl-XL. The x-ray crystal structure of this peptide bound to M11 reveals the mechanism by which the M11 BH3 domain-binding groove accommodates this M11-specific peptide. This information was used to develop a cell-permeable peptide inhibitor that selectively inhibits M11-mediated, but not Bcl-XL-mediated, down-regulation of autophagy.
Targeting gamma-herpesvirus 68 Bcl-2-mediated down-regulation of autophagy.,Su M, Mei Y, Sanishvili R, Levine B, Colbert CL, Sinha S J Biol Chem. 2014 Mar 21;289(12):8029-40. doi: 10.1074/jbc.M113.515361. Epub 2014, Jan 17. PMID:24443581[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Wang GH, Garvey TL, Cohen JI. The murine gammaherpesvirus-68 M11 protein inhibits Fas- and TNF-induced apoptosis. J Gen Virol. 1999 Oct;80 ( Pt 10):2737-2740. doi: 10.1099/0022-1317-80-10-2737. PMID:10573168 doi:http://dx.doi.org/10.1099/0022-1317-80-10-2737
- ↑ Roy DJ, Ebrahimi BC, Dutia BM, Nash AA, Stewart JP. Murine gammaherpesvirus M11 gene product inhibits apoptosis and is expressed during virus persistence. Arch Virol. 2000;145(11):2411-20. doi: 10.1007/s007050070030. PMID:11205127 doi:http://dx.doi.org/10.1007/s007050070030
- ↑ de Lima BD, May JS, Marques S, Simas JP, Stevenson PG. Murine gammaherpesvirus 68 bcl-2 homologue contributes to latency establishment in vivo. J Gen Virol. 2005 Jan;86(Pt 1):31-40. doi: 10.1099/vir.0.80480-0. PMID:15604429 doi:http://dx.doi.org/10.1099/vir.0.80480-0
- ↑ Ku B, Woo JS, Liang C, Lee KH, Hong HS, E X, Kim KS, Jung JU, Oh BH. Structural and Biochemical Bases for the Inhibition of Autophagy and Apoptosis by Viral BCL-2 of Murine gamma-Herpesvirus 68. PLoS Pathog. 2008 Feb 1;4(2):e25. PMID:18248095 doi:07-PLPA-RA-0558
- ↑ Sinha S, Colbert CL, Becker N, Wei Y, Levine B. Molecular basis of the regulation of Beclin 1-dependent autophagy by the gamma-herpesvirus 68 Bcl-2 homolog M11. Autophagy. 2008 Nov 18;4(8). PMID:18797192
- ↑ Su M, Mei Y, Sanishvili R, Levine B, Colbert CL, Sinha S. Targeting gamma-herpesvirus 68 Bcl-2-mediated down-regulation of autophagy. J Biol Chem. 2014 Mar 21;289(12):8029-40. doi: 10.1074/jbc.M113.515361. Epub 2014, Jan 17. PMID:24443581 doi:http://dx.doi.org/10.1074/jbc.M113.515361
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