Targeting γ-Herpesvirus 68 Bcl-2-mediated Down-regulation of Autophagy
Year: 2014
Type: article
Abstract: γ-herpesviruses (γHVs) 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 γHV68 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 γHV68 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.
Source: Journal of Biological Chemistry
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,430
Funders: National Institutes of Health, Centers for Disease Control and Prevention, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Neurological Disorders and Stroke, National Center for Research Resources
Awards: G1416491957, G1487426800, G1879940576, G2473778919, Center for Protease Research, G2589219045, Molecular mechanism by which gamma-herpesviruses evade autophagy, New Strategies for Targeting Protease in Disease, G7465428165, Beclin 1-Bcl-2 Interactions: Effects on Autophagy, G9000195212, G9000231702, G9000270047
OpenAlex ID: W2055346100