Abstract
Programmed cell death or apoptosis is an important component of host defense systems against viral infection. The B-cell lymphoma 2 (Bcl-2) proteins family is the main arbiter of mitochondrially mediated apoptosis, and viruses have evolved sequence and structural mimics of Bcl-2 to subvert premature host cell apoptosis in response to viral infection. The sequencing of the canarypox virus genome identified a putative pro-survival Bcl-2 protein, CNP058. However, a role in apoptosis inhibition for CNP058 has not been identified to date. Here, we report that CNP058 is able to bind several host cell pro-death Bcl-2 proteins, including Bak and Bax, as well as several BH3 only-proteins including Bim, Bid, Bmf, Noxa, Puma, and Hrk with high to moderate affinities. We then defined the structural basis for CNP058 binding to pro-death Bcl-2 proteins by determining the crystal structure of CNP058 bound to Bim BH3. CNP058 adopts the conserved Bcl-2 like fold observed in cellular pro-survival Bcl-2 proteins, and utilizes the canonical ligand binding groove to bind Bim BH3. We then demonstrate that CNP058 is a potent inhibitor of ultraviolet (UV) induced apoptosis in a cell culture model. Our findings suggest that CNP058 is a potent inhibitor of apoptosis that is able to bind to BH3 domain peptides from a broad range of pro-death Bcl-2 proteins, and may play a key role in countering premature host apoptosis.
Highlights
Apoptosis is a form of programmed cell death that can be triggered via external or internal stimuli.Apoptosis plays a major role in the removal of damaged, unwanted or infected cells, impacting processes ranging from cellular homeostasis to the immune response against viral infection [1]
The host intrinsic apoptosis pathway can be downregulated by viruses through the expression of B-cell lymphoma 2 (Bcl-2) mimics, which nullify the activity of host cell apoptosis inducing Bcl-2 family members [2,3]
Our findings demonstrate that CNP058 is a Bcl-2 protein that potently inhibits apoptosis, is able to interact with the BH3 domain of pro-death Bcl-2 proteins, and provide a platform to understand apoptosis inhibition by CNP058
Summary
Apoptosis is a form of programmed cell death that can be triggered via external (extrinsic pathway or receptor mediated) or internal stimuli (intrinsic pathway or mitochondria mediated).Apoptosis plays a major role in the removal of damaged, unwanted or infected cells, impacting processes ranging from cellular homeostasis to the immune response against viral infection [1]. Apoptosis is a form of programmed cell death that can be triggered via external (extrinsic pathway or receptor mediated) or internal stimuli (intrinsic pathway or mitochondria mediated). Many viruses express decoy receptors to neutralize the Tumor Necrosis Factor receptor superfamily, the effectors of extrinsic apoptosis pathway [1]. The host intrinsic apoptosis pathway can be downregulated by viruses through the expression of B-cell lymphoma 2 (Bcl-2) mimics (vBcl-2), which nullify the activity of host cell apoptosis inducing Bcl-2 family members [2,3]. The Bcl-2 family proteins are the gatekeepers of the intrinsic apoptosis pathway, with the family members being characterized by the presence of at least one of the four conserved Bcl-2 homology (BH) domains. Bcl-2 proteins can be divided into two major classes: pro-death and pro-survival [4]
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