Viral Subversion of Apoptotic Enzymes: Escape from Death Row

Abstract

To prolong cell viability and facilitate replication, viruses have evolved multiple mechanisms to inhibit the host apoptotic response. Cellular proteases such as caspases and serine proteases are instrumental in promoting apoptosis. Thus, these enzymes are logical targets for virus-mediated modulation to suppress cell death. Four major classes of viral inhibitors antagonize caspase function: serpins, p35 family members, inhibitor of apoptosis proteins, and viral FLICE-inhibitory proteins. Viruses also subvert activity of the serine proteases, granzyme B and HtrA2/Omi, to avoid cell death. The combined efforts of viruses to suppress apoptosis suggest that this response should be avoided at all costs. However, some viruses utilize caspases during replication to aid virus protein maturation, progeny release, or both. Hence, a multifaceted relationship exists between viruses and the apoptotic response they induce. Examination of these interactions contributes to our understanding of both virus pathogenesis and the regulation of apoptotic enzymes in normal cellular functions.

Modulation of Inflammasome Pathways by Bacterial and Viral Pathogens

“…In fact, viruses provide some of the best characterized mechanisms by which microbial pathogens hijack the inflammasome. Indeed, the cowpox virus protein cytokine response modifier A (CrmA) and its homologs in orthopoxviruses such as vaccinia, ectromelia, and rabbitpox virus directly target the enzymatic activity of caspase-1 (44)(45)(46)(47). CrmA inhibits caspase-1 activity with an inhibition constant of 0.01 nM, rendering it one of the most effective caspase-1 inhibitors.…”

“…CrmA inhibits caspase-1 activity with an inhibition constant of 0.01 nM, rendering it one of the most effective caspase-1 inhibitors. This is accomplished by acting as a pseudosubstrate inhibitor of caspase-1, which entails the cleavage of CrmA in a first step that is followed by the formation of a permanent covalent bond with the active site cysteine of caspase-1 to render the protease inactive (44,48,49). Notably, CrmA has two homologs in rodents (50) and shares 54% amino acid identity with the human serpin PI-9 (51).…”

Advances in dissecting mosquito innate immune responses to arbovirus infection

“…Whilst important in development, at least in vertebrates, apoptosis (programmed cell death) is also an innate response to virus infection that can limit virus replication and spread (Best, 2008). Little is known about apoptotic processes in arbovirus-infected mosquitoes or mosquito cell lines.…”

Granzyme A expression reveals distinct cytolytic CTL subsets following influenza A virus infection

“…Although effector CTL express abundant levels of grzB protein at the peak of the response [8], this is largely turned off as the CTL population contracts into memory [9][10][11][12]. Given its important role in CTL-mediated killing, many viruses have evolved strategies that target and disable grzB function [13]. In the face of such inhibitors, presumably other grz family members must be utilised if CTL killing is to proceed upon virus infection.…”