Anti-apoptotic Bcl-XL but not Mcl-1 contributes to protection against virus-induced apoptosis.

Michaela Ohmer,Gerd Sutter,Albert Zimmermann,Katrin Ehrhardt,Georg Häcker,Arnim Weber

doi:10.1038/cddis.2016.242

Abstract

Infection of mammalian cells with viruses often induces apoptosis. How the recognition of viruses leads to apoptosis of the infected cell and which host cell factors regulate this cell death is incompletely understood. In this study, we focussed on two major anti-apoptotic proteins of the host cell, whose abundance and activity are important for cell survival, the Bcl-2-like proteins Mcl-1 and Bcl-XL. During infection of epithelial cells and fibroblasts with modified vaccinia virus Ankara (MVA), Mcl-1 protein levels dropped but the MVA Bcl-2-like protein F1L could replace Mcl-1 functionally; a similar activity was found in vaccinia virus (VACV)-infected cells. During infection with murine cytomegalovirus (MCMV), Mcl-1-levels were not reduced but a viral Mcl-1-like activity was also generated. Infection of mouse macrophages with any of these viruses, on the other hand, induced apoptosis. Virus-induced macrophage apoptosis was unaltered in the absence of Mcl-1. However, apoptosis was substantially increased in infected Bcl-XL-deficient macrophages or macrophages treated with the Bcl-2/Bcl-XL-inhibitor ABT-737. Genetic loss of Bcl-XL or treatment of macrophages with ABT-737 reduced the generation of infectious VACV. These data show that Mcl-1 is dispensable for the regulation of apoptosis during infection with different large DNA viruses, either because the viruses replace its function (in fibroblasts and epithelial cells) or because the pro-apoptotic activity generated by the infection appears not to be blocked by it (in macrophages). Bcl-XL, on the other hand, can be important to maintain survival of virus-infected cells, and its activity can determine outcome of the infection.

Highlights

Apoptosis of the infected cell is a defence strategy of higher organisms against viral infection
Infection of epithelial cells and fibroblasts by Modified Virus Ankara (MVA) leads to a loss of Mcl-1 protein but viruses can replace Mcl-1 functionally
This loss was not seen at the mRNA level (where there was even some increase during infection (Supplementary Figure S1A and B)) and may in part be due to the induction of the Mcl-1-antagonist Noxa, which can trigger the degradation of Mcl-1,21 and which is known to be upregulated in the response of HeLa cells to MVA infection (Figure 1a).[22]

Summary

Introduction

Apoptosis of the infected cell is a defence strategy of higher organisms against viral infection. Recognition occurs by pattern recognition receptors of innate immunity, which most often recognize viral nucleic acids differing in certain structural characteristics from host cell nucleic acids (for review, see Hornung et al.[3]) How this recognition machinery is linked to the apoptosis apparatus is less clear. Apoptosis may be triggered by upregulation or in some cases activation of BH3-only proteins, or by the loss of anti-apoptotic proteins Both Poxviruses and herpes viruses are large, doublestranded DNA viruses with very different cell biology. The mammalian Bcl-2-like anti-apoptotic proteins have an overall similar, conserved structural fold and all can block apoptosis by binding to pro-apoptotic Bcl-2-family proteins, they substantially differ in terms of this binding affinity as well as their biological function. Deletion of individual anti-apoptotic Bcl-2-proteins in mice produces rather different

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Results

Conclusion