Activation of the Mitochondrial Apoptotic Signaling Platform during Rubella Virus Infection.

Claudia Claus,Sarah Roßmark,Teryl Frey,Mareen Reins,Uwe Liebert,Alice Petzold,Annette Mankertz,Claudia Große,Lena Manssen,Denise Hübner,Viktoria Bothe

doi:10.3390/v7122928

Abstract

Mitochondria- as well as p53-based signaling pathways are central for the execution of the intrinsic apoptotic cascade. Their contribution to rubella virus (RV)-induced apoptosis was addressed through time-specific evaluation of characteristic parameters such as permeabilization of the mitochondrial membrane and subsequent release of the pro-apoptotic proteins apoptosis-inducing factor (AIF) and cytochrome c from mitochondria. Additionally, expression and localization pattern of p53 and selected members of the multifunctional and stress-inducible cyclophilin family were examined. The application of pifithrin μ as an inhibitor of p53 shuttling to mitochondria reduced RV-induced cell death to an extent similar to that of the broad spectrum caspase inhibitor z-VAD-fmk (benzyloxycarbonyl-V-A-D-(OMe)-fmk). However, RV progeny generation was not altered. This indicates that, despite an increased survival rate of its cellular host, induction of apoptosis neither supports nor restricts RV replication. Moreover, some of the examined apoptotic markers were affected in a strain-specific manner and differed between the cell culture-adapted strains: Therien and the HPV77 vaccine on the one hand, and a clinical isolate on the other. In summary, the results presented indicate that the transcription-independent mitochondrial p53 program contributes to RV-induced apoptosis.

Highlights

Rubella virus (RV) as the only member of the Rubivirus genus in the family Togaviridae causes a mild childhood disease, but acts as an extremely efficient teratogen when infection occurs during the first trimester of pregnancy
PFTμ is an inhibitor of the mitochondrial translocation of p53, which reduces the binding affinity of p53 to B cell lymphoma-extra large (Bcl-xL) and acts upstream of Bax [19]
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Summary

Introduction

Rubella virus (RV) as the only member of the Rubivirus genus in the family Togaviridae causes a mild childhood disease, but acts as an extremely efficient teratogen when infection occurs during the first trimester of pregnancy. RV-induced apoptosis occurs in a complex, multi-step and rather cell type-specific manner [2]. Prolonged survival of RV-infected cells is ensured by the induction of the phosphatidylinositol 3I-kinase (PI3K)/AKT survival pathway [6] and by anti-apoptotic activities of the viral C protein [7,8]. These viral infection-promoting activities of the C protein involve its localization to mitochondria and its interaction with the pro-apoptotic protein B-cell lymphoma-2 (Bcl-2)-associated X protein (Bax) and the mitochondrial matrix protein p32 (gC1qR), [7,9]. In addition to its interaction with mitochondrial proteins, RV infection has an impact on mitochondrial bioenergetic function [11,12]

Methods

Results

Conclusion