Peroxisomes support human herpesvirus 8 latency by stabilizing the viral oncogenic protein vFLIP via the MAVS-TRAF complex.

Young Bong Choi,Yeeun Choi,Edward William Harhaj,Pinghui Feng

doi:10.1371/journal.ppat.1007058

Young Bong Choi, Yeeun Choi + Show 2 more

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https://doi.org/10.1371/journal.ppat.1007058

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Abstract

Human herpesvirus 8 (HHV-8) is causally related to human malignancies. HHV-8 latent viral FLICE-inhibitory protein (vFLIP) is a viral oncoprotein that is linked to pathogenesis, but how its expression is regulated is largely unknown. In an attempt to understand the role of the mitochondrial antiviral signaling (MAVS) adaptor in HHV-8 infection, we discovered that vFLIP expression was post-translationally up-regulated by the MAVS signaling complex on peroxisomes. Furthermore, we demonstrated that vFLIP could be targeted to the peroxisomes, where it was oncogenically active, in a PEX19-dependent manner. Targeted disruption of vFLIP and MAVS interaction resulted in a decrease in vFLIP expression and selectively promoted death of latently HHV-8-infected cells, providing therapeutic potential for treating HHV-8 diseases. Collectively, our experimental results suggest novel involvement of peroxisomes and MAVS in the stabilization of vFLIP and thereby in the establishment or maintenance of HHV-8 latency and associated pathogenesis.

Highlights

In response to virus infection, a host innate immune response is activated to restrict virus replication and dissemination
Human herpesvirus 8 (HHV-8), known as Kaposi’s sarcoma associated herpesvirus (KSHV), is the etiological agent of several malignancies occurring in individuals with severe immunosuppression, as occurs in acquired immunodeficiency syndrome and transplantation
We found that viral FLICE-inhibitory protein (vFLIP) can localize to peroxisomes where it is stabilized by its association with the mitochondria antiviral signaling adaptor protein mitochondrial antiviral signaling (MAVS), which mediates K63-linked polyubiquitination of vFLIP by tumor necrosis factor (TNF) receptor-associated factors (TRAFs) and renders it resistant to degradation induced by autophagy and the ubiquitin-proteasome pathway

Summary

Introduction

In response to virus infection, a host innate immune response is activated to restrict virus replication and dissemination. Upon RNA virus infection, viral RNA is recognized by a class of specialized pattern recognition receptors (PRRs); cytosolic viral RNA is sensed by RIG-I-like receptors (RLRs) including RIG-I and MDA5 [1, 2], and viral RNA in endosomes is sensed by Toll-like receptors (TLRs) including TLR3 and TLR7 [3, 4] Upon recognition of these RNA species, RLRs and TLRs recruit specific intracellular adaptor proteins to initiate signaling pathways culminating in activation of transcription factors, nuclear factor-κB (NF-κB) and interferon (IFN) regulatory factors (IRFs), that upregulate expression of antiviral cytokines. This antiviral activity of MAVS appears to be dependent on its localization to mitochondria rather than peroxisomes [19, 20], inducing mitochondrial dysfunction and oxidative stress by interacting with cellular proapoptotic effector proteins including SARM1 [21], VDAC1 [20], MKK7/JNK2 [22], and caspase-8 [23]

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