Activation of NIX-mediated mitophagy by an interferon regulatory factor homologue of human herpesvirus

Mai Tram Vo,John Nicholas,Barbara J Smith,Young Bong Choi

doi:10.1038/s41467-019-11164-2

Abstract

Viral control of mitochondrial quality and content has emerged as an important mechanism for counteracting the host response to virus infection. Despite the knowledge of this crucial function of some viruses, little is known about how herpesviruses regulate mitochondrial homeostasis during infection. Human herpesvirus 8 (HHV-8) is an oncogenic virus causally related to AIDS-associated malignancies. Here, we show that HHV-8-encoded viral interferon regulatory factor 1 (vIRF-1) promotes mitochondrial clearance by activating mitophagy to support virus replication. Genetic interference with vIRF-1 expression or targeting to the mitochondria inhibits HHV-8 replication-induced mitophagy and leads to an accumulation of mitochondria. Moreover, vIRF-1 binds directly to a mitophagy receptor, NIX, on the mitochondria and activates NIX-mediated mitophagy to promote mitochondrial clearance. Genetic and pharmacological interruption of vIRF-1/NIX-activated mitophagy inhibits HHV-8 productive replication. Our findings uncover an essential role of vIRF-1 in mitophagy activation and promotion of HHV-8 lytic replication via this mechanism.

Highlights

Viral control of mitochondrial quality and content has emerged as an important mechanism for counteracting the host response to virus infection
MitoTracker Red staining of mitochondria showed an apparent decrease in the levels of mitochondria of viral interferon regulatory factor 1 (vIRF-1)-expressing lytic cells (Supplementary Fig. 1b), implying that the reduced levels of mitochondrial antiviral signaling adaptor protein (MAVS) and TOM20 might result from a loss of mitochondria content rather than a specific inhibition of the expression or stability of the proteins
Other lytic proteins including K1, vIL-6, vGPCR, and ORF45 may inhibit the initiation of autophagy by activating PI3K/AKT/mTOR signaling[40]

Summary

Introduction

Viral control of mitochondrial quality and content has emerged as an important mechanism for counteracting the host response to virus infection. In the innate immune response to virus infection, the RIGI-like receptors (RLRs) RIG-I and MDA-5 recognize cytosolic viral RNA and promote the oligomerization of the mitochondrial antiviral signaling adaptor protein (MAVS; known as IPS-1, VISA, and Cardif)[4], which recruits TBK1 and IKKi kinases to activate IRF3 and IRF7 transcription factors[2]. These activated IRFs induce the expression of type I interferon (IFN) genes, the products of which restrict virus replication. We identify a role of vIRF-1 in its activation of mitophagy and support of virus replication via this pathway

Methods

Results

Conclusion