Dynamic interplay between the co-opted Fis1 mitochondrial fission protein and membrane contact site proteins in supporting tombusvirus replication.

Wenwu Lin,Zhike Feng,Peter D Nagy,K Reddisiva Prasanth,Yuyan Liu,Hui-Shan Guo

doi:10.1371/journal.ppat.1009423

Wenwu Lin, Zhike Feng + Show 4 more

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https://doi.org/10.1371/journal.ppat.1009423

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Abstract

Plus-stranded RNA viruses have limited coding capacity and have to co-opt numerous pro-viral host factors to support their replication. Many of the co-opted host factors support the biogenesis of the viral replication compartments and the formation of viral replicase complexes on subverted subcellular membrane surfaces. Tomato bushy stunt virus (TBSV) exploits peroxisomal membranes, whereas the closely-related carnation Italian ringspot virus (CIRV) hijacks the outer membranes of mitochondria. How these organellar membranes can be recruited into pro-viral roles is not completely understood. Here, we show that the highly conserved Fis1 mitochondrial fission protein is co-opted by both TBSV and CIRV via direct interactions with the p33/p36 replication proteins. Deletion of FIS1 in yeast or knockdown of the homologous Fis1 in plants inhibits tombusvirus replication. Instead of the canonical function in mitochondrial fission and peroxisome division, the tethering function of Fis1 is exploited by tombusviruses to facilitate the subversion of membrane contact site (MCS) proteins and peroxisomal/mitochondrial membranes for the biogenesis of the replication compartment. We propose that the dynamic interactions of Fis1 with MCS proteins, such as the ER resident VAP tethering proteins, Sac1 PI4P phosphatase and the cytosolic OSBP-like oxysterol-binding proteins, promote the formation and facilitate the stabilization of virus-induced vMCSs, which enrich sterols within the replication compartment. We show that this novel function of Fis1 is exploited by tombusviruses to build nuclease-insensitive viral replication compartment.

Highlights

Due to the rather limited coding capacity of their small RNA genomes, positive-strand RNA viruses co-opt many pro-viral host factors to support their replication. (+)RNA virus replication requires the biogenesis of viral replication compartments, called viral replication organelles (VROs)
Fis1 mitochondrial fission protein is co-opted for tethering at virus-induced membrane contact site protein
The pro-viral function of Fis1 is manifested through binding to the Tomato bushy stunt virus (TBSV) p33 replication protein that results in recruitment into the replication compartment formed from aggregated peroxisomes

Summary

Introduction

Due to the rather limited coding capacity of their small RNA genomes, positive-strand RNA viruses co-opt many pro-viral host factors to support their replication. (+)RNA virus replication requires the biogenesis of viral replication compartments, called viral replication organelles (VROs). In addition to co-opting cellular proteins, viruses bind to phospholipids and sterols, deform membranes, and modulate lipid biosynthesis and lipid transfer and vesicular trafficking [8,9,10,11,12] All these cellular changes, including the hijacked cellular membranes, serve the purpose to protect the viral RNA, including the dsRNA replication intermediate, from recognition and elimination by the cellular innate immune system [13,14]. The membranous VROs help concentrate viral and co-opted host proteins together with the viral (+)RNA All these processes are needed for optimal VRCs formation [9,11,15,16,17,18,19,20,21]. This is a rapidly expanding research field with possible applications and new therapies to control RNA virus replication

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