Phase Transitions Drive the Formation of Vesicular Stomatitis Virus Replication Compartments

ABSTRACT RNA viruses that replicate in the cell cytoplasm typically concentrate their replication machinery within specialized compartments. This concentration favors enzymatic reactions and shields viral RNA from detection by cytosolic pattern recognition receptors. Nonsegmented negative-strand (NN...

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Autores principales:	Bianca S. Heinrich, Zoltan Maliga, David A. Stein, Anthony A. Hyman, Sean P. J. Whelan
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	negative-strand RNA virus phase separation rhabdovirus viral replication viroplasm virus-host interactions Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/6513b5d6e98d4908b78ef9dda1bca69e
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spelling	oai:doaj.org-article:6513b5d6e98d4908b78ef9dda1bca69e2021-11-15T15:58:21ZPhase Transitions Drive the Formation of Vesicular Stomatitis Virus Replication Compartments10.1128/mBio.02290-172150-7511https://doaj.org/article/6513b5d6e98d4908b78ef9dda1bca69e2018-11-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02290-17https://doaj.org/toc/2150-7511ABSTRACT RNA viruses that replicate in the cell cytoplasm typically concentrate their replication machinery within specialized compartments. This concentration favors enzymatic reactions and shields viral RNA from detection by cytosolic pattern recognition receptors. Nonsegmented negative-strand (NNS) RNA viruses, which include some of the most significant human, animal, and plant pathogens extant, form inclusions that are sites of RNA synthesis and are not circumscribed by a membrane. These inclusions share similarities with cellular protein/RNA structures such as P granules and nucleoli, which are phase-separated liquid compartments. Here we show that replication compartments of vesicular stomatitis virus (VSV) have the properties of liquid-like compartments that form by phase separation. Expression of the individual viral components of the replication machinery in cells demonstrates that the 3 viral proteins required for replication are sufficient to drive cytoplasmic phase separation. Therefore, liquid-liquid phase separation, previously linked to organization of P granules, nucleolus homeostasis, and cell signaling, plays a key role in host-pathogen interactions. This work suggests novel therapeutic approaches to the problem of combating NNS RNA viral infections. IMPORTANCE RNA viruses compartmentalize their replication machinery to evade detection by host pattern recognition receptors and concentrate the machinery of RNA synthesis. For positive-strand RNA viruses, RNA replication occurs in a virus-induced membrane-associated replication organelle. For NNS RNA viruses, the replication compartment is a cytoplasmic inclusion that is not circumscribed by a cellular membrane. Such structures were first observed in the cell bodies of neurons from humans infected with rabies virus and were termed Negri bodies. How the replication machinery that forms this inclusion remains associated in the absence of a membrane has been an enduring mystery. In this article, we present evidence that the VSV replication compartments form through phase separation. Phase separation is increasingly recognized as responsible for cellular structures as diverse as processing bodies (P-bodies) and nucleoli and was recently demonstrated for rabies virus. This article further links the fields of host-pathogen interaction with that of phase separation.Bianca S. HeinrichZoltan MaligaDavid A. SteinAnthony A. HymanSean P. J. WhelanAmerican Society for Microbiologyarticlenegative-strand RNA virusphase separationrhabdovirusviral replicationviroplasmvirus-host interactionsMicrobiologyQR1-502ENmBio, Vol 9, Iss 5 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	negative-strand RNA virus phase separation rhabdovirus viral replication viroplasm virus-host interactions Microbiology QR1-502
spellingShingle	negative-strand RNA virus phase separation rhabdovirus viral replication viroplasm virus-host interactions Microbiology QR1-502 Bianca S. Heinrich Zoltan Maliga David A. Stein Anthony A. Hyman Sean P. J. Whelan Phase Transitions Drive the Formation of Vesicular Stomatitis Virus Replication Compartments
description	ABSTRACT RNA viruses that replicate in the cell cytoplasm typically concentrate their replication machinery within specialized compartments. This concentration favors enzymatic reactions and shields viral RNA from detection by cytosolic pattern recognition receptors. Nonsegmented negative-strand (NNS) RNA viruses, which include some of the most significant human, animal, and plant pathogens extant, form inclusions that are sites of RNA synthesis and are not circumscribed by a membrane. These inclusions share similarities with cellular protein/RNA structures such as P granules and nucleoli, which are phase-separated liquid compartments. Here we show that replication compartments of vesicular stomatitis virus (VSV) have the properties of liquid-like compartments that form by phase separation. Expression of the individual viral components of the replication machinery in cells demonstrates that the 3 viral proteins required for replication are sufficient to drive cytoplasmic phase separation. Therefore, liquid-liquid phase separation, previously linked to organization of P granules, nucleolus homeostasis, and cell signaling, plays a key role in host-pathogen interactions. This work suggests novel therapeutic approaches to the problem of combating NNS RNA viral infections. IMPORTANCE RNA viruses compartmentalize their replication machinery to evade detection by host pattern recognition receptors and concentrate the machinery of RNA synthesis. For positive-strand RNA viruses, RNA replication occurs in a virus-induced membrane-associated replication organelle. For NNS RNA viruses, the replication compartment is a cytoplasmic inclusion that is not circumscribed by a cellular membrane. Such structures were first observed in the cell bodies of neurons from humans infected with rabies virus and were termed Negri bodies. How the replication machinery that forms this inclusion remains associated in the absence of a membrane has been an enduring mystery. In this article, we present evidence that the VSV replication compartments form through phase separation. Phase separation is increasingly recognized as responsible for cellular structures as diverse as processing bodies (P-bodies) and nucleoli and was recently demonstrated for rabies virus. This article further links the fields of host-pathogen interaction with that of phase separation.
format	article
author	Bianca S. Heinrich Zoltan Maliga David A. Stein Anthony A. Hyman Sean P. J. Whelan
author_facet	Bianca S. Heinrich Zoltan Maliga David A. Stein Anthony A. Hyman Sean P. J. Whelan
author_sort	Bianca S. Heinrich
title	Phase Transitions Drive the Formation of Vesicular Stomatitis Virus Replication Compartments
title_short	Phase Transitions Drive the Formation of Vesicular Stomatitis Virus Replication Compartments
title_full	Phase Transitions Drive the Formation of Vesicular Stomatitis Virus Replication Compartments
title_fullStr	Phase Transitions Drive the Formation of Vesicular Stomatitis Virus Replication Compartments
title_full_unstemmed	Phase Transitions Drive the Formation of Vesicular Stomatitis Virus Replication Compartments
title_sort	phase transitions drive the formation of vesicular stomatitis virus replication compartments
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/6513b5d6e98d4908b78ef9dda1bca69e
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Phase Transitions Drive the Formation of Vesicular Stomatitis Virus Replication Compartments

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