Annexin A6-Balanced Late Endosomal Cholesterol Controls Influenza A Replication and Propagation

ABSTRACT Influenza is caused by influenza A virus (IAV), an enveloped, negative-stranded RNA virus that derives its envelope lipids from the host cell plasma membrane. Here, we examined the functional role of cellular cholesterol in the IAV infection cycle. We show that shifting of cellular choleste...

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Autores principales:	Agnes Musiol, Sandra Gran, Christina Ehrhardt, Stephan Ludwig, Thomas Grewal, Volker Gerke, Ursula Rescher
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2013
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/23356f7cd3f145528b52b3d8c98f50ab
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spelling	oai:doaj.org-article:23356f7cd3f145528b52b3d8c98f50ab2021-11-15T15:42:31ZAnnexin A6-Balanced Late Endosomal Cholesterol Controls Influenza A Replication and Propagation10.1128/mBio.00608-132150-7511https://doaj.org/article/23356f7cd3f145528b52b3d8c98f50ab2013-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00608-13https://doaj.org/toc/2150-7511ABSTRACT Influenza is caused by influenza A virus (IAV), an enveloped, negative-stranded RNA virus that derives its envelope lipids from the host cell plasma membrane. Here, we examined the functional role of cellular cholesterol in the IAV infection cycle. We show that shifting of cellular cholesterol pools via the Ca2+-regulated membrane-binding protein annexin A6 (AnxA6) affects the infectivity of progeny virus particles. Elevated levels of cellular AnxA6, which decrease plasma membrane and increase late endosomal cholesterol levels, impaired IAV replication and propagation, whereas RNA interference-mediated AnxA6 ablation increased viral progeny titers. Pharmacological accumulation of late endosomal cholesterol also diminished IAV virus propagation. Decreased IAV replication caused by upregulated AnxA6 expression could be restored either by exogenous replenishment of host cell cholesterol or by ectopic expression of the late endosomal cholesterol transporter Niemann-Pick C1 (NPC1). Virus released from AnxA6-overexpressing cells displayed significantly reduced cholesterol levels. Our results show that IAV replication depends on maintenance of the cellular cholesterol balance and identify AnxA6 as a critical factor in linking IAV to cellular cholesterol homeostasis. IMPORTANCE Influenza A virus (IAV) is a major public health concern, and yet, major host-pathogen interactions regulating IAV replication still remain poorly understood. It is known that host cell cholesterol is a critical factor in the influenza virus life cycle. The viral envelope is derived from the host cell membrane during the process of budding and, hence, equips the virus with a special lipid-protein mixture which is high in cholesterol. However, the influence of host cell cholesterol homeostasis on IAV infection is largely unknown. We show that IAV infection success critically depends on host cell cholesterol distribution. Cholesterol sequestration in the endosomal compartment impairs progeny titer and infectivity and is associated with reduced cholesterol content in the viral envelope.Agnes MusiolSandra GranChristina EhrhardtStephan LudwigThomas GrewalVolker GerkeUrsula RescherAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 4, Iss 6 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Agnes Musiol Sandra Gran Christina Ehrhardt Stephan Ludwig Thomas Grewal Volker Gerke Ursula Rescher Annexin A6-Balanced Late Endosomal Cholesterol Controls Influenza A Replication and Propagation
description	ABSTRACT Influenza is caused by influenza A virus (IAV), an enveloped, negative-stranded RNA virus that derives its envelope lipids from the host cell plasma membrane. Here, we examined the functional role of cellular cholesterol in the IAV infection cycle. We show that shifting of cellular cholesterol pools via the Ca2+-regulated membrane-binding protein annexin A6 (AnxA6) affects the infectivity of progeny virus particles. Elevated levels of cellular AnxA6, which decrease plasma membrane and increase late endosomal cholesterol levels, impaired IAV replication and propagation, whereas RNA interference-mediated AnxA6 ablation increased viral progeny titers. Pharmacological accumulation of late endosomal cholesterol also diminished IAV virus propagation. Decreased IAV replication caused by upregulated AnxA6 expression could be restored either by exogenous replenishment of host cell cholesterol or by ectopic expression of the late endosomal cholesterol transporter Niemann-Pick C1 (NPC1). Virus released from AnxA6-overexpressing cells displayed significantly reduced cholesterol levels. Our results show that IAV replication depends on maintenance of the cellular cholesterol balance and identify AnxA6 as a critical factor in linking IAV to cellular cholesterol homeostasis. IMPORTANCE Influenza A virus (IAV) is a major public health concern, and yet, major host-pathogen interactions regulating IAV replication still remain poorly understood. It is known that host cell cholesterol is a critical factor in the influenza virus life cycle. The viral envelope is derived from the host cell membrane during the process of budding and, hence, equips the virus with a special lipid-protein mixture which is high in cholesterol. However, the influence of host cell cholesterol homeostasis on IAV infection is largely unknown. We show that IAV infection success critically depends on host cell cholesterol distribution. Cholesterol sequestration in the endosomal compartment impairs progeny titer and infectivity and is associated with reduced cholesterol content in the viral envelope.
format	article
author	Agnes Musiol Sandra Gran Christina Ehrhardt Stephan Ludwig Thomas Grewal Volker Gerke Ursula Rescher
author_facet	Agnes Musiol Sandra Gran Christina Ehrhardt Stephan Ludwig Thomas Grewal Volker Gerke Ursula Rescher
author_sort	Agnes Musiol
title	Annexin A6-Balanced Late Endosomal Cholesterol Controls Influenza A Replication and Propagation
title_short	Annexin A6-Balanced Late Endosomal Cholesterol Controls Influenza A Replication and Propagation
title_full	Annexin A6-Balanced Late Endosomal Cholesterol Controls Influenza A Replication and Propagation
title_fullStr	Annexin A6-Balanced Late Endosomal Cholesterol Controls Influenza A Replication and Propagation
title_full_unstemmed	Annexin A6-Balanced Late Endosomal Cholesterol Controls Influenza A Replication and Propagation
title_sort	annexin a6-balanced late endosomal cholesterol controls influenza a replication and propagation
publisher	American Society for Microbiology
publishDate	2013
url	https://doaj.org/article/23356f7cd3f145528b52b3d8c98f50ab
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Annexin A6-Balanced Late Endosomal Cholesterol Controls Influenza A Replication and Propagation

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