Virus Control of Trafficking from Sorting Endosomes

ABSTRACT The maintenance of cell surface proteins is critical to the ability of a cell to sense and respond to information in its environment. As such, modulation of cell surface composition and receptor trafficking is a potentially important target of control in virus infection. Sorting endosomes (...

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Autores principales:	Sebastian Zeltzer, Carol A. Zeltzer, Suzu Igarashi, Jean Wilson, Julie G. Donaldson, Felicia Goodrum
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	ARF6 TRE17 USP6 cytomegalovirus endocytic trafficking endosomes Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/573a9dae25924d1fb9b99a983ff9ce7e
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spelling	oai:doaj.org-article:573a9dae25924d1fb9b99a983ff9ce7e2021-11-15T16:00:14ZVirus Control of Trafficking from Sorting Endosomes10.1128/mBio.00683-182150-7511https://doaj.org/article/573a9dae25924d1fb9b99a983ff9ce7e2018-09-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00683-18https://doaj.org/toc/2150-7511ABSTRACT The maintenance of cell surface proteins is critical to the ability of a cell to sense and respond to information in its environment. As such, modulation of cell surface composition and receptor trafficking is a potentially important target of control in virus infection. Sorting endosomes (SEs) are control stations regulating the recycling or degradation of internalized plasma membrane proteins. Here we report that human cytomegalovirus (HCMV), a ubiquitous betaherpesvirus, alters the fate of internalized clathrin-independent endocytosis (CIE) cargo proteins, retaining them in virally reprogrammed SEs. We show that the small G protein ARF6 (ADP ribosylation factor 6), a regulator of CIE trafficking, is highly associated with SE membranes relative to uninfected cells. Combined with the observation of accumulated CIE cargo at the SE, these results suggest that infection diminishes the egress of ARF6 and its cargo from the SE. Expression of ubiquitin-specific protease 6 (USP6), also known as TRE17, was sufficient to restore ARF6 and some ARF6 cargo trafficking to the cell surface in infected cells. The USP activity of TRE17 was required to rescue both ARF6 and associated cargo from SE retention in infection. The finding that TRE17 expression does not rescue the trafficking of all CIE cargos retained at SEs in infection suggests that HCMV hijacks the normal sorting machinery and selectively sorts specific cargos into endocytic microdomains that are subject to alternative sorting fates. IMPORTANCE Cells maintain their surface composition, take up nutrients, and respond to their environment through the internalization and recycling of cargo at the cell surface through endocytic trafficking pathways. During infection with human cytomegalovirus (HCMV), host endocytic membranes are reorganized into a juxtanuclear structure associated with viral assembly and egress. Less appreciated is the effect of this reorganization on the trafficking of host proteins through the endocytic pathway. We show that HCMV retains internalized cargo and the effector of clathrin-independent endocytosis at sorting endosomes. The retention of some cargo, but not all, was reversed by overexpression of a ubiquitin-specific protease, TRE17. Our results demonstrate that HCMV induces profound reprogramming of endocytic trafficking and influences cargo sorting decisions. Further, our work suggests the presence of a novel ubiquitin-regulated checkpoint for the recycling of cargo from sorting endosome. These findings have important implications for host signaling and immune pathways in the context of HCMV infection.Sebastian ZeltzerCarol A. ZeltzerSuzu IgarashiJean WilsonJulie G. DonaldsonFelicia GoodrumAmerican Society for MicrobiologyarticleARF6TRE17USP6cytomegalovirusendocytic traffickingendosomesMicrobiologyQR1-502ENmBio, Vol 9, Iss 4 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	ARF6 TRE17 USP6 cytomegalovirus endocytic trafficking endosomes Microbiology QR1-502
spellingShingle	ARF6 TRE17 USP6 cytomegalovirus endocytic trafficking endosomes Microbiology QR1-502 Sebastian Zeltzer Carol A. Zeltzer Suzu Igarashi Jean Wilson Julie G. Donaldson Felicia Goodrum Virus Control of Trafficking from Sorting Endosomes
description	ABSTRACT The maintenance of cell surface proteins is critical to the ability of a cell to sense and respond to information in its environment. As such, modulation of cell surface composition and receptor trafficking is a potentially important target of control in virus infection. Sorting endosomes (SEs) are control stations regulating the recycling or degradation of internalized plasma membrane proteins. Here we report that human cytomegalovirus (HCMV), a ubiquitous betaherpesvirus, alters the fate of internalized clathrin-independent endocytosis (CIE) cargo proteins, retaining them in virally reprogrammed SEs. We show that the small G protein ARF6 (ADP ribosylation factor 6), a regulator of CIE trafficking, is highly associated with SE membranes relative to uninfected cells. Combined with the observation of accumulated CIE cargo at the SE, these results suggest that infection diminishes the egress of ARF6 and its cargo from the SE. Expression of ubiquitin-specific protease 6 (USP6), also known as TRE17, was sufficient to restore ARF6 and some ARF6 cargo trafficking to the cell surface in infected cells. The USP activity of TRE17 was required to rescue both ARF6 and associated cargo from SE retention in infection. The finding that TRE17 expression does not rescue the trafficking of all CIE cargos retained at SEs in infection suggests that HCMV hijacks the normal sorting machinery and selectively sorts specific cargos into endocytic microdomains that are subject to alternative sorting fates. IMPORTANCE Cells maintain their surface composition, take up nutrients, and respond to their environment through the internalization and recycling of cargo at the cell surface through endocytic trafficking pathways. During infection with human cytomegalovirus (HCMV), host endocytic membranes are reorganized into a juxtanuclear structure associated with viral assembly and egress. Less appreciated is the effect of this reorganization on the trafficking of host proteins through the endocytic pathway. We show that HCMV retains internalized cargo and the effector of clathrin-independent endocytosis at sorting endosomes. The retention of some cargo, but not all, was reversed by overexpression of a ubiquitin-specific protease, TRE17. Our results demonstrate that HCMV induces profound reprogramming of endocytic trafficking and influences cargo sorting decisions. Further, our work suggests the presence of a novel ubiquitin-regulated checkpoint for the recycling of cargo from sorting endosome. These findings have important implications for host signaling and immune pathways in the context of HCMV infection.
format	article
author	Sebastian Zeltzer Carol A. Zeltzer Suzu Igarashi Jean Wilson Julie G. Donaldson Felicia Goodrum
author_facet	Sebastian Zeltzer Carol A. Zeltzer Suzu Igarashi Jean Wilson Julie G. Donaldson Felicia Goodrum
author_sort	Sebastian Zeltzer
title	Virus Control of Trafficking from Sorting Endosomes
title_short	Virus Control of Trafficking from Sorting Endosomes
title_full	Virus Control of Trafficking from Sorting Endosomes
title_fullStr	Virus Control of Trafficking from Sorting Endosomes
title_full_unstemmed	Virus Control of Trafficking from Sorting Endosomes
title_sort	virus control of trafficking from sorting endosomes
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/573a9dae25924d1fb9b99a983ff9ce7e
work_keys_str_mv	AT sebastianzeltzer viruscontroloftraffickingfromsortingendosomes AT carolazeltzer viruscontroloftraffickingfromsortingendosomes AT suzuigarashi viruscontroloftraffickingfromsortingendosomes AT jeanwilson viruscontroloftraffickingfromsortingendosomes AT juliegdonaldson viruscontroloftraffickingfromsortingendosomes AT feliciagoodrum viruscontroloftraffickingfromsortingendosomes
_version_	1718426967105077248

Virus Control of Trafficking from Sorting Endosomes

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