Granzyme B inhibits vaccinia virus production through proteolytic cleavage of eukaryotic initiation factor 4 gamma 3.

Cytotoxic T lymphocytes (CTLs) are the major killer of virus-infected cells. Granzyme B (GrB) from CTLs induces apoptosis in target cells by cleavage and activation of substrates like caspase-3 and Bid. However, while undergoing apoptosis, cells are still capable of producing infectious viruses unle...

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Autores principales:	Marcelo Marcet-Palacios, Brenda Lee Duggan, Irene Shostak, Michele Barry, Tracy Geskes, John A Wilkins, Akiko Yanagiya, Nahum Sonenberg, R Chris Bleackley
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/e62d452e261744aab8febc051a25e5bf
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spelling	oai:doaj.org-article:e62d452e261744aab8febc051a25e5bf2021-11-18T06:04:57ZGranzyme B inhibits vaccinia virus production through proteolytic cleavage of eukaryotic initiation factor 4 gamma 3.1553-73661553-737410.1371/journal.ppat.1002447https://doaj.org/article/e62d452e261744aab8febc051a25e5bf2011-12-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22194691/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Cytotoxic T lymphocytes (CTLs) are the major killer of virus-infected cells. Granzyme B (GrB) from CTLs induces apoptosis in target cells by cleavage and activation of substrates like caspase-3 and Bid. However, while undergoing apoptosis, cells are still capable of producing infectious viruses unless a mechanism exists to specifically inhibit viral production. Using proteomic approaches, we identified a novel GrB target that plays a major role in protein synthesis: eukaryotic initiation factor 4 gamma 3 (eIF4G3). We hypothesized a novel role for GrB in translation of viral proteins by targeting eIF4G3, and showed that GrB cleaves eIF4G3 specifically at the IESD(1408)S sequence. Both GrB and human CTL treatment resulted in degradation of eIF4G3 and reduced rates of translation. When Jurkat cells infected with vaccinia virus were treated with GrB, there was a halt in viral protein synthesis and a decrease in production of infectious new virions. The GrB-induced inhibition of viral translation was independent of the activation of caspases, as inhibition of protein synthesis still occurred with addition of the pan-caspase inhibitor zVAD-fmk. This demonstrated for the first time that GrB prevents the production of infectious vaccinia virus by targeting the host translational machinery.Marcelo Marcet-PalaciosBrenda Lee DugganIrene ShostakMichele BarryTracy GeskesJohn A WilkinsAkiko YanagiyaNahum SonenbergR Chris BleackleyPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 7, Iss 12, p e1002447 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Marcelo Marcet-Palacios Brenda Lee Duggan Irene Shostak Michele Barry Tracy Geskes John A Wilkins Akiko Yanagiya Nahum Sonenberg R Chris Bleackley Granzyme B inhibits vaccinia virus production through proteolytic cleavage of eukaryotic initiation factor 4 gamma 3.
description	Cytotoxic T lymphocytes (CTLs) are the major killer of virus-infected cells. Granzyme B (GrB) from CTLs induces apoptosis in target cells by cleavage and activation of substrates like caspase-3 and Bid. However, while undergoing apoptosis, cells are still capable of producing infectious viruses unless a mechanism exists to specifically inhibit viral production. Using proteomic approaches, we identified a novel GrB target that plays a major role in protein synthesis: eukaryotic initiation factor 4 gamma 3 (eIF4G3). We hypothesized a novel role for GrB in translation of viral proteins by targeting eIF4G3, and showed that GrB cleaves eIF4G3 specifically at the IESD(1408)S sequence. Both GrB and human CTL treatment resulted in degradation of eIF4G3 and reduced rates of translation. When Jurkat cells infected with vaccinia virus were treated with GrB, there was a halt in viral protein synthesis and a decrease in production of infectious new virions. The GrB-induced inhibition of viral translation was independent of the activation of caspases, as inhibition of protein synthesis still occurred with addition of the pan-caspase inhibitor zVAD-fmk. This demonstrated for the first time that GrB prevents the production of infectious vaccinia virus by targeting the host translational machinery.
format	article
author	Marcelo Marcet-Palacios Brenda Lee Duggan Irene Shostak Michele Barry Tracy Geskes John A Wilkins Akiko Yanagiya Nahum Sonenberg R Chris Bleackley
author_facet	Marcelo Marcet-Palacios Brenda Lee Duggan Irene Shostak Michele Barry Tracy Geskes John A Wilkins Akiko Yanagiya Nahum Sonenberg R Chris Bleackley
author_sort	Marcelo Marcet-Palacios
title	Granzyme B inhibits vaccinia virus production through proteolytic cleavage of eukaryotic initiation factor 4 gamma 3.
title_short	Granzyme B inhibits vaccinia virus production through proteolytic cleavage of eukaryotic initiation factor 4 gamma 3.
title_full	Granzyme B inhibits vaccinia virus production through proteolytic cleavage of eukaryotic initiation factor 4 gamma 3.
title_fullStr	Granzyme B inhibits vaccinia virus production through proteolytic cleavage of eukaryotic initiation factor 4 gamma 3.
title_full_unstemmed	Granzyme B inhibits vaccinia virus production through proteolytic cleavage of eukaryotic initiation factor 4 gamma 3.
title_sort	granzyme b inhibits vaccinia virus production through proteolytic cleavage of eukaryotic initiation factor 4 gamma 3.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/e62d452e261744aab8febc051a25e5bf
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Granzyme B inhibits vaccinia virus production through proteolytic cleavage of eukaryotic initiation factor 4 gamma 3.

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