A gammaherpesvirus complement regulatory protein promotes initiation of infection by activation of protein kinase Akt/PKB.

<h4>Background</h4>Viruses have evolved to evade the host's complement system. The open reading frames 4 (ORF4) of gammaherpesviruses encode homologs of regulators of complement activation (RCA) proteins, which inhibit complement activation at the level of C3 and C4 deposition. Besi...

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Autores principales:	Beatrix Steer, Barbara Adler, Stipan Jonjic, James P Stewart, Heiko Adler
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a1acac407f004e75b28c4940117bd50d
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spelling	oai:doaj.org-article:a1acac407f004e75b28c4940117bd50d2021-12-02T20:19:54ZA gammaherpesvirus complement regulatory protein promotes initiation of infection by activation of protein kinase Akt/PKB.1932-620310.1371/journal.pone.0011672https://doaj.org/article/a1acac407f004e75b28c4940117bd50d2010-07-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20657771/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>Viruses have evolved to evade the host's complement system. The open reading frames 4 (ORF4) of gammaherpesviruses encode homologs of regulators of complement activation (RCA) proteins, which inhibit complement activation at the level of C3 and C4 deposition. Besides complement regulation, these proteins are involved in heparan sulfate and glycosaminoglycan binding, and in case of MHV-68, also in viral DNA synthesis in macrophages.<h4>Methodology/principal findings</h4>Here, we made use of MHV-68 to study the role of ORF4 during infection of fibroblasts. While attachment and penetration of virions lacking the RCA protein were not affected, we observed a delayed delivery of the viral genome to the nucleus of infected cells. Analysis of the phosphorylation status of a variety of kinases revealed a significant reduction in phosphorylation of the protein kinase Akt in cells infected with ORF4 mutant virus, when compared to cells infected with wt virus. Consistent with a role of Akt activation in initial stages of infection, inhibition of Akt signaling in wt virus infected cells resulted in a phenotype resembling the phenotype of the ORF4 mutant virus, and activation of Akt by addition of insulin partially reversed the phenotype of the ORF4 mutant virus. Importantly, the homologous ORF4 of KSHV was able to rescue the phenotype of the MHV-68 ORF4 mutant, indicating that ORF4 is functionally conserved and that ORF4 of KSHV might have a similar function in infection initiation.<h4>Conclusions/significance</h4>In summary, our studies demonstrate that ORF4 contributes to efficient infection by activation of the protein kinase Akt and thus reveal a novel function of a gammaherpesvirus RCA protein.Beatrix SteerBarbara AdlerStipan JonjicJames P StewartHeiko AdlerPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 5, Iss 7, p e11672 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Beatrix Steer Barbara Adler Stipan Jonjic James P Stewart Heiko Adler A gammaherpesvirus complement regulatory protein promotes initiation of infection by activation of protein kinase Akt/PKB.
description	<h4>Background</h4>Viruses have evolved to evade the host's complement system. The open reading frames 4 (ORF4) of gammaherpesviruses encode homologs of regulators of complement activation (RCA) proteins, which inhibit complement activation at the level of C3 and C4 deposition. Besides complement regulation, these proteins are involved in heparan sulfate and glycosaminoglycan binding, and in case of MHV-68, also in viral DNA synthesis in macrophages.<h4>Methodology/principal findings</h4>Here, we made use of MHV-68 to study the role of ORF4 during infection of fibroblasts. While attachment and penetration of virions lacking the RCA protein were not affected, we observed a delayed delivery of the viral genome to the nucleus of infected cells. Analysis of the phosphorylation status of a variety of kinases revealed a significant reduction in phosphorylation of the protein kinase Akt in cells infected with ORF4 mutant virus, when compared to cells infected with wt virus. Consistent with a role of Akt activation in initial stages of infection, inhibition of Akt signaling in wt virus infected cells resulted in a phenotype resembling the phenotype of the ORF4 mutant virus, and activation of Akt by addition of insulin partially reversed the phenotype of the ORF4 mutant virus. Importantly, the homologous ORF4 of KSHV was able to rescue the phenotype of the MHV-68 ORF4 mutant, indicating that ORF4 is functionally conserved and that ORF4 of KSHV might have a similar function in infection initiation.<h4>Conclusions/significance</h4>In summary, our studies demonstrate that ORF4 contributes to efficient infection by activation of the protein kinase Akt and thus reveal a novel function of a gammaherpesvirus RCA protein.
format	article
author	Beatrix Steer Barbara Adler Stipan Jonjic James P Stewart Heiko Adler
author_facet	Beatrix Steer Barbara Adler Stipan Jonjic James P Stewart Heiko Adler
author_sort	Beatrix Steer
title	A gammaherpesvirus complement regulatory protein promotes initiation of infection by activation of protein kinase Akt/PKB.
title_short	A gammaherpesvirus complement regulatory protein promotes initiation of infection by activation of protein kinase Akt/PKB.
title_full	A gammaherpesvirus complement regulatory protein promotes initiation of infection by activation of protein kinase Akt/PKB.
title_fullStr	A gammaherpesvirus complement regulatory protein promotes initiation of infection by activation of protein kinase Akt/PKB.
title_full_unstemmed	A gammaherpesvirus complement regulatory protein promotes initiation of infection by activation of protein kinase Akt/PKB.
title_sort	gammaherpesvirus complement regulatory protein promotes initiation of infection by activation of protein kinase akt/pkb.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/a1acac407f004e75b28c4940117bd50d
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A gammaherpesvirus complement regulatory protein promotes initiation of infection by activation of protein kinase Akt/PKB.

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