Human Cytomegalovirus Infection Upregulates the Mitochondrial Transcription and Translation Machineries

ABSTRACT Infection with human cytomegalovirus (HCMV) profoundly affects cellular metabolism. Like in tumor cells, HCMV infection increases glycolysis, and glucose carbon is shifted from the mitochondrial tricarboxylic acid cycle to the biosynthesis of fatty acids. However, unlike in many tumor cells...

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Autores principales:	S. Karniely, M. P. Weekes, R. Antrobus, J. Rorbach, L. van Haute, Y. Umrania, D. L. Smith, R. J. Stanton, M. Minczuk, P. J. Lehner, J. H. Sinclair
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Lenguaje:	EN
Publicado:	American Society for Microbiology 2016
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/562645d9a5af495c9902557cb328f688
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spelling	oai:doaj.org-article:562645d9a5af495c9902557cb328f6882021-11-15T15:41:41ZHuman Cytomegalovirus Infection Upregulates the Mitochondrial Transcription and Translation Machineries10.1128/mBio.00029-162150-7511https://doaj.org/article/562645d9a5af495c9902557cb328f6882016-05-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00029-16https://doaj.org/toc/2150-7511ABSTRACT Infection with human cytomegalovirus (HCMV) profoundly affects cellular metabolism. Like in tumor cells, HCMV infection increases glycolysis, and glucose carbon is shifted from the mitochondrial tricarboxylic acid cycle to the biosynthesis of fatty acids. However, unlike in many tumor cells, where aerobic glycolysis is accompanied by suppression of mitochondrial oxidative phosphorylation, HCMV induces mitochondrial biogenesis and respiration. Here, we affinity purified mitochondria and used quantitative mass spectrometry to determine how the mitochondrial proteome changes upon HCMV infection. We found that the mitochondrial transcription and translation systems are induced early during the viral replication cycle. Specifically, proteins involved in biogenesis of the mitochondrial ribosome were highly upregulated by HCMV infection. Inhibition of mitochondrial translation with chloramphenicol or knockdown of HCMV-induced ribosome biogenesis factor MRM3 abolished the HCMV-mediated increase in mitochondrially encoded proteins and significantly impaired viral growth under bioenergetically restricting conditions. Our findings demonstrate how HCMV manipulates mitochondrial biogenesis to support its replication. IMPORTANCE Human cytomegalovirus (HCMV), a betaherpesvirus, is a leading cause of morbidity and mortality during congenital infection and among immunosuppressed individuals. HCMV infection significantly changes cellular metabolism. Akin to tumor cells, in HCMV-infected cells, glycolysis is increased and glucose carbon is shifted from the tricarboxylic acid cycle to fatty acid biosynthesis. However, unlike in tumor cells, HCMV induces mitochondrial biogenesis even under aerobic glycolysis. Here, we have affinity purified mitochondria and used quantitative mass spectrometry to determine how the mitochondrial proteome changes upon HCMV infection. We find that the mitochondrial transcription and translation systems are induced early during the viral replication cycle. Specifically, proteins involved in biogenesis of the mitochondrial ribosome were highly upregulated by HCMV infection. Inhibition of mitochondrial translation with chloramphenicol or knockdown of HCMV-induced ribosome biogenesis factor MRM3 abolished the HCMV-mediated increase in mitochondrially encoded proteins and significantly impaired viral growth. Our findings demonstrate how HCMV manipulates mitochondrial biogenesis to support its replication.S. KarnielyM. P. WeekesR. AntrobusJ. RorbachL. van HauteY. UmraniaD. L. SmithR. J. StantonM. MinczukP. J. LehnerJ. H. SinclairAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 7, Iss 2 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 S. Karniely M. P. Weekes R. Antrobus J. Rorbach L. van Haute Y. Umrania D. L. Smith R. J. Stanton M. Minczuk P. J. Lehner J. H. Sinclair Human Cytomegalovirus Infection Upregulates the Mitochondrial Transcription and Translation Machineries
description	ABSTRACT Infection with human cytomegalovirus (HCMV) profoundly affects cellular metabolism. Like in tumor cells, HCMV infection increases glycolysis, and glucose carbon is shifted from the mitochondrial tricarboxylic acid cycle to the biosynthesis of fatty acids. However, unlike in many tumor cells, where aerobic glycolysis is accompanied by suppression of mitochondrial oxidative phosphorylation, HCMV induces mitochondrial biogenesis and respiration. Here, we affinity purified mitochondria and used quantitative mass spectrometry to determine how the mitochondrial proteome changes upon HCMV infection. We found that the mitochondrial transcription and translation systems are induced early during the viral replication cycle. Specifically, proteins involved in biogenesis of the mitochondrial ribosome were highly upregulated by HCMV infection. Inhibition of mitochondrial translation with chloramphenicol or knockdown of HCMV-induced ribosome biogenesis factor MRM3 abolished the HCMV-mediated increase in mitochondrially encoded proteins and significantly impaired viral growth under bioenergetically restricting conditions. Our findings demonstrate how HCMV manipulates mitochondrial biogenesis to support its replication. IMPORTANCE Human cytomegalovirus (HCMV), a betaherpesvirus, is a leading cause of morbidity and mortality during congenital infection and among immunosuppressed individuals. HCMV infection significantly changes cellular metabolism. Akin to tumor cells, in HCMV-infected cells, glycolysis is increased and glucose carbon is shifted from the tricarboxylic acid cycle to fatty acid biosynthesis. However, unlike in tumor cells, HCMV induces mitochondrial biogenesis even under aerobic glycolysis. Here, we have affinity purified mitochondria and used quantitative mass spectrometry to determine how the mitochondrial proteome changes upon HCMV infection. We find that the mitochondrial transcription and translation systems are induced early during the viral replication cycle. Specifically, proteins involved in biogenesis of the mitochondrial ribosome were highly upregulated by HCMV infection. Inhibition of mitochondrial translation with chloramphenicol or knockdown of HCMV-induced ribosome biogenesis factor MRM3 abolished the HCMV-mediated increase in mitochondrially encoded proteins and significantly impaired viral growth. Our findings demonstrate how HCMV manipulates mitochondrial biogenesis to support its replication.
format	article
author	S. Karniely M. P. Weekes R. Antrobus J. Rorbach L. van Haute Y. Umrania D. L. Smith R. J. Stanton M. Minczuk P. J. Lehner J. H. Sinclair
author_facet	S. Karniely M. P. Weekes R. Antrobus J. Rorbach L. van Haute Y. Umrania D. L. Smith R. J. Stanton M. Minczuk P. J. Lehner J. H. Sinclair
author_sort	S. Karniely
title	Human Cytomegalovirus Infection Upregulates the Mitochondrial Transcription and Translation Machineries
title_short	Human Cytomegalovirus Infection Upregulates the Mitochondrial Transcription and Translation Machineries
title_full	Human Cytomegalovirus Infection Upregulates the Mitochondrial Transcription and Translation Machineries
title_fullStr	Human Cytomegalovirus Infection Upregulates the Mitochondrial Transcription and Translation Machineries
title_full_unstemmed	Human Cytomegalovirus Infection Upregulates the Mitochondrial Transcription and Translation Machineries
title_sort	human cytomegalovirus infection upregulates the mitochondrial transcription and translation machineries
publisher	American Society for Microbiology
publishDate	2016
url	https://doaj.org/article/562645d9a5af495c9902557cb328f688
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Human Cytomegalovirus Infection Upregulates the Mitochondrial Transcription and Translation Machineries

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