Activation of NIX-mediated mitophagy by an interferon regulatory factor homologue of human herpesvirus

Mai Tram Vo; Barbara J. Smith; John Nicholas; Young Bong Choi

doi:10.1038/s41467-019-11164-2

Activation of NIX-mediated mitophagy by an interferon regulatory factor homologue of human herpesvirus

Mai Tram Vo, Barbara J. Smith, John Nicholas, Young Bong Choi

School of Medicine

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

Abstract

Viral control of mitochondrial quality and content has emerged as an important mechanism for counteracting the host response to virus infection. Despite the knowledge of this crucial function of some viruses, little is known about how herpesviruses regulate mitochondrial homeostasis during infection. Human herpesvirus 8 (HHV-8) is an oncogenic virus causally related to AIDS-associated malignancies. Here, we show that HHV-8-encoded viral interferon regulatory factor 1 (vIRF-1) promotes mitochondrial clearance by activating mitophagy to support virus replication. Genetic interference with vIRF-1 expression or targeting to the mitochondria inhibits HHV-8 replication-induced mitophagy and leads to an accumulation of mitochondria. Moreover, vIRF-1 binds directly to a mitophagy receptor, NIX, on the mitochondria and activates NIX-mediated mitophagy to promote mitochondrial clearance. Genetic and pharmacological interruption of vIRF-1/NIX-activated mitophagy inhibits HHV-8 productive replication. Our findings uncover an essential role of vIRF-1 in mitophagy activation and promotion of HHV-8 lytic replication via this mechanism.

Original language	English (US)
Article number	3203
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-11164-2
State	Published - Dec 1 2019

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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title = "Activation of NIX-mediated mitophagy by an interferon regulatory factor homologue of human herpesvirus",

abstract = "Viral control of mitochondrial quality and content has emerged as an important mechanism for counteracting the host response to virus infection. Despite the knowledge of this crucial function of some viruses, little is known about how herpesviruses regulate mitochondrial homeostasis during infection. Human herpesvirus 8 (HHV-8) is an oncogenic virus causally related to AIDS-associated malignancies. Here, we show that HHV-8-encoded viral interferon regulatory factor 1 (vIRF-1) promotes mitochondrial clearance by activating mitophagy to support virus replication. Genetic interference with vIRF-1 expression or targeting to the mitochondria inhibits HHV-8 replication-induced mitophagy and leads to an accumulation of mitochondria. Moreover, vIRF-1 binds directly to a mitophagy receptor, NIX, on the mitochondria and activates NIX-mediated mitophagy to promote mitochondrial clearance. Genetic and pharmacological interruption of vIRF-1/NIX-activated mitophagy inhibits HHV-8 productive replication. Our findings uncover an essential role of vIRF-1 in mitophagy activation and promotion of HHV-8 lytic replication via this mechanism.",

author = "Vo, {Mai Tram} and Smith, {Barbara J.} and John Nicholas and Choi, {Young Bong}",

note = "Funding Information: We thank Dr. Edward Harhaj for critical reading of this manuscript. This work was supported by National Cancer Institute (NCI) grant R01CA214131 to Y.B.C. and by National Institute of Allergy and Infectious Diseases (NIAID) grant R21Al117168 to Y.B. C. The Sidney Kimmel Cancer Center Flow Cytometry core facility, used for particular aspects of the study, is supported by Cancer Center Grant NCI CCSG P30 CA006973. This research was funded in part by a 2016-2017 developmental grant to Y.B.C. from the Johns Hopkins University Center for AIDS Research, funded by NIH program grant P30AI094189, and an NIH Shared Instrumentation grant (S10OD016374 to the JHU Microscope Facility). Publisher Copyright: {\textcopyright} 2019, The Author(s).",

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AU - Nicholas, John

AU - Choi, Young Bong

N1 - Funding Information: We thank Dr. Edward Harhaj for critical reading of this manuscript. This work was supported by National Cancer Institute (NCI) grant R01CA214131 to Y.B.C. and by National Institute of Allergy and Infectious Diseases (NIAID) grant R21Al117168 to Y.B. C. The Sidney Kimmel Cancer Center Flow Cytometry core facility, used for particular aspects of the study, is supported by Cancer Center Grant NCI CCSG P30 CA006973. This research was funded in part by a 2016-2017 developmental grant to Y.B.C. from the Johns Hopkins University Center for AIDS Research, funded by NIH program grant P30AI094189, and an NIH Shared Instrumentation grant (S10OD016374 to the JHU Microscope Facility). Publisher Copyright: © 2019, The Author(s).

PY - 2019/12/1

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N2 - Viral control of mitochondrial quality and content has emerged as an important mechanism for counteracting the host response to virus infection. Despite the knowledge of this crucial function of some viruses, little is known about how herpesviruses regulate mitochondrial homeostasis during infection. Human herpesvirus 8 (HHV-8) is an oncogenic virus causally related to AIDS-associated malignancies. Here, we show that HHV-8-encoded viral interferon regulatory factor 1 (vIRF-1) promotes mitochondrial clearance by activating mitophagy to support virus replication. Genetic interference with vIRF-1 expression or targeting to the mitochondria inhibits HHV-8 replication-induced mitophagy and leads to an accumulation of mitochondria. Moreover, vIRF-1 binds directly to a mitophagy receptor, NIX, on the mitochondria and activates NIX-mediated mitophagy to promote mitochondrial clearance. Genetic and pharmacological interruption of vIRF-1/NIX-activated mitophagy inhibits HHV-8 productive replication. Our findings uncover an essential role of vIRF-1 in mitophagy activation and promotion of HHV-8 lytic replication via this mechanism.

AB - Viral control of mitochondrial quality and content has emerged as an important mechanism for counteracting the host response to virus infection. Despite the knowledge of this crucial function of some viruses, little is known about how herpesviruses regulate mitochondrial homeostasis during infection. Human herpesvirus 8 (HHV-8) is an oncogenic virus causally related to AIDS-associated malignancies. Here, we show that HHV-8-encoded viral interferon regulatory factor 1 (vIRF-1) promotes mitochondrial clearance by activating mitophagy to support virus replication. Genetic interference with vIRF-1 expression or targeting to the mitochondria inhibits HHV-8 replication-induced mitophagy and leads to an accumulation of mitochondria. Moreover, vIRF-1 binds directly to a mitophagy receptor, NIX, on the mitochondria and activates NIX-mediated mitophagy to promote mitochondrial clearance. Genetic and pharmacological interruption of vIRF-1/NIX-activated mitophagy inhibits HHV-8 productive replication. Our findings uncover an essential role of vIRF-1 in mitophagy activation and promotion of HHV-8 lytic replication via this mechanism.

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Activation of NIX-mediated mitophagy by an interferon regulatory factor homologue of human herpesvirus

Abstract

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