Hepatitis C Virus Infection Induces Hepatic Expression of NF-κB-Inducing Kinase and Lipogenesis by Downregulating miR-122

ABSTRACT Hepatitis C virus (HCV) harnesses host dependencies to infect human hepatocytes. We previously identified a pivotal role of IκB kinase α (IKK-α) in regulating cellular lipogenesis and HCV assembly. In this study, we defined and characterized NF-κB-inducing kinase (NIK) as an IKK-α upstream...

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Autores principales:	Brianna Lowey, Laura Hertz, Stephan Chiu, Kristin Valdez, Qisheng Li, T. Jake Liang
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	cell signaling hepatic inflammation lipid synthesis microRNA viral pathogenesis Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/e59efabd77914dc6b864d606912cfb20
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spelling	oai:doaj.org-article:e59efabd77914dc6b864d606912cfb202021-11-15T16:22:10ZHepatitis C Virus Infection Induces Hepatic Expression of NF-κB-Inducing Kinase and Lipogenesis by Downregulating miR-12210.1128/mBio.01617-192150-7511https://doaj.org/article/e59efabd77914dc6b864d606912cfb202019-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01617-19https://doaj.org/toc/2150-7511ABSTRACT Hepatitis C virus (HCV) harnesses host dependencies to infect human hepatocytes. We previously identified a pivotal role of IκB kinase α (IKK-α) in regulating cellular lipogenesis and HCV assembly. In this study, we defined and characterized NF-κB-inducing kinase (NIK) as an IKK-α upstream serine/threonine kinase in IKK-α-mediated proviral effects and the mechanism whereby HCV exploits this innate pathway to its advantage. We manipulated NIK expression in Huh7.5.1 cells through loss- and gain-of-function approaches and examined the effects on IKK-α activation, cellular lipid metabolism, and viral assembly. We demonstrated that NIK interacts with IKK-α to form a kinase complex in association with the stress granules, in which IKK-α is phosphorylated upon HCV infection. Depletion of NIK significantly diminished cytosolic lipid droplet content and impaired HCV particle production. NIK overexpression enhanced HCV assembly, and this process was abrogated in cells deprived of IKK-α, suggesting that NIK acts upstream of IKK-α. NIK abundance was increased in HCV-infected hepatocytes, liver tissues from Alb-uPA/Scid mice engrafted with human hepatocytes, and chronic hepatitis C patients. NIK mRNA contains an miR-122 seed sequence binding site in the 3′ untranslated region (UTR). miR-122 mimic and hairpin inhibitor directly affected NIK levels. In our hepatic models, miR-122 levels were significantly reduced by HCV infection. We demonstrated that HNF4A, a known transcriptional regulator of pri-miR-122, was downregulated by HCV infection. NIK represents a bona fide target of miR-122 whose transcription is downregulated by HCV through reduced HNF4A expression. This effect, together with the sequestering of miR-122 by HCV replication, results in “derepression” of NIK expression to deregulate lipid metabolism. IMPORTANCE Chronic hepatitis C virus (HCV) infection is a major global public health problem. Infection often leads to severe liver injury that may progress to cirrhosis, hepatocellular carcinoma, and death. HCV coopts cellular machineries for propagation and triggers pathological processes in the liver. We previously identified a pivotal role of IKK-α in regulating cellular lipid metabolism and HCV assembly. In this study, we characterized NIK as acting upstream of IKK-α and characterized how HCV exploits this innate pathway to its advantage. Through extensive mechanistic studies, we demonstrated that NIK is a direct target of miR-122, which is regulated at the transcription level by HNF4A, a hepatocyte-specific transcription factor. We show in HCV infection that NIK expression is increased while both HNF4A and miR-122 levels are decreased. NIK represents an important host dependency that links HCV assembly, hepatic lipogenesis, and miRNA biology.Brianna LoweyLaura HertzStephan ChiuKristin ValdezQisheng LiT. Jake LiangAmerican Society for Microbiologyarticlecell signalinghepatic inflammationlipid synthesismicroRNAviral pathogenesisMicrobiologyQR1-502ENmBio, Vol 10, Iss 4 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	cell signaling hepatic inflammation lipid synthesis microRNA viral pathogenesis Microbiology QR1-502
spellingShingle	cell signaling hepatic inflammation lipid synthesis microRNA viral pathogenesis Microbiology QR1-502 Brianna Lowey Laura Hertz Stephan Chiu Kristin Valdez Qisheng Li T. Jake Liang Hepatitis C Virus Infection Induces Hepatic Expression of NF-κB-Inducing Kinase and Lipogenesis by Downregulating miR-122
description	ABSTRACT Hepatitis C virus (HCV) harnesses host dependencies to infect human hepatocytes. We previously identified a pivotal role of IκB kinase α (IKK-α) in regulating cellular lipogenesis and HCV assembly. In this study, we defined and characterized NF-κB-inducing kinase (NIK) as an IKK-α upstream serine/threonine kinase in IKK-α-mediated proviral effects and the mechanism whereby HCV exploits this innate pathway to its advantage. We manipulated NIK expression in Huh7.5.1 cells through loss- and gain-of-function approaches and examined the effects on IKK-α activation, cellular lipid metabolism, and viral assembly. We demonstrated that NIK interacts with IKK-α to form a kinase complex in association with the stress granules, in which IKK-α is phosphorylated upon HCV infection. Depletion of NIK significantly diminished cytosolic lipid droplet content and impaired HCV particle production. NIK overexpression enhanced HCV assembly, and this process was abrogated in cells deprived of IKK-α, suggesting that NIK acts upstream of IKK-α. NIK abundance was increased in HCV-infected hepatocytes, liver tissues from Alb-uPA/Scid mice engrafted with human hepatocytes, and chronic hepatitis C patients. NIK mRNA contains an miR-122 seed sequence binding site in the 3′ untranslated region (UTR). miR-122 mimic and hairpin inhibitor directly affected NIK levels. In our hepatic models, miR-122 levels were significantly reduced by HCV infection. We demonstrated that HNF4A, a known transcriptional regulator of pri-miR-122, was downregulated by HCV infection. NIK represents a bona fide target of miR-122 whose transcription is downregulated by HCV through reduced HNF4A expression. This effect, together with the sequestering of miR-122 by HCV replication, results in “derepression” of NIK expression to deregulate lipid metabolism. IMPORTANCE Chronic hepatitis C virus (HCV) infection is a major global public health problem. Infection often leads to severe liver injury that may progress to cirrhosis, hepatocellular carcinoma, and death. HCV coopts cellular machineries for propagation and triggers pathological processes in the liver. We previously identified a pivotal role of IKK-α in regulating cellular lipid metabolism and HCV assembly. In this study, we characterized NIK as acting upstream of IKK-α and characterized how HCV exploits this innate pathway to its advantage. Through extensive mechanistic studies, we demonstrated that NIK is a direct target of miR-122, which is regulated at the transcription level by HNF4A, a hepatocyte-specific transcription factor. We show in HCV infection that NIK expression is increased while both HNF4A and miR-122 levels are decreased. NIK represents an important host dependency that links HCV assembly, hepatic lipogenesis, and miRNA biology.
format	article
author	Brianna Lowey Laura Hertz Stephan Chiu Kristin Valdez Qisheng Li T. Jake Liang
author_facet	Brianna Lowey Laura Hertz Stephan Chiu Kristin Valdez Qisheng Li T. Jake Liang
author_sort	Brianna Lowey
title	Hepatitis C Virus Infection Induces Hepatic Expression of NF-κB-Inducing Kinase and Lipogenesis by Downregulating miR-122
title_short	Hepatitis C Virus Infection Induces Hepatic Expression of NF-κB-Inducing Kinase and Lipogenesis by Downregulating miR-122
title_full	Hepatitis C Virus Infection Induces Hepatic Expression of NF-κB-Inducing Kinase and Lipogenesis by Downregulating miR-122
title_fullStr	Hepatitis C Virus Infection Induces Hepatic Expression of NF-κB-Inducing Kinase and Lipogenesis by Downregulating miR-122
title_full_unstemmed	Hepatitis C Virus Infection Induces Hepatic Expression of NF-κB-Inducing Kinase and Lipogenesis by Downregulating miR-122
title_sort	hepatitis c virus infection induces hepatic expression of nf-κb-inducing kinase and lipogenesis by downregulating mir-122
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/e59efabd77914dc6b864d606912cfb20
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Hepatitis C Virus Infection Induces Hepatic Expression of NF-κB-Inducing Kinase and Lipogenesis by Downregulating miR-122

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