Quinolinate Phosphoribosyltransferase is an Antiviral Host Factor Against Hepatitis C Virus Infection
Abstract HCV infection can decrease NAD+/NADH ratio, which could convert lipid metabolism to favor HCV replication. In hepatocytes, quinolinate phosphoribosyl transferase (QPRT) catabolizes quinolinic acid (QA) to nicotinic acid mononucleotide (NAMN) for de novo NAD synthesis. However, whether and h...
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2017
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oai:doaj.org-article:77de0a4c4b0a46f29cc04950151173032021-12-02T12:32:33ZQuinolinate Phosphoribosyltransferase is an Antiviral Host Factor Against Hepatitis C Virus Infection10.1038/s41598-017-06254-42045-2322https://doaj.org/article/77de0a4c4b0a46f29cc04950151173032017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-06254-4https://doaj.org/toc/2045-2322Abstract HCV infection can decrease NAD+/NADH ratio, which could convert lipid metabolism to favor HCV replication. In hepatocytes, quinolinate phosphoribosyl transferase (QPRT) catabolizes quinolinic acid (QA) to nicotinic acid mononucleotide (NAMN) for de novo NAD synthesis. However, whether and how HCV modulates QPRT hence the lipogenesis is unknown. In this work, we found QPRT was reduced significantly in livers of patients or humanized C/OTg mice with persistent HCV infection. Mechanistic studies indicated that HCV NS3/4A promoted proteasomal degradation of QPRT through Smurf2, an E3 ubiquitin-protein ligase, in Huh7.5.1 cells. Furthermore, QPRT enzymatic activity involved in suppression of HCV replication in cells. Activation of QPRT with clofibrate (CLO) or addition of QPRT catabolite NAD both inhibited HCV replication in cells, probably through NAD+-dependent Sirt1 inhibition of cellular lipogenesis. More importantly, administration of CLO, a hypolipidemic drug used in clinics, could significantly reduce the viral load in HCV infected C/OTg mice. Take together, these results suggested that HCV infection triggered proteasomal degradation of QPRT and consequently reduced de novo NAD synthesis and lipogenesis, in favor of HCV replication. Hepatic QPRT thus likely served as a cellular factor that dampened productive HCV replication.Zhilong WangYanhang GaoChao ZhangHaiming HuDongwei GuoYi XuQiuping XuWeihong ZhangSisi DengPingyun LvYan YangYanhua DingQingquan LiChangjiang WengXinwen ChenSitang GongHairong ChenJunqi NiuHong TangNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-10 (2017) |
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DOAJ |
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| topic |
Medicine R Science Q |
| spellingShingle |
Medicine R Science Q Zhilong Wang Yanhang Gao Chao Zhang Haiming Hu Dongwei Guo Yi Xu Qiuping Xu Weihong Zhang Sisi Deng Pingyun Lv Yan Yang Yanhua Ding Qingquan Li Changjiang Weng Xinwen Chen Sitang Gong Hairong Chen Junqi Niu Hong Tang Quinolinate Phosphoribosyltransferase is an Antiviral Host Factor Against Hepatitis C Virus Infection |
| description |
Abstract HCV infection can decrease NAD+/NADH ratio, which could convert lipid metabolism to favor HCV replication. In hepatocytes, quinolinate phosphoribosyl transferase (QPRT) catabolizes quinolinic acid (QA) to nicotinic acid mononucleotide (NAMN) for de novo NAD synthesis. However, whether and how HCV modulates QPRT hence the lipogenesis is unknown. In this work, we found QPRT was reduced significantly in livers of patients or humanized C/OTg mice with persistent HCV infection. Mechanistic studies indicated that HCV NS3/4A promoted proteasomal degradation of QPRT through Smurf2, an E3 ubiquitin-protein ligase, in Huh7.5.1 cells. Furthermore, QPRT enzymatic activity involved in suppression of HCV replication in cells. Activation of QPRT with clofibrate (CLO) or addition of QPRT catabolite NAD both inhibited HCV replication in cells, probably through NAD+-dependent Sirt1 inhibition of cellular lipogenesis. More importantly, administration of CLO, a hypolipidemic drug used in clinics, could significantly reduce the viral load in HCV infected C/OTg mice. Take together, these results suggested that HCV infection triggered proteasomal degradation of QPRT and consequently reduced de novo NAD synthesis and lipogenesis, in favor of HCV replication. Hepatic QPRT thus likely served as a cellular factor that dampened productive HCV replication. |
| format |
article |
| author |
Zhilong Wang Yanhang Gao Chao Zhang Haiming Hu Dongwei Guo Yi Xu Qiuping Xu Weihong Zhang Sisi Deng Pingyun Lv Yan Yang Yanhua Ding Qingquan Li Changjiang Weng Xinwen Chen Sitang Gong Hairong Chen Junqi Niu Hong Tang |
| author_facet |
Zhilong Wang Yanhang Gao Chao Zhang Haiming Hu Dongwei Guo Yi Xu Qiuping Xu Weihong Zhang Sisi Deng Pingyun Lv Yan Yang Yanhua Ding Qingquan Li Changjiang Weng Xinwen Chen Sitang Gong Hairong Chen Junqi Niu Hong Tang |
| author_sort |
Zhilong Wang |
| title |
Quinolinate Phosphoribosyltransferase is an Antiviral Host Factor Against Hepatitis C Virus Infection |
| title_short |
Quinolinate Phosphoribosyltransferase is an Antiviral Host Factor Against Hepatitis C Virus Infection |
| title_full |
Quinolinate Phosphoribosyltransferase is an Antiviral Host Factor Against Hepatitis C Virus Infection |
| title_fullStr |
Quinolinate Phosphoribosyltransferase is an Antiviral Host Factor Against Hepatitis C Virus Infection |
| title_full_unstemmed |
Quinolinate Phosphoribosyltransferase is an Antiviral Host Factor Against Hepatitis C Virus Infection |
| title_sort |
quinolinate phosphoribosyltransferase is an antiviral host factor against hepatitis c virus infection |
| publisher |
Nature Portfolio |
| publishDate |
2017 |
| url |
https://doaj.org/article/77de0a4c4b0a46f29cc0495015117303 |
| work_keys_str_mv |
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| _version_ |
1718394041775685632 |