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Sci Rep. 2017 Jul 19;7(1):5876. doi: 10.1038/s41598-017-06254-4.

Quinolinate Phosphoribosyltransferase is an Antiviral Host Factor Against Hepatitis C Virus Infection.

Author information

1
The Joint Laboratory for Translational Precision Medicine of Wuhan Institute of Virology, Chinese Academy of Sciences and Guangzhou Women and Children`s Medical Center, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei, 430071, China.
2
CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
3
University of Chinese Academy of Sciences, Beijing, 10049, China.
4
Department of Hepatology, The First Hospital of Jilin University, Changchun, Jilin, 130021, China.
5
Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Heilong Jiang, 150001, China.
6
The Joint Laboratory for Translational Precision Medicine of Wuhan Institute of Virology, Chinese Academy of Sciences and Guangzhou Women and Children`s Medical Center, Guangzhou Women and Children's Medical Center, Guangzhou, 510623, China.
7
Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China.
8
The Joint Laboratory for Translational Precision Medicine of Wuhan Institute of Virology, Chinese Academy of Sciences and Guangzhou Women and Children`s Medical Center, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei, 430071, China. htang@ips.ac.cn.
9
CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China. htang@ips.ac.cn.
10
Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China. htang@ips.ac.cn.

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.

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