当前位置： SCI文献检索 > GASTROENTEROLOGY期刊下所有文献 > A genetic screen identifies interferon-α effector genes required to suppress hepatitis C virus replication.

A genetic screen identifies interferon-α effector genes required to suppress hepatitis C virus replication.

Abstract：

BACKGROUND & AIMS:Hepatitis C virus (HCV) infection is a leading cause of end-stage liver disease. Interferon-α (IFNα) is an important component of anti-HCV therapy; it up-regulates transcription of IFN-stimulated genes, many of which have been investigated for their antiviral effects. However, all of the genes required for the antiviral function of IFNα (IFN effector genes [IEGs]) are not known. IEGs include not only IFN-stimulated genes, but other nontranscriptionally induced genes that are required for the antiviral effect of IFNα. In contrast to candidate approaches based on analyses of messenger RNA (mRNA) expression, identification of IEGs requires a broad functional approach. METHODS:We performed an unbiased genome-wide small interfering RNA screen to identify IEGs that inhibit HCV. Huh7.5.1 hepatoma cells were transfected with small interfering RNAs incubated with IFNα and then infected with JFH1 HCV. Cells were stained using HCV core antibody, imaged, and analyzed to determine the percent infection. Candidate IEGs detected in the screen were validated and analyzed further. RESULTS:The screen identified 120 previously unreported IEGs. From these, we more fully evaluated the following: asparagine-linked glycosylation 10 homolog (yeast, α-1,2-glucosyltransferase); butyrylcholinesterase; dipeptidyl-peptidase 4 (CD26, adenosine deaminase complexing protein 2); glucokinase (hexokinase 4) regulator; guanylate cyclase 1, soluble, β 3; MYST histone acetyltransferase 1; protein phosphatase 3 (formerly 2B), catalytic subunit, β isoform; peroxisomal proliferator-activated receptor-γ-DBD-interacting protein 1; and solute carrier family 27 (fatty acid transporter), member 2; and demonstrated that they enabled IFNα-mediated suppression of HCV at multiple steps of its life cycle. Expression of these genes had more potent effects against flaviviridae because a subset was required for IFNα to suppress dengue virus but not influenza A virus. In addition, many of the host genes detected in this screen (92%) were not transcriptionally stimulated by IFNα; these genes represent a heretofore unknown class of non-IFN-stimulated gene IEGs. CONCLUSIONS:We performed a whole-genome loss-of-function screen to identify genes that mediate the effects of IFNα against human pathogenic viruses. We found that IFNα restricts HCV via actions of general and specific IEGs.

journal_name

Gastroenterology

journal_title

Gastroenterology

authors

Fusco DN,Brisac C,John SP,Huang YW,Chin CR,Xie T,Zhao H,Jilg N,Zhang L,Chevaliez S,Wambua D,Lin W,Peng L,Chung RT,Brass AL

doi

10.1053/j.gastro.2013.02.026

subject

Has Abstract

pub_date

2013-06-01 00:00:00

pages

1438-49, 1449.e1-9

issue

eissn

0016-5085

issn

1528-0012

pii

S0016-5085(13)00237-0

journal_volume

144

pub_type

杂志文章

在线工具

A genetic screen identifies interferon-α effector genes required to suppress hepatitis C virus replication.