Genome-wide RNAi Screen Reveals a New Role of a WNT/CTNNB1 Signaling Pathway as Negative Regulator of Virus-induced Innate Immune Responses

被引：70

作者：

Baril, Martin ^{[1
]}

Es-Saad, Salwa ^{[1
]}

Chatel-Chaix, Laurent ^{[1
]}

Fink, Karin ^{[2
]}

Pham, Tram ^{[3
]}

Raymond, Valerie-Ann ^{[2
]}

Audette, Karine ^{[1
]}

Guenier, Anne-Sophie ^{[1
]}

Duchaine, Jean ^{[1
]}

Servant, Marc ^{[4
]}

Bilodeau, Marc ^{[2
,5
]}

Cohen, Eric ^{[3
]}

Grandvaux, Nathalie ^{[2
,5
]}

Lamarre, Daniel ^{[1
,2
,5
]}

机构：

[1] Univ Montreal, IRIC, Montreal, PQ H3C 3J7, Canada

[2] Hop St Luc, CRCHUM, Montreal, PQ, Canada

[3] IRCM, Montreal, PQ, Canada

[4] Univ Montreal, Fac Pharm, Montreal, PQ H3C 3J7, Canada

[5] Univ Montreal, Fac Med, Montreal, PQ H3C 3J7, Canada

来源：

PLOS PATHOGENS | 2013年 / 9卷 / 06期

基金：

加拿大创新基金会;

关键词：

HEPATITIS-C-VIRUS; GLYCOGEN-SYNTHASE KINASE-3; NF-KAPPA-B; INTERFERON ANTIVIRAL RESPONSE; TUMOR-NECROSIS-FACTOR; BETA-CATENIN; RIG-I; TRANSMEMBRANE PROTEIN; HUMAN HEPATOCYTES; ADAPTER PROTEIN;

D O I：

10.1371/journal.ppat.1003416

中图分类号：

Q93 [微生物学];

学科分类号：

071005 [微生物学];

摘要：

To identify new regulators of antiviral innate immunity, we completed the first genome-wide gene silencing screen assessing the transcriptional response at the interferon-beta (IFNB1) promoter following Sendai virus (SeV) infection. We now report a novel link between WNT signaling pathway and the modulation of retinoic acid-inducible gene I (RIG-I)-like receptor (RLR)-dependent innate immune responses. Here we show that secretion of WNT2B and WNT9B and stabilization of beta-catenin (CTNNB1) upon virus infection negatively regulate expression of representative inducible genes IFNB1, IFIT1 and TNF in a CTNNB1-dependent effector mechanism. The antiviral response is drastically reduced by glycogen synthase kinase 3 (GSK3) inhibitors but restored in CTNNB1 knockdown cells. The findings confirm a novel regulation of antiviral innate immunity by a canonical-like WNT/CTNNB1 signaling pathway. The study identifies novel avenues for broad-spectrum antiviral targets and preventing immune-mediated diseases upon viral infection.

引用

页数：19

共 75 条

[1]

Wntless, a conserved membrane protein dedicated to the secretion of Wnt proteins from signaling cells [J].