Oligoadenylate-Synthetase-Family Protein OASL Inhibits Activity of the DNA Sensor cGAS during DNA Virus Infection to Limit Interferon Production

被引：97

作者：

Ghosh, Arundhati ^{[1
,2
]}

Shao, Lulu ^{[1
,2
]}

Sampath, Padmavathi ^{[1
,3
]}

Zhao, Baoyu ^{[4
]}

Patel, Nidhi, V ^{[1
]}

Zhu, Jianzhong ^{[1
,2
,8
]}

Behl, Bharat ^{[5
]}

Parise, Robert A. ^{[6
]}

Beumer, Jan H. ^{[6
]}

O'Sullivan, Roderick J. ^{[7
]}

DeLuca, Neal A. ^{[1
,2
]}

Thorne, Stephen H. ^{[1
,3
]}

Rathinam, Vijay A. K. ^{[5
]}

Li, Pingwei ^{[4
]}

Sarkar, Saumendra N. ^{[1
,2
]}

机构：

[1] Univ Pittsburgh, Canc Inst, Canc Virol Program, Pittsburgh, PA 15213 USA

[2] Univ Pittsburgh, Dept Microbiol & Mol Genet, Pittsburgh, PA 15219 USA

[3] Univ Pittsburgh, Dept Cell Biol, Sch Med, Pittsburgh, PA 15261 USA

[4] Texas A&M Univ, Dept Biochem & Biophys, College Stn, TX 77843 USA

[5] Univ Connecticut Hlth, Dept Immunol, Sch Med, Farmington, CT 06030 USA

[6] Univ Pittsburgh, Dept Pharmaceut Sci, Sch Pharm, Pittsburgh, PA 15213 USA

[7] Univ Pittsburgh, Dept Pharmacol & Chem Biol, Pittsburgh, PA 15219 USA

[8] Yangzhou Univ, Coll Vet Med, Yangzhou, Jiangsu, Peoples R China

来源：

IMMUNITY | 2019年 / 50卷 / 01期

关键词：

GMP-AMP SYNTHASE; HOST; PROMOTES; BETA; REPLICATION; EXPRESSION; MECHANISM; REVEALS; GENES; CELLS;

D O I：

10.1016/j.immuni.2018.12.013

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Interferon-inducible human oligoadenylate synthetase-like (OASL) and its mouse ortholog, Oasl2, enhance RNA-sensor RIG-I-mediated type I interferon (IFN) induction and inhibit RNA virus replication. Here, we show that OASL and Oasl2 have the opposite effect in the context of DNA virus infection. In Oasl2(-/-) mice and OASL-deficient human cells, DNA viruses such as vaccinia, herpes simplex, and adenovirus induced increased IFN production, which resulted in reduced virus replication and pathology. Correspondingly, ectopic expression of OASL in human cells inhibited IFN induction through the cGAS-STING DNA-sensing pathway. cGAS was necessary for the reduced DNA virus replication observed in OASL-deficient cells. OASL directly and specifically bound to cGAS independently of double-stranded DNA, resulting in a non-competitive inhibition of the second messenger cyclic GMP-AMP production. Our findings define distinct mechanisms by which OASL differentially regulates host IFN responses during RNA and DNA virus infection and identify OASL as a negative-feedback regulator of cGAS.

引用

页码：51 / +

页数：18

共 65 条

[1] Cell intrinsic immunity spreads to bystander cells via the intercellular transfer of cGAMP [J].