Oligoadenylate-Synthetase-Family Protein OASL Inhibits Activity of the DNA Sensor cGAS during DNA Virus Infection to Limit Interferon Production
Oligoadenylate-Synthetase-Family Protein OASL Inhibits Activity of the DNA Sensor cGAS during DNA Virus Infection to Limit Interferon Production
复制标题
DOI：
10.1016/j.immuni.2018.12.013
复制
发表时间：
2019-01-15
期刊：
影响因子：
32.4
通讯作者：
Sarkar, Saumendra N.
中科院分区：
文献类型：
--
作者：
Ghosh, Arundhati;Shao, Lulu;Sarkar, Saumendra N.
干扰素诱导的人寡腺苷合成酶样物(OASL)及其小鼠同源基因Oas12可增强RNA传感器RIG-I介导的I型干扰素(IFN)的诱导并抑制RNA病毒的复制。在这里，我们表明，在DNA病毒感染的背景下，OAS1和OAS12具有相反的作用。在Oas12(-/-)小鼠和OASL缺陷的人类细胞中，DNA病毒如牛痘病毒、单纯疱疹病毒和腺病毒诱导的干扰素产生增加，导致病毒复制和病理减少。相应地，OASL在人细胞中的异位表达通过cGAS-sting DNA传感途径抑制了干扰素的诱导。在OASL缺陷细胞中观察到cGAS是减少DNA病毒复制所必需的。OASL不依赖于双链DNA而直接和特异性地与cGAS结合，导致非竞争性抑制第二信使环状GMP-AMP的产生。我们的发现明确了OASL在RNA和DNA病毒感染期间差异调节宿主干扰素反应的不同机制，并确定OASL是cGAS的负反馈调节因子。
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.