Induction of Siglec-G by RNA Viruses Inhibits the Innate Immune Response by Promoting RIG-I Degradation

Weilin Chen4, Chaofeng Han4, Bin Xie4, Xiang Hu, Qian Yu, Liyun Shi, Qingqing Wang, Dongling Li, Jianli Wang, Pan Zheng, Yang Liu, Xuetao Cao

Highlights
RNA virus infection specifically upregulates Siglecg expression in macrophages
Siglec-G selectively inhibits RIG-I-triggered IFN-β production in a feedback manner
Siglec-G promotes c-Cbl-mediated K48-linked ubiquitination and degradation of RIG-I
Lys813 of RIG-I is the critical site for degradation of RIG-I

Summary
RIG-I is a critical RNA virus sensor that serves to initiate antiviral innate immunity. However, posttranslational regulation of RIG-I signaling remains to be fully understood. We report here that RNA viruses, but not DNA viruses or bacteria, specifically upregulate lectin family member Siglecg expression in macrophages by RIG-I- or NF-κB-dependent mechanisms. Siglec-G-induced recruitment of SHP2 and the E3 ubiquitin ligase c-Cbl to RIG-I leads to RIG-I degradation via K48-linked ubiquitination at Lys813 by c-Cbl. By increasing type I interferon production, targeted inactivation of Siglecg protects mice against lethal RNA virus infection. Taken together, our data reveal a negative feedback loop of RIG-I signaling and identify a Siglec-G-mediated immune evasion pathway exploited by RNA viruses with implication in antiviral applications. These findings also provide insights into the functions and crosstalk of Siglec-G, a known adaptive response regulator, in innate immunity.

http://www.cell.com/abstract/S0092-8674(13)00017-2