Cell
Volume 152, Issue 3, 31 January 2013, Pages 467-478
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Article
Induction of Siglec-G by RNA Viruses Inhibits the Innate Immune Response by Promoting RIG-I Degradation

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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.

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

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These authors contributed equally to this work