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Viperin binds STING and enhances the type‐I interferon response following dsDNA detection
Author(s) -
Crosse Keaton M,
Monson Ebony A,
Dumbrepatil Arti B,
Smith Monique,
Tseng YeuYang,
Van der Hoek Kylie H,
Revill Peter A,
Saker Subir,
Tscharke David C,
G Marsh E Neil,
Beard Michael R,
Helbig Karla J
Publication year - 2021
Publication title -
immunology and cell biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.999
H-Index - 104
eISSN - 1440-1711
pISSN - 0818-9641
DOI - 10.1111/imcb.12420
Subject(s) - innate immune system , interferon , signal transduction , tank binding kinase 1 , microbiology and biotechnology , biology , interferon type i , immune system , samhd1 , stimulator of interferon genes , interferon regulatory factors , irf3 , virology , immunology , genetics , gene , rna , reverse transcriptase , mitogen activated protein kinase kinase , protein kinase c
Abstract Viperin is an interferon‐inducible protein that is pivotal for eliciting an effective immune response against an array of diverse viral pathogens. Here we describe a mechanism of viperin’s broad antiviral activity by demonstrating the protein’s ability to synergistically enhance the innate immune dsDNA signaling pathway to limit viral infection. Viperin co‐localized with the key signaling molecules of the innate immune dsDNA sensing pathway, STING and TBK1; binding directly to STING and inducing enhanced K63‐linked polyubiquitination of TBK1. Subsequent analysis identified viperin’s necessity to bind the cytosolic iron‐sulfur assembly component 2A, to prolong its enhancement of the type‐I interferon response to aberrant dsDNA. Here we show that viperin facilitates the formation of a signaling enhanceosome, to coordinate efficient signal transduction following activation of the dsDNA signaling pathway, which results in an enhanced antiviral state. We also provide evidence for viperin’s radical SAM enzymatic activity to self‐limit its immunomodulatory functions. These data further define viperin’s role as a positive regulator of innate immune signaling, offering a mechanism of viperin’s broad antiviral capacity.