STING activation of IRF3 is tuned by PELI2 to suppress basal activation and reinforce the anti-viral response
Ritchie, C.; Li, L.
Show abstract
The STING pathway is the first line of defense against a variety of threats. STING activation leads to two main signaling branches, IRF3 signaling and NF-{kappa}B signaling, that have differential roles in anti-cancer, anti-viral, and anti-bacterial immunity and autoimmunity. However, it is unknown how these two signaling branches are differentially regulated depending on context. Here, we identify PELI2 as a regulator of STING that preferentially inhibits IRF3 signaling while enhancing NF-{kappa}B signaling. Mechanistically, we show that PELI2 inhibits IRF3 signaling by binding to phosphorylated Thr354 and Thr356 on the C-terminal tail of STING, leading to ubiquitination and function switching of TBK1. PELI2 is expressed under basal conditions to suppress IRF3 signaling and prevent interferonopathies. During viral infection, however, STING signaling rapidly downregulates PELI2 to unleash production of anti-viral type-I interferons. Normally, PELI2 levels are restored following viral clearance. However, lupus patients have insufficient PELI2 levels and high basal interferon production, suggesting dysregulation of PELI2 may have a causative role in lupus and other interferonopathies.
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