STING nuclear partners contribute to innate immune signaling responses

Charles R Dixon,Poonam Malik,Jose I De Las Heras,Natalia Saiz-Ros,Flavia De Lima Alves,Mark Tingey,Eleanor Gaunt,A Christine Richardson,David A Kelly,Martin W Goldberg,Greg J Towers,Weidong Yang,Juri Rappsilber,Paul Digard,Eric C Schirmer

doi:10.1016/j.isci.2021.103055

Abstract

SummarySTimulator of INterferon Genes (STING) is an adaptor for cytoplasmic DNA sensing by cGAMP/cGAS that helps trigger innate immune responses (IIRs). Although STING is mostly localized in the ER, we find a separate inner nuclear membrane pool of STING that increases mobility and redistributes to the outer nuclear membrane upon IIR stimulation by transfected dsDNA or dsRNA mimic poly(I:C). Immunoprecipitation of STING from isolated nuclear envelopes coupled with mass spectrometry revealed a distinct nuclear envelope-STING proteome consisting of known nuclear membrane proteins and enriched in DNA- and RNA-binding proteins. Seventeen of these nuclear envelope STING partners are known to bind direct interactors of IRF3/7 transcription factors, and testing a subset of these revealed STING partners SYNCRIP, MEN1, DDX5, snRNP70, RPS27a, and AATF as novel modulators of dsDNA-triggered IIRs. Moreover, we find that SYNCRIP is a novel antagonist of the RNA virus, influenza A, potentially shedding light on reports of STING inhibition of RNA viruses.

Highlights

STING (STimulator of INterferon Genes), called MITA, ERIS, MPYS, NET23, and TMEM173, is an important player in the innate immune response (IIR), the first line of defense against pathogens (Chen and Jiang, 2013; Unterholzner, 2013), yet several studies indicate it has a much wider range of important cellular functions
SUMMARY STimulator of INterferon Genes (STING) is an adaptor for cytoplasmic DNA sensing by cGAMP/Cyclic GMP-AMP synthase (cGAS) that helps trigger innate immune responses (IIRs)
STING is mostly localized in the ER, we find a separate inner nuclear membrane pool of STING that increases mobility and redistributes to the outer nuclear membrane upon IIR stimulation by transfected dsDNA or dsRNA mimic poly(I:C)

Summary

Introduction

STING (STimulator of INterferon Genes), called MITA, ERIS, MPYS, NET23, and TMEM173, is an important player in the innate immune response (IIR), the first line of defense against pathogens (Chen and Jiang, 2013; Unterholzner, 2013), yet several studies indicate it has a much wider range of important cellular functions. Cyclic GMP-AMP synthase (cGAS) senses cytoplasmic dsDNA and catalyzes the synthesis of a second messenger, cGAMP, which binds to and activates dimeric STING at the ER, activating IIR signaling cascades that stimulate IRF3/7 transcription factors to activate IIR genes such as type I interferons (IFNs) (Ablasser and Chen, 2019; Ahn and Barber, 2019; Cai et al, 2014; Ishikawa and Barber, 2008; Ishikawa et al, 2009; Motwani et al, 2019; Sun et al, 2013). The many distinct functions and localizations reported for STING in IIRs make it difficult to distinguish direct from downstream signaling effects

Results

Discussion

Conclusion