STING nuclear partners contribute to innate immune signaling responses

Abstract

STimulator 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.

Comprehensive dissection of immune microenvironment in the progression of early gastric cancer at spatial and single-cell resolution

“…B-c0 and B-c5 mainly originated from non-EGC groups while in B-c1, B-c2, B-c3, B-c4 and B-c6, cells from EGC and AG groups predominated (Supplementary Figure 10C). Gene expression analysis showed the similar up-regulated genes between B-c0 and B-c5, DDX5 35 36 , DDX3X 37 and NCL 38 were all anti-pathogens and anti-tumor genes. As plenty of oncogenes significantly up-regulated in B-c1 cluster, we inferred it was deteriorating cell populations induced by tumor cells.…”

Nuclear soluble cGAS senses double-stranded DNA virus infection

“…Our study also indicates that nuclear soluble cGAS-mediated innate immune response is STING dependent. Several recent studies reported the inner nuclear membrane localization of STING 38 , 39 , which raises an interesting question of whether nuclear STING is a receptor for nuclear cGAMP. Although it has been suggested that cGAMP might diffuse freely through nuclear pores 18 , we cannot exclude the possibility that nuclear cGAMP binds and activates nuclear STING.…”

STING1 in Different Organelles: Location Dictates Function

“…STING1 can bind the DNA-dependent protein kinase (DNA-PK) complex in the inner nuclear membrane, which protects breast cancer cells from DNA instability by promoting DDR in a CGAS-independent manner ( 14 ). Nuclear STING1 also interacts with various nucleotide-binding proteins, which regulate gene transcription of type I IFNs ( 89 ). STING1 redistributes from the nucleus to the ER, increasing both dsDNA- and dsRNA-triggered immune responses.…”

“…STING1 redistributes from the nucleus to the ER, increasing both dsDNA- and dsRNA-triggered immune responses. In addition, subcellular localization analysis and the nuclear interactome show that STING1 co-localizes with the lamina, which serves as an anchoring point for chromatin and transcription factors and interacts with transcriptional activators and co-activators ( 14 , 89 ), indicating that nuclear STING1 may be directly involved in the regulation of gene transcriptional activity ( Figure 2 ).…”

“…The precise nuclear location and function of STING1 is still controversial. By using structured illumination super-resolution microscopy, STING1 has been found redistributed into different nuclear envelope locations ( 89 ). Given that the ER is adjacent to the nuclear envelope, STING1 may diffuse to the contiguous nuclear membrane after its initial insertion into ER membranes ( 90 ).…”