p-T,4S-IRF3 is dimerized Dimerized phospho-IRF3 migrates to the nucleus IFI16 binds cytosolic dsDNA STING recruits TBK1 and IRF3 STING binds c-di-GMP IRF3 is phosphorylated by TBK1 TBK1 is phosphorylated whithin STING:TBK1:IRF3 complex PathwayStep6994 PathwayStep6993 PathwayStep7003 PathwayStep7002 PathwayStep7001 PathwayStep7000 PathwayStep7004 STING mediated induction of type 1 IFN Authored: Shamovsky, V, 2012-07-09 GENE ONTOLOGYGO:0032481 Pubmed18724357 Pubmed19433799 Pubmed19776740 Pubmed19926846 Pubmed20107183 Pubmed20871604 Pubmed20890285 Pubmed21820332 Pubmed21892174 Pubmed21947006 Pubmed22394562 Pubmed22607800 Pubmed22706339 Reactome Database ID Release 431834941 Reactome, http://www.reactome.org ReactomeREACT_147841 Reviewed: D'Eustachio, P, 2012-07-18 Reviewed: Jin, Lei, 2012-08-18 STING (stimulator of IFN genes; also known as MITA/ERIS/MPYS/TMEM173) is an endoplasmic reticulum (ER) resident, which is required for effective type I IFN production in response to nucleic acids. Indeed, select pathogen-derived DNA or RNA were shown to activate STING in human and mouse cells [Ishikawa H and Barber GN 2008; Ishikawa H et al 2009; Sun W et al 2009; Prantner D et al 2010]. Importantly, in vitro studies have shown that STING is essential for Mycobacterium tuberculosis [Manzanillo PS et al 2012], Plasmodium falciparum [Sharma S et al 2011] and human immunodeficiency virus (HIV) induced type I IFN production [Yan N et al 2010]. Mycobacterium tuberculosis, plasmodium falciparum and HIV are three deadliest pathogens, which kill millions of people each year worldwide.<p>STING has been also implicated in type I IFN response which was stimulated by fusion of viral and target-cell membrane in a manner independent of DNA, RNA and viral capsid [Holm CK et al 2012].<p>Under steady state conditions, STING is positioned at the translocon complex within the ER membrane. However upon stimulation with intracellular DNA it translocates from ER to perinuclear vesicles via the Golgi by mechanisms that remain unclear [Ishikawa H and Barber GN 2008; Sun W et al 2009; Ishikawa H et al 2009; Saitoh T et al 2009]. Mouse Sting trafficking in dsDNA-stimulated mouse embryonic fibroblasts (MEF) cells was found to depend on autophagy-related gene 9a (Atg9a) [Saitoh T et al 2009].<p>STING was reported to function as a signaling adaptor or coreceptor in response to cytosolic dsDNA [Unterholzner L et al 2010; Zhang Z et al 2011]. Additionally, STING is thought to function as a direct sensor of cyclic dinucleotides. STING was shown to interact directly with c-di-GMP in human embryonic kidney HEK293T cell lysates and [Burdette DL et al 2011]. Once STING is stimulated, its C-terminus serves as a signaling scaffold to recruit IRF3 and TBK1, which leads to TBK1-dependent phosphorylation of IRF3 [Tanaka Y and Chen ZJ 2012].