STING Operation at the ER/Golgi Interface

Abstract

DNA is present in the nucleus and mitochondria of eukaryotic cells. There are, however, certain instances in which DNA emerges in the cytosol. The two major sources of cytosolic DNA are self DNA that is leaked out from the nucleus or mitochondria, and non-self DNA from DNA viruses. The cytosolic DNA triggers the host immune response. Recent studies have identified two key molecules, cyclic GMP-AMP (cGAMP) synthase (cGAS) and stimulator of interferon genes (STING) in this immune response. STING is an endoplasmic reticulum (ER) protein. After STING binding to cGAMP, STING exits the ER and translocates to the Golgi, where STING triggers the type I interferon- and proinflammatory responses through the activation of interferon regulatory factor 3 (IRF3) and nuclear factor-kappa B (NF-κB). STING also activates other cellular responses including cell senescence, autophagy, and cell death. In this review, we focus on emerging issues regarding the regulation of STING by membrane traffic, with a particular focus on the retrograde membrane traffic from the Golgi to the ER. The retrograde membrane traffic is recently shown by us and others to be critical for silencing the STING signaling pathway and the defect in this traffic underlies the pathogenesis of the COPA syndrome, a monogenic autoinflammatory disease caused by missense mutations of coatomer protein complex subunit α (COP-α).

The cGAS-STING Pathway: A Promising Immunotherapy Target

“…Activated STING stimulated type I IFN-driven inflammation in COPA model mice that was rescued in STING-deficient animals. Also, STING deficiency reversed the significant increase of activated effector T cells caused by mutant COPA ( 12 , 94 , 95 ). These results suggested that STING played a key role in COPA mutation-induced immune disorders, mainly by promoting the differentiation of effector T cells, which indicated that we could develop effective STING pathway inhibitors to treat COPA symptoms.…”

A Novel Mutation c.841C>T in COPA Syndrome of an 11-Year-Old Boy: A Case Report and Short Literature Review

“…But pulmonary inflammation plays differential roles in COPA and SAVI ( 11 ). Recent reports show that a defect in COPI transport causes ligand-independent activation of STING and COPA maintains immune homeostasis by regulating STING transport at the Golgi ( 3 , 4 , 12 ). These findings tell the link between COPA mutants and STING-mediated interferon signaling ( 3 , 4 , 12 , 13 ).…”

“…Recent reports show that a defect in COPI transport causes ligand-independent activation of STING and COPA maintains immune homeostasis by regulating STING transport at the Golgi ( 3 , 4 , 12 ). These findings tell the link between COPA mutants and STING-mediated interferon signaling ( 3 , 4 , 12 , 13 ). The expression of COPA mutants enables STING to accumulate in the Golgi, whereas COPA overexpression does not affect the localization of STING in the ER.…”

“…As an innate immunity ER protein, STING acts as a cargo of the retrograde membrane transport. Having bound to cGAMP, STING is translocated from the ER and into the Golgi, then triggers type I interferon and proinflammatory responses through activating interferon regulatory factor 3 (IRF3) and nuclear factor-kappa B (NF-kB) ( 3 , 4 ). Surf4, a protein that circulates between the ER/ER-Golgi intermediate compartment/Golgi, binds to STING and α-COP, and mediates the retrograde transport of STING to the ER ( 4 ).…”

Therapeutic Development by Targeting the cGAS-STING Pathway in Autoimmune Disease and Cancer

“…The membrane transport of STING is co-mediated by COP-II and COP-I. Thus, using the regulatory agents to target membrane transport is likely to be a novel strategy for treating autoimmune diseases ( Taguchi et al, 2021 ). However, the regulatory factors of STING transfer from the Golgi apparatus to the lysosome and the mechanisms of STING, NF-κB, and autophagy remain to be further studied.…”