Exploring Mechanisms Through Which STING Alleles Impact Clinical Penetrance of COPA Syndrome - Project Summary / Abstract Interstitial lung diseases (ILD) are disorders in which lung inflammation and scarring cause reduced lung function. When seen in the context of connective tissue disease (CTD), ILDs are treated with generalized immune suppression as mechanisms driving disease remain poorly understood. COPA syndrome is a monogenic autosomal dominant autoimmune disease causing CTD ILD that often progresses despite immune suppression, with several patients with this rare disease requiring lung transplant. Importantly, this syndrome provides a model for identifying disease pathways driving CTD ILD. Studies from the laboratory of Dr. Anthony Shum (my sponsor) defined COPA syndrome and determined that disease is caused by failed retrieval of stimulator of interferon genes (STING) from the Golgi to the Endoplasmic Reticulum (ER) by coatomer subunit α (COPA). STING, a key innate immune adaptor, can only signal from the Golgi, and our group and others have shown that the pathogenic mechanism causing COPA syndrome is constitutive STING activation and signaling. COPA syndrome has a non-penetrance rate of ~30%, with unaffected carriers showing no signs of disease. As STING drives pathogenesis of COPA syndrome, we hypothesized that STING alleles might act as genetic modifiers impacting disease penetrance. Remarkably, we found perfect co-segregation of diseases non- penetrance with heterozygosity for the common R71H-G230A-R293Q (HAQ) STING allele in 25 carriers of pathogenic COPA mutations. As such, we propose HAQ STING as a suppressor allele for COPA syndrome. This proposal seeks to define the mechanisms by which HAQ STING is protective in COPA syndrome. STING is an ER-localized signaling hub for innate immune activation in response to cytosolic DNA. STING activation results in interferon signaling and multiple other outputs including NFkB activation, autophagy, senescence, and cell death. While HAQ STING has been shown to have impaired interferon signaling, this allele is highly prevalent (over 30% of non-Africans have at least one copy) and is thus likely to be competent for some but not all STING roles. How HAQ STING confers protection in COPA syndrome will be determined at many levels. Differences in HAQ STING in the presence or absence of pathogenic COPA mutations will be established at the mRNA and protein expression levels, through intracellular localization in resting and stimulated cells, and via interferon dependent and independent read outs of STING activation. With STING implicated broadly in ILD and other forms of lung inflammation, these studies hold potential for identifying novel therapeutic approaches for COPA syndrome and other forms of ILD. Discovery of additional disease modifying approaches is critically needed as ILDs have limited treatment options, resulting in high morbidity and mortality.
