A defect in COPI-mediated transport of STING causes immune dysregulation in COPA syndrome

Shum, Anthony K.; Deng, Zimu; Law, Christopher S.; Mukai, Kojiro; Ho, Frances O.; Martinu, T.; Backes, Bradley J.; Eckalbar, Walter L.; Taguchi, Tomohiko

doi:10.1101/2020.05.20.106500

Cited by 6 publications

(12 citation statements)

References 32 publications

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“…Therefore, retrograde transport of STING would require an adaptor protein. This hypothesis is supported by prepublication data from two laboratories, demonstrating that COPA binding to STING is dependent on Surfeit protein 4 (SURF4) (47,48). This also agrees with our proteomic analysis, where SURF4 and COPA were immunoprecipitated with STING after overexpression in HEK293T cells (Figure 2A).…”

Section: Discussionsupporting

confidence: 91%

Activation of STING due to COPI-deficiency

Steiner

Hrovat-Schaale

Prigione

et al. 2020

Preprint

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COPA syndrome is caused by loss-of-function mutations in the COP-α subunit of coatomer protein complex I (COPI), which participates in retrograde vesicular trafficking of proteins from the Golgi to the endoplasmic reticulum (ER). Disease manifests early in life with arthritis, lung pathology, kidney dysfunction and systemic inflammation associated with NF-κB activation and type I interferon (IFNαβ) production. Here, we generated in vitro models for COPA syndrome and interrogated inflammatory signalling pathways via a range of biochemical and molecular biological techniques. Results were confirmed with cell lines in which mutant COPA was overexpressed and with COPA syndrome patient PBMCs. We identified Stimulator of Interferon Genes (STING), as a driver of inflammation in COPA syndrome. Furthermore, we found that genetic deletion of COPG1, another COPI subunit protein, induced NF-κB and type I IFN pathways similar to COPA-deficiency. Finally, we demonstrate that in vitro, inflammation due to COPA syndrome mutations was ameliorated by treatment with the small molecule STING inhibitor H-151. Therefore, inflammation induced by deletion of COPI subunits in general suggests a link between retrograde trafficking and STING regulation, and this innate immune sensor represents a novel therapeutic target in COPA syndrome.

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Section: Discussionsupporting

confidence: 91%

Activation of STING due to COPI-deficiency

Steiner

Hrovat-Schaale

Prigione

et al. 2020

Preprint

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“…All rights reserved [138]. Interestingly, STING activation has also recently been implicated in COPA syndrome, an autoimmune disorder caused by mutations in coatomer subunit  (COPA), which shares overlapping features with SAVI, including upregulated IFN activity [139,140]. COPA, a subunit of the COPI complex, is involved in retrograde transport from the Golgi to ER.…”

Section: Accepted Articlementioning

confidence: 99%

“…Copa E241K/+ ) shows spontaneous activation and localisation of STING to the Golgi under basal conditions [140]. In addition, crossing Copa E241K/+ mice to Sting Gt/Gt rescued the type I IFN signature in splenocytes, thymocytes and thymic epithelial cells, while Sting Gt/Gt also protected homozygous Copa E241K/E241K mice from embryonic lethality [140].…”

Section: Accepted Articlementioning

confidence: 99%

“…Importantly, pharmacological inhibition of STING in Copa E241K/+ mice in vivo, as well as ex vivo patient peripheral blood mononuclear cells (PBMCs) also resolved the IFN signature, suggesting that targeting STING may serve as a promising therapeutic for COPA syndrome [140]. Mechanistically, it has been proposed that COPA deficiency prevents the recycling of STING back to the ER, leading to accumulation and prolonged activation of STING at the Golgi (Figure 5) [139,140].…”

Section: Accepted Articlementioning

confidence: 99%

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Molecular and spatial mechanisms governing STING signalling

Balka

Nardo

2020

The FEBS Journal

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Detection of microbial nucleic acids via innate immune receptors is critical for establishing host defence against pathogens. The DNA-sensing cGAS-STING pathway has gained increasing attention in the last decade as a key pathway for combating viral and bacterial infections. cGAS-STING activation primarily promotes the secretion of antiviral type I IFNs via the key transcription factor, IRF3. In addition, cGAS-STING signalling also elicits pro-inflammatory cytokines through NF-B activity. Activation of IRF3 and NF-B is mediated by the chief signalling receptor protein STING. Interestingly, STING undergoes significant trafficking events across multiple subcellular locations, which regulates both the activation of downstream signalling pathways, as well as appropriate termination of the responses. Studies to date have provided a comprehensive view of the regulation and role of the IRF3-IFN pathway downstream of STING. However, many aspects of STING signalling remain relatively poorly defined. This review will explore the current understanding of the mechanisms through which STING elicits inflammatory and antimicrobial responses, focusing on the precise signalling and intracellular trafficking events that occur. We will also discuss exciting and emerging concepts in the field, including the importance of IFN-independent STING responses for host defence and during STINGrelated disease.

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“…110 Consistent with this finding, COPA has been found to regulate normal trafficking of STING. 111,112 However, a murine model implicated autoreactive T cells derived through abnormal thymic function, suggesting that COPA might be a monogenic autoimmune disease in addition to (or rather than) a monogenic autoinflammatory condition, illustrating the challenge of distinguishing unambiguously between categories of immune dysfunction. 113 Numerous immunosuppressive agents have been trialed in COPA syndrome with variable success.…”

Section: Autoinflammation Mediated By Other Mechanismsmentioning

confidence: 99%