Pathogenic COPA variants cause a Mendelian syndrome of immune dysregulation with elevated type I interferon signaling. COPA is a subunit of coat protein complex I (COPI) that mediates Golgi to ER transport. Missense mutations of the COPA WD40 domain impair binding and sorting of proteins targeted for ER retrieval, but how this causes disease remains unknown. Given the importance of COPA in Golgi–ER transport, we speculated that type I interferon signaling in COPA syndrome involves missorting of STING. We show that a defect in COPI transport causes ligand-independent activation of STING. Furthermore, SURF4 is an adapter molecule that facilitates COPA-mediated retrieval of STING at the Golgi. Activated STING stimulates type I interferon–driven inflammation in CopaE241K/+ mice that is rescued in STING-deficient animals. Our results demonstrate that COPA maintains immune homeostasis by regulating STING transport at the Golgi. In addition, activated STING contributes to immune dysregulation in COPA syndrome and may be a new molecular target in treating the disease.
The COPA syndrome is a monogenic, autoimmune lung and joint disorder first identified in 2015. This study sought to define the main pulmonary features of the COPA syndrome in an international cohort of patients, analyse patient responses to treatment and highlight when genetic testing should be considered.We established a cohort of subjects (N=14) with COPA syndrome seen at multiple centres including the University of California, San Francisco, CA, USA. All subjects had one of the previously established mutations in the COPA gene, and had clinically apparent lung disease and arthritis. We analysed cohort characteristics using descriptive statistics.All subjects manifested symptoms before the age of 12 years, had a family history of disease, and developed diffuse parenchymal lung disease and arthritis. 50% had diffuse alveolar haemorrhage. The most common pulmonary findings included cysts on chest computed tomography and evidence of follicular bronchiolitis on lung biopsy. All subjects were positive for anti-neutrophil cytoplasmic antibody, anti-nuclear antibody or both and 71% of subjects had rheumatoid factor positivity. All subjects received immunosuppressive therapy.COPA syndrome is an autoimmune disorder defined by diffuse parenchymal lung disease and arthritis. We analysed an international cohort of subjects with genetically confirmed COPA syndrome and found that common pulmonary features included cysts, follicular bronchiolitis and diffuse alveolar haemorrhage. Common extrapulmonary features included early age of onset, family history of disease, autoantibody positivity and arthritis. Longitudinal data demonstrated improvement on chest radiology but an overall decline in pulmonary function despite chronic treatment.
The adaptive immune system in vertebrates relies on an enormous repertoire of antigen receptors. The variable domains of antigen receptors are encoded by extensive arrays of variety, diversity and joining (V, D, and J) gene segments flanked by conserved recombination signal sequences (RSSs) [1]. During the early lymphoid-specific process known as V(D)J recombination, RAG1 and RAG2 recognize and pair two RSSs based on the 12/23 rule and introduce a pair of double-strand breaks (DSB) between each RSS and its adjoining coding segment [2]. The non-homologous DNA end-joining pathway then rejoins the coding segments together and generates functional receptors [3].Murine RAG1 contains 1 040 amino acids, and RAG2 contains 527 amino acids. Biochemical studies have confirmed that the core regions of RAG1 (aa 384-1 008) and RAG2 (aa 1-387) are fundamental for the cleavage reaction in vitro [4]. Core RAG1 is capable of recognizing RSSs and can form tetramers with RAG2 in which the DDE triad is responsible for the DNA cleavage activity [5]. Core RAG2 contains Kelch motifs that assist RAG1 binding and cutting of the RSSs [6]. The plant homology domain within the RAG2 non-core region has recently been shown to bind histone H3K4Me3 and activate the recombination reaction [7,8]. Regarding the non-core region, especially the N-terminal region of RAG1 (aa 1-383), several conserved clusters of basic residues have been identified within residues 1-264 [9]. This region is thought to bind to a zinc ion and associate with KPNA1 and SRP1 [10][11][12]. A recently defined WW-like domain (aa 179-205) might mediate protein-protein interactions [13]. Residues 265-383 of RAG1 contain a C3HC4 ring-finger domain harboring E3 ubiquitin ligase activity [14]. However, the roles of these domains or motifs in V(D)J recombination have not been fully elucidated.The impaired V(D)J recombination in core RAG1 knock-in mice suggests that non-core RAG1 increases the efficiency and accuracy of recombination, yet quite a number of lymphocytes can mature, indicating that non-core RAG1 is dispensable for basic recombination activity [15]. Nevertheless, in some Omenn syndrome Cell Research (2015) 25:181-192.
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