Alt. symbols: HEP-COP

Approved name: COPI coat complex subunit alpha
Alt. names: coatomer protein complex, subunit alpha | proxenin, xenin

Location: 1q23.2: 160288594 - 160343566 (-)
Gene type: protein_coding, 35 transcripts.

Scores: LoFtool: 0.312000 | pLI: 1.00000000 | LOEUF: 0.105

HGNC: 2230

NCBI: 1314, RefSeq: NG_050927.1

Ensembl: ENSG00000122218.17

LRG_1336 | Status: public

OMIM: 601924

Expression | ProteinAtlas

COPA encodes subunit alpha of the coatomer, a cytosolic protein complex that binds to dilysine motifs and reversibly associates with Golgi non-clathrin-coated vesicles, which mediate biosynthetic protein transport from the ER, via the Golgi up to the trans Golgi network. Coatomer complex is required for budding from Golgi membranes, and is essential for the retrograde Golgi-to-ER transport of dilysine-tagged proteins. In mammals, the coatomer can only be recruited by membranes associated to ADP-ribosylation factors (ARFs), which are small GTP-binding proteins; the complex also influences the Golgi structural integrity, as well as the processing, activity, and endocytic recycling of LDL receptors. In terms of immune homeostasis, COPA is emerging as a key regulator of type I interferon-mediated inflammatory responses via ER-Golgi trafficking of key adaptor proteins such as STING.

Heterozygous missense mutations in COPA lead to an autosomal dominant disorder of systemic autoinflammation and immune dysregulation clinically resembling type I IFN-mediated disease due to STING gain-of-function, a condition also known as SAVI (STING-associated vasculopathy with onset in infancy). All pathogenic COPA mutations identified thus far are missense mutations in the N-terminal exons encoding WD40 repeat regions of the COPA protein. In a recent study, Lepelley et al. (2020) observed el evated levels of IFN-stimulated genes (ISGs) and IFN-alpha in the blood of symptomatic COPA patients (PMID: 32725128). The authors of this study and another by Deng et al. (2020) provide in vitro and mouse model evidence, respectively, for the importance of COPA in maintaining immune homeostasis by regulating STING sorting at the Golgi (PMID: 32725126). COPA loss-of-function is thought to cause enhanced type I IFN signaling due to defective Golgi-to-ER STING retrieval. Additional immunological features include high-titer autoantibody production (i.e. most commonly ANA and RF, but c- and p-ANCA may also be present), elevated IL-1beta and IL-6 levels, and increased polarization towards a Th17 vs Th1 axis, as well as hypergammaglobulinemia and/or T cell lymphopenia. Classic clinical presentations include interstitial lung disease often with the development of pulmonary hemorrhage and fibrosis, inflammatory polyarthritis, and immune complex-mediated renal disease. Symptoms emerge later than for SAVI, but usually by the second decade of life, and also differentiating this condition from SAVI is the greater frequency of elevated ESR without coincidentally elevated CRP. Of note, up to 25-30% clinical non-penetrance has been reported, making diagnosis extremely challenging (PMID: 33532887). The clinical phenotype continues to expand as more patients are identified – additionally reported features include recurrent fevers, recurrent infections, skin vasculopathy, neurological involvement (including reports of neuromyelitis optica, meningitis, intracranial aneurysm, ischemic stroke), autoimmune thyroiditis, autoimmune hepatitis and neuroendocrine hyperplasia and malignancy (PMID: 30385646; 33532887, Morgan et al. Neurology Apr 2019, 92 (15 Supplement) P1.2-042). Of note, though COPA patients typically have normal lymphoid numbers and proportions along with unremarkable immunoglobulin levels and intact production of specific antibodies, some COPA patients have been described with either increased or decreased serum IgA levels (PMID: 29137621, 27048656, 25894502). [Load More]