Heterozygous mutations in the C-terminal domain of COPA underlie a complex autoinflammatory syndrome
Selket Delafontaine, … , Jérôme Delon, Isabelle Meyts
Selket Delafontaine, … , Jérôme Delon, Isabelle Meyts
Published January 4, 2024
Citation Information: J Clin Invest. 2024;134(4):e163604. https://doi.org/10.1172/JCI163604.
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Research Article Immunology

Heterozygous mutations in the C-terminal domain of COPA underlie a complex autoinflammatory syndrome

Abstract

Mutations in the N-terminal WD40 domain of coatomer protein complex subunit α (COPA) cause a type I interferonopathy, typically characterized by alveolar hemorrhage, arthritis, and nephritis. We described 3 heterozygous mutations in the C-terminal domain (CTD) of COPA (p.C1013S, p.R1058C, and p.R1142X) in 6 children from 3 unrelated families with a similar syndrome of autoinflammation and autoimmunity. We showed that these CTD COPA mutations disrupt the integrity and the function of coat protein complex I (COPI). In COPAR1142X and COPAR1058C fibroblasts, we demonstrated that COPI dysfunction causes both an anterograde ER-to-Golgi and a retrograde Golgi-to-ER trafficking defect. The disturbed intracellular trafficking resulted in a cGAS/STING-dependent upregulation of the type I IFN signaling in patients and patient-derived cell lines, albeit through a distinct molecular mechanism in comparison with mutations in the WD40 domain of COPA. We showed that CTD COPA mutations induce an activation of ER stress and NF-κB signaling in patient-derived primary cell lines. These results demonstrate the importance of the integrity of the CTD of COPA for COPI function and homeostatic intracellular trafficking, essential to ER homeostasis. CTD COPA mutations result in disease by increased ER stress, disturbed intracellular transport, and increased proinflammatory signaling.

Authors

Selket Delafontaine, Alberto Iannuzzo, Tarin M. Bigley, Bram Mylemans, Ruchit Rana, Pieter Baatsen, Maria Cecilia Poli, Daisy Rymen, Katrien Jansen, Djalila Mekahli, Ingele Casteels, Catherine Cassiman, Philippe Demaerel, Alice Lepelley, Marie-Louise Frémond, Rik Schrijvers, Xavier Bossuyt, Katlijn Vints, Wim Huybrechts, Rachida Tacine, Karen Willekens, Anniek Corveleyn, Bram Boeckx, Marco Baggio, Lisa Ehlers, Sebastian Munck, Diether Lambrechts, Arnout Voet, Leen Moens, Giorgia Bucciol, Megan A. Cooper, Carla M. Davis, Jérôme Delon, Isabelle Meyts

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Figure 2

Genetic aspects and in silico pathogenicity prediction of mutations in the CTD of COPA.

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Genetic aspects and in silico pathogenicity prediction of mutations in t...
(A) Schematic illustration of the COPA protein and its domains. Previously reported mutations in the WD40 domain are depicted in black (filled circle, functionally validated; open circle, functional validation unavailable), mutations in the CTD of COPA in color (color code correlates with Figure 1A). Numbers in parentheses refer to the number of families identified, number of mutation carriers, and number of diseased, respectively. Coatomer WDAD, coatomer WD-associated region. (B) Population genetics of the previously described COPA mutations affecting the WD40 domain, previously published not functionally validated CTD mutations, and CTD COPA mutations. MAF, minor allele frequency; MSC, mutation significance cutoff; CADD, combined annotation-dependent depletion score. (C) Conserved sequence homology at the site of the identified mutations in distantly related eukaryotes. (D) Biomodeling of the mutations affecting the CTD of COPA. The central figure depicts the main proteins of COPI, COPA (orange), COPB (teal), COPB2 (blue), and COPE (purple). Left: The physical interaction between COPAR1142X and COPAWT is depicted. In the top representation, COPAWT is shown as surface and COPAR1142X as a cartoon inside the surface, illustrating complete removal of the dimerization interface of COPAR1142X with the neighboring COPAWT (oval). This exposes the hydrophobic interface of the COPE binding helices, thus disrupting the COPA-COPE dimer. In the bottom representation, the absent residues are colored in gray. Right: The interaction between COPAR1058C, COPAC1013S, and COPE is shown. COPAR1058C and COPAC1013S likely disturb the conformation of the α-helices on which they are located and subsequently disrupt COPA’s overall structure. (E) Magnification of biomodeling of the α-helices, which compose the main body of the CTD and comprise residues 1013 and 1058, and form a binding site for singleton tryptophan motif (STM). STMs are known to be crucial for COPA homo-oligomerization and ER tethering of COPI vesicles.