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

Simple item page
dc.contributor.authorDelafontaine, Selket
dc.contributor.authorIannuzzo, Alberto
dc.contributor.authorBigley, Tarin
dc.contributor.authorMylemans, Bram
dc.contributor.authorRana, Ruchit
dc.contributor.authorBaatsen, Pieter
dc.contributor.authorPoli Harlowe, María Cecilia
dc.contributor.authorRymen, Daisy
dc.contributor.authorJansen, Katrien
dc.contributor.authorMekahli, Djalila
dc.contributor.authorCasteels, Ingele
dc.contributor.authorCassiman, Catherine
dc.contributor.authorDemaerel, Philippe
dc.contributor.authorLepelley. Alice
dc.contributor.authorFrémond, Marie
dc.contributor.authorSchrijvers, Rik
dc.contributor.authorBossuyt, Xavier
dc.contributor.authorVints, Katlijn
dc.contributor.authorHuybrechts, Wim
dc.contributor.authorTacine, Rachida
dc.contributor.authorWillekens, Karen
dc.contributor.authorCorveleyn, Anniek
dc.contributor.authorBoeckx, Bram
dc.contributor.authorBaggio, Marco
dc.contributor.authorEhlers, Lisa
dc.contributor.authorMunck, Sebastian
dc.contributor.authorLambrechts, Diether
dc.contributor.authorVoet, Arnout
dc.contributor.authorMoens, Leen
dc.contributor.authorBucciol, Giorgia
dc.contributor.authorCooper, Megan
dc.contributor.authorDavis, Carla
dc.contributor.authorDelon, Jérôme
dc.contributor.authorMeyts, Isabelle
dc.date.accessioned2025-01-13T17:05:53Z
dc.date.available2025-01-13T17:05:53Z
dc.date.issued2024
dc.description.abstractMutations 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.
dc.description.versionVersión Publicada
dc.identifier.citationDelafontaine S, Iannuzzo A, Bigley TM, Mylemans B, Rana R, Baatsen P, Poli MC, Rymen D, Jansen K, Mekahli D, Casteels I, Cassiman C, Demaerel P, Lepelley A, Frémond ML, Schrijvers R, Bossuyt X, Vints K, Huybrechts W, Tacine R, Willekens K, Corveleyn A, Boeckx B, Baggio M, Ehlers L, Munck S, Lambrechts D, Voet A, Moens L, Bucciol G, Cooper MA, Davis CM, Delon J, Meyts I. Heterozygous mutations in the C-terminal domain of COPA underlie a complex autoinflammatory syndrome. J Clin Invest. 2024 Jan 4;134(4):e163604. doi: 10.1172/JCI163604
dc.identifier.doihttps://doi.org/10.1172/JCI163604
dc.identifier.urihttps://hdl.handle.net/11447/9632
dc.language.isoen
dc.subjectCell stress
dc.subjectImmunology
dc.subjectInnate immunity
dc.subjectMonogenic diseases
dc.titleHeterozygous mutations in the C-terminal domain of COPA underlie a complex autoinflammatory syndrome
dc.typeArticle
dcterms.accessRightsAcceso Abierto
dcterms.sourceThe Journal of clinical investigation
dspace.entity.typePublication
relation.isAuthorOfPublicationbf711dbf-cd6f-4a66-97fb-64c15f664de3
relation.isAuthorOfPublication.latestForDiscoverybf711dbf-cd6f-4a66-97fb-64c15f664de3

Files

Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
Heterozygous mutations in the C-terminal domain of COPA underlie a complex autoinflammatory syndrome.pdf
Size:
17.55 MB
Format:
Adobe Portable Document Format
Description:
Texto Completo
Download
License bundle
Now showing 1 - 1 of 1
No Thumbnail Available
Name:
license.txt
Size:
347 B
Format:
Item-specific license agreed upon to submission
Description:
Download

Collections

Artículos Medicina y Ciencias de la Salud

Implementado por OpenGeek Services