Collagen VII maintains proteostasis in dermal fibroblasts by scaffolding TANGO1 cargo.
Collagen VII
ER stress
TANGO1
and TGFβ signaling
recessive dystrophic epidermolysis bullosa
thrombospondin
Journal
Matrix biology : journal of the International Society for Matrix Biology
ISSN: 1569-1802
Titre abrégé: Matrix Biol
Pays: Netherlands
ID NLM: 9432592
Informations de publication
Date de publication:
08 2022
08 2022
Historique:
received:
15
02
2022
revised:
15
06
2022
accepted:
27
06
2022
pubmed:
3
7
2022
medline:
9
9
2022
entrez:
2
7
2022
Statut:
ppublish
Résumé
Lack of type VII collagen (C7) disrupts cellular proteostasis yet the mechanism remains undescribed. By studying the relationship between C7 and the extracellular matrix (ECM)-associated proteins thrombospondin-1 (TSP1), type XII collagen (C12) and tissue transglutaminase (TGM2) in primary human dermal fibroblasts from multiple donors with or without the genetic disease recessive dystrophic epidermolysis bullosa (RDEB) (n=31), we demonstrate that secretion of each of these proteins is increased in the presence of C7. In dermal fibroblasts isolated from patients with RDEB, where C7 is absent or defective, association with the COPII outer coat protein SEC31 and ultimately secretion of each of these ECM-associated proteins is reduced and intracellular levels are increased. In RDEB fibroblasts, overall collagen secretion (as determined by the levels of hydroxyproline in the media) is unchanged while traffic from the ER to Golgi of TSP1, C12 and TGM2 occurs in a type I collagen (C1) dependent manner. In normal fibroblasts association of TSP1, C12 and TGM2 with the ER exit site transmembrane protein Transport ANd Golgi Organization-1 (TANGO1) as determined by proximity ligation assays, requires C7. In the absence of wild-type C7, or when ECM-associated proteins are overexpressed, C1 proximity and intracellular levels increase resulting in elevated cellular stress responses and elevated TGFβ signaling. Collectively, these data demonstrate a role for C7 in loading COPII vesicle cargo and provides a mechanism for disrupted proteostasis, elevated cellular stress and increased TGFβ signaling in patients with RDEB. Furthermore, our data point to a threshold of cargo loading that can be exceeded with increased protein levels leading to pathological outcomes in otherwise normal cells.
Identifiants
pubmed: 35779741
pii: S0945-053X(22)00088-9
doi: 10.1016/j.matbio.2022.06.008
pmc: PMC9683098
mid: NIHMS1849912
pii:
doi:
Substances chimiques
Collagen Type VII
0
Transforming Growth Factor beta
0
Transglutaminases
EC 2.3.2.13
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
226-244Subventions
Organisme : NCI NIH HHS
ID : R01 CA244522
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA056036
Pays : United States
Informations de copyright
Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Competing Interest Statement A.P.S. holds stock in Krystal Biotech Inc. and consults for and has ownership interests in Zikani Therapeutics.
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