Collagen VII maintains proteostasis in dermal fibroblasts by scaffolding TANGO1 cargo

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dc.contributor.authorCao, Qingqing
dc.contributor.authorTartaglia, Grace
dc.contributor.authorAlexander, Michael
dc.contributor.authorPark, Pyung Hung
dc.contributor.authorPoojan, Shiv
dc.contributor.authorFarshchian, Mehdi
dc.contributor.authorFuentes, Ignacia
dc.contributor.authorChen, Mei
dc.contributor.authorMcGrath, John A.
dc.contributor.authorPalisson, Francis
dc.contributor.authorSalas -Alanis, Julio
dc.contributor.authorSouth, Andrew P.
dc.date.accessioned2023-07-07T17:14:25Z
dc.date.available2023-07-07T17:14:25Z
dc.date.issued2022
dc.description.abstractLack 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.
dc.description.versionVersión publicada
dc.identifier.citationCao Q, Tartaglia G, Alexander M, Park PH, Poojan S, Farshchian M, Fuentes I, Chen M, McGrath JA, Palisson F, Salas-Alanis J, South AP. Collagen VII maintains proteostasis in dermal fibroblasts by scaffolding TANGO1 cargo. Matrix Biol. 2022 Aug;111:226-244. doi: 10.1016/j.matbio.2022.06.008. Epub 2022 Jun 30. PMID: 35779741; PMCID: PMC9683098.
dc.identifier.doihttps://doi.org/10.1016/j.matbio.2022.06.008
dc.identifier.urihttps://repositorio.udd.cl/handle/11447/7662
dc.language.isoen
dc.subjectCollagen VII
dc.subjectER stress
dc.subjectTANGO1
dc.subjectTGFβ signaling
dc.subjectrecessive dystrophic epidermolysis bullosa
dc.subjectThrombospondin
dc.titleCollagen VII maintains proteostasis in dermal fibroblasts by scaffolding TANGO1 cargo
dc.typeArticle
dcterms.accessRightsAcceso abierto
dcterms.sourceMatrix Biology

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