@article{bab2833698dc4b90a63628c6171f0dd5,
title = "Collagen VII maintains proteostasis in dermal fibroblasts by scaffolding TANGO1 cargo",
abstract = "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.",
keywords = "and TGFβ signaling, Collagen VII, ER stress, recessive dystrophic epidermolysis bullosa, TANGO1, thrombospondin",
author = "Qingqing Cao and Grace Tartaglia and Michael Alexander and Park, {Pyung Hung} and Shiv Poojan and Mehdi Farshchian and Ignacia Fuentes and Mei Chen and McGrath, {John A.} and Francis Palisson and Julio Salas-Alanis and South, {Andrew P.}",
note = "Funding Information: This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs and the Defense Health Agency J9, Research and Development Directorate, through the Congressionally Directed Medical Research Program under Award No. W81XWH-18-1-0382; and in part by the EB Research Partnership, The EB Medical Research Foundation, and the National Cancer Institute of the National Institutes of Health, Award No. R01 CA244522. Opinions, interpretations, conclusions and recommendations are those of the authors and are not necessarily endorsed by the Department of Defense or the NIH. We would like to thank all the patients who contributed to this study and the Microscopy Shared Resource at the Sidney Kimmel Cancer Center, supported by the NCI, grant 5P30CA056036-17. Figures 6 and S1 are created with BioRender.com. Funding Information: This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs and the Defense Health Agency J9, Research and Development Directorate, through the Congressionally Directed Medical Research Program under Award No. W81XWH-18-1-0382; and in part by the EB Research Partnership, The EB Medical Research Foundation, and the National Cancer Institute of the National Institutes of Health, Award No. R01 CA244522. Opinions, interpretations, conclusions and recommendations are those of the authors and are not necessarily endorsed by the Department of Defense or the NIH. We would like to thank all the patients who contributed to this study and the Microscopy Shared Resource at the Sidney Kimmel Cancer Center, supported by the NCI, grant 5P30CA056036-17. Figures 6 and S1 are created with BioRender.com. Publisher Copyright: {\textcopyright} 2022 The Authors",
year = "2022",
month = aug,
doi = "10.1016/j.matbio.2022.06.008",
language = "English",
volume = "111",
pages = "226--244",
journal = "Matrix Biology",
issn = "0945-053X",
publisher = "Elsevier",
}
