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bioRxiv · 10.1101/2021.03.25.436925

The endosome is a master regulator of plasma membrane collagen fibril assembly

CHANG, J.·PICKARD, A.·GARVA, R.·Lu, Y.·Gullberg, D.·KADLER, K. E.
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Abstract

Collagen-I fibrillogenesis is crucial to health and development, where dysregulation is a hallmark of fibroproliferative diseases. Here, we show that collagen-I fibril assembly required a functional endocytic system that recycles collagen-I to assemble new fibrils. Endogenous collagen production was not required for fibrillogenesis if exogenous collagen was available, but the circadian-regulated vacuolar protein sorting (VPS) 33b and collagen-binding integrin 11 subunit were crucial to fibrillogenesis. Cells lacking VPS33B secrete soluble collagen-I protomers but were deficient in fibril formation, thus secretion and assembly are separately controlled. Overexpression of VPS33B led to loss of fibril rhythmicity and over-abundance of fibrils, which was mediated through integrin 11{beta}1. Endocytic recycling of collagen-I was enhanced in human fibroblasts isolated from idiopathic pulmonary fibrosis, where VPS33B and integrin 11 subunit were overexpressed at the fibrogenic front; this correlation between VPS33B, integrin 11 subunit, and abnormal collagen deposition was also observed in samples from patients with chronic skin wounds. In conclusion, our study showed that circadian-regulated endocytic recycling is central to homeostatic assembly of collagen fibrils and is disrupted in diseases.

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CHANG, J., PICKARD, A., GARVA, R., Lu, Y., Gullberg, D., KADLER, K. E.. 2021-03-25. The endosome is a master regulator of plasma membrane collagen fibril assembly. https://doi.org/10.1101/2021.03.25.436925

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