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J Biol Chem. 2019 Sep 13;294(37):13769-13780. doi: 10.1074/jbc.RA119.008641. Epub 2019 Jul 25.

C-terminal proteolysis of the collagen VI α3 chain by BMP-1 and proprotein convertase(s) releases endotrophin in fragments of different sizes.

Author information

1
Center for Biochemistry, Faculty of Medicine, University of Cologne, 50931 Cologne, Germany.
2
Tissue Biology and Therapeutic Engineering Laboratory, UMR5305 CNRS/University of Lyon, 69367 Lyon, France.
3
Commissariat à l'Energie Atomique (CEA)-Marcoule, DRF/JOLIOT/DMTS/SPI/Li2D, Innovative Technologies for Detection and Diagnostics Laboratory, 30200 Bagnols-sur-Cèze, France.
4
Colzyx AB, Medicon Village, SE-223 81 Lund, Sweden.
5
Cologne Center for Musculoskeletal Biomechanics (CCMB), 50931 Cologne, Germany.
6
Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany.
7
Department of Pediatrics and Adolescent Medicine, Experimental Neonatology, Faculty of Medicine and University Hospital Cologne, 50931 Cologne, Germany.
8
Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany.
9
Tissue Biology and Therapeutic Engineering Laboratory, UMR5305 CNRS/University of Lyon, 69367 Lyon, France catherine.moali@ibcp.fr.
10
Center for Biochemistry, Faculty of Medicine, University of Cologne, 50931 Cologne, Germany raimund.wagener@uni-koeln.de.

Abstract

The assembly of collagen VI microfibrils is a multistep process in which proteolytic processing within the C-terminal globular region of the collagen VI α3 chain plays a major role. However, the mechanisms involved remain elusive. Moreover, C5, the short and most C-terminal domain of the α3 chain, recently has been proposed to be released as an adipokine that enhances tumor progression, fibrosis, inflammation, and insulin resistance and has been named "endotrophin." Serum endotrophin could be a useful biomarker to monitor the progression of such disorders as chronic obstructive pulmonary disease, systemic sclerosis, and kidney diseases. Here, using biochemical and isotopic MS-based analyses, we found that the extracellular metalloproteinase bone morphogenetic protein 1 (BMP-1) is involved in endotrophin release and determined the exact BMP-1 cleavage site. Moreover, we provide evidence that several endotrophin-containing fragments are present in various tissues and body fluids. Among these, a large C2-C5 fragment, which contained endotrophin, was released by furin-like proprotein convertase cleavage. By using immunofluorescence microscopy and EM, we also demonstrate that these proteolytic maturations occur after secretion of collagen VI tetramers and during microfibril assembly. Differential localization of N- and C-terminal regions of the collagen VI α3 chain revealed that cleavage products are deposited in tissue and cell cultures. The detailed information on the processing of the collagen VI α3 chain reported here provides a basis for unraveling the function of endotrophin (C5) and larger endotrophin-containing fragments and for refining their use as biomarkers of disease progression.

KEYWORDS:

BMP-1; Kunitz domain; Pro-C6; collagen; collagen VI; electron microscopy (EM); endotrophin; extracellular matrix protein; microfibrils; muscular dystrophy; proprotein convertase; protein processing

PMID:
31346034
PMCID:
PMC6746452
[Available on 2020-09-13]
DOI:
10.1074/jbc.RA119.008641

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