Abstract
A disintegrin and metalloproteinase with thrombospondin type I motif (ADAMTS)2 and ADAMTS14 were originally known for their ability to cleave the aminopropeptides of fibrillar collagens. Previous work using N-terminomic approach (N-TAILS) in vitro led to the identification of new substrates, including some molecules involved in TGF-β signaling. Here, N-TAILS was used to investigate the substrates of these two enzymes in vivo, by comparing the N-terminomes of the skin of wild type mice, mice deficient in ADAMTS2, in ADAMTS14 and in both ADAMTS2 and ADAMTS14. This study identified 68 potential extracellular and cell surface proteins, with the majority of them being cleaved by both enzymes. These analyses comfort their role in collagen matrix organization and suggest their implication in inflammatory processes. Regarding fibrillar collagen, this study demonstrates that both ADAMTS2 and ADAMTS14 are involved in the processing of the aminopropeptide of alpha1 and alpha2 type V collagen. It also revealed the existence of several cleavage sites in the Col1 domain and in the C-propeptide of type I collagens. In addition to collagens and other extracellular proteins, two major components of the cell cytoskeleton, actin and vimentin, were also identified as potential substrates. The latter data were confirmed in vitro using purified enzymes and could potentially indicate other functions for ADAMTS2 and 14. This original investigation of mouse skin degradomes by N-terminomic highlights the essential role of ADAMTS2 and ADAMTS14 in collagen matrix synthesis and turnover, and gives clues to better understand their functions in skin pathophysiology. Data are available via ProteomeXchange with identifier PXD022179.
Highlights
Ehlers-Danlos syndrome (EDS) encompasses a group of inherited diseases caused by mutations affecting genes involved in the homeostasis of connective tissues (Beighton et al, 1998)
ADAMTS2 and ADAMTS14 are clearly implicated in several physio-pathological processes (Colige et al, 1999; Kesteloot et al, 2007; Dubail et al, 2010; Dupont et al, 2018; Wang et al, 2020). To better understand their in vivo roles in skin physiology and extracellular matrix homeostasis, N-terminomic experiments have been performed on skin of mice, either wild type (Wt), deficient in Adamts2 (TS2−/−), deficient in Adamts14 (TS14−/−)
Sixty-eight proteins located at the cell surface or being part of the extracellular matrix were identified as potential substrates of ADAMTS2 and/or ADAMTS14, from which fibrillary collagens were the most represented in terms of identified peptides
Summary
Ehlers-Danlos syndrome (EDS) encompasses a group of inherited diseases caused by mutations affecting genes involved in the homeostasis of connective tissues (Beighton et al, 1998). Absence of ADAMTS2 activity causes dermatosparaxis EDS presenting with extreme skin fragility, characteristic craniofacial features, redundant skin with excessive skin folds at the wrists and ankles, umbilical hernia and severe bruising with a risk of subcutaneous hematomas and hemorrhages (Colige et al, 1999). In these patients and in animal models of deficiency in Adamts (TS2−/−) electron microscopy shows collagen fibrils with a highly typical hieroglyphic or ribbon-like pattern. These differences in the morphology of collagen fib rils in arthrochalasia and dermatosparaxis, while persistence of N-propeptides is observed in both diseases, suggested that ADAMTS2 has possibly substrates other than type I procollagens
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