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The formation of disulphide bonds, which occurs by oxidation of Cys side chains, is important for the correct folding of proteins in the endoplasmic reticulum. The enzyme quiescin sulfhydryl oxidase 1 (QSOX1) catalyses disulphide bond formation, but its physiological function was unclear as it was previously reported to localize to the Golgi and to the extracellular environment. Ilani et al. now show that extracellular QSOX1 controls the composition of the extracellular matrix (ECM) and has a key role in cell adhesion and migration.

The authors set out to determine the role of QSOX1 in cultured confluent fibroblasts, which normally secrete QSOX1. siRNA-mediated depletion of this enzyme resulted in the detachment of cells from the substrate (although cell–cell adhesion was not impaired), and this effect was prevented by the addition of QSOX1 to the culture medium. This suggests that extracellular QSOX1 is required for cell–ECM adhesion.

As fibroblasts synthesize large amounts of ECM, the authors investigated whether its composition might be altered when QSOX1 is absent. Although collagen IV, fibronectin and other major ECM proteins were not affected, there was a dramatic decrease of laminin (a key basement membrane component) within the ECM and concomitant appearance of soluble laminin in the culture medium. This was reversed by the addition of QSOX1 to the medium, indicating that QSOX1 activity is required for laminin incorporation into the ECM.

Laminin is secreted as a heterotrimer of α-, β- and γ-subunits — each of which has multiple isotypes that confer different properties to the trimer. Unincorporated laminin produced by QSOX1-depleted fibroblasts was still trimeric, indicating that QSOX1 is not required for trimer assembly but for the integration of assembled trimers, particularly those containing an α4 subunit, into the ECM.

This work elucidates a crucial physiological function of secreted QSOX1 — laminin incorporation into the ECM — that is important for cell adhesion to the ECM. Laminin is also known to guide cell migration during normal development and metastatic invasion. Consistently, the authors found that the migration of lung carcinoma cells across a fibroblast layer was impaired upon QSOX1 depletion. Moreover, treatment with a new monoclonal antibody that inhibits QSOX1 decreased cell adhesion and migration, and so this might be useful to modulate ECM properties.