Demodex cathepsin L degrades host macromolecules and keratinocyte proteins, implicating it in cutaneous injury

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The molecular mechanisms underlying skin injury induced by Demodex mites remain largely unclear. Our previous transcriptomic analysis identified cathepsin L (CatL) as a putative virulence factor; however, its proteolytic function and pathogenic roles in demodicosis have not been characterised. In the present study, recombinant CatL proteins from D. folliculorum (Df.rCatL) and D. brevis (Db.rCatL) were expressed, purified, and biochemically characterised. Fluorogenic substrates, host macromolecules, and HaCaT keratinocyte lysates were used to evaluate proteolytic activity. Enzymatic activity was quantified fluorimetrically, and protein degradation products were analysed by sodium dodecyl sulphate-polyacrylamide gel electrophoresis and liquid chromatography–tandem mass spectrometry-based proteomics. We revealed that both proteases exhibited cysteine-dependent activity under acidic pH and wide temperature adaptability. Notably, Df.rCatL exhibited markedly stronger proteolytic potency than Db.rCatL. Functionally, Df.rCatL hydrolysed a broader spectrum of host macromolecules including albumin, IgM, fibrinogen, and fibronectin, while Db.rCatL predominantly degraded only albumin. Proteomic profiling identified hundreds of keratinocyte proteins showing reduced abundance following rCatL treatment, including those involved in immune regulation, stress responses, protein homeostasis, energy metabolism, and apoptosis. Although Db.rCatL targeted a more diverse protein repertoire, Df.rCatL induced more extensive degradation, indicating higher enzymatic efficiency. In Conclusion, these findings strongly support a putative pathogenic role for Demodex CatL in epidermal barrier disruption and cutaneous injury, and highlight CatL as a potential therapeutic target for this inflammatory skin disorder.

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