Proteases: common culprits in human skin disorders

•Proteases execute a wide range of fundamental processes in epidermal biology.•Proteases and their inhibitors have key roles in a growing number of skin diseases.•Loss of a single protease or inhibitor can severely disrupt epidermal homeostasis.•Proteases are emerging as crucial signalling molecules in several cellular pathways.

Recent findings from the clinic and the laboratory have transformed the way proteases and their inhibitors are perceived in the outermost layer of the skin, the epidermis. It now appears that an integrated proteolytic network operates within the epidermis, comprising more than 30 enzymes that carry out a growing list of essential functions. Equally, defective regulation or execution of protease-mediated processes is emerging as a key contributor to diverse human skin pathologies, and in recent years the number of diseases attributable to aberrant proteolytic activity has more than doubled. Here, we survey the different roles of proteases in epidermal homeostasis (from processing enzymes to signalling molecules) and explore the spectrum of rare and common human skin disorders where proteolytic pathways are dysregulated.