The matriptase‐prostasin proteolytic cascade in dermatologic diseases

Abstract

The matriptase-prostasin cascade is a series of proteolytic reactions playing critical roles in multiple epithelial tissues. [1] Specifically, this cascade has unique components and functions in the epidermis. The matriptase-prostasin proteolytic cascade has been the subject of extensive recent dermatologic research, which has clarified its role in regulating differentiation and desquamation in the epidermis and follicular units. Additionally, genetic alterations in proteases in this cascade have been associated with human dermatologic diseases, including ichthyosis-hypotrichosis syndrome (IHS) and Netherton syndrome (NS). The matriptase-prostasin cascade is thus essential for proper epidermal function, and its dysfunction has clinical consequences. Given the relevance of this pathway to dermatology, we here provide an updated review of this cascade, with critical insight into multiple dermatologic diseases.

Reconstructing the epidermal proteolytic cascades in health and disease

“…At the transcriptional level, the mRNAs encoding KLKs are transcribed by keratinocytes located at the SG. The membrane-bound serine protease prostasin activates the epithelial sodium channel (ENaC), causing Na + influx in SG keratinocytes which, in turn, depolarizes the membrane and induces Ca 2+ influx through the voltage-gated calcium channel [15] to favor KLK expression [16,17].…”

Hepsin: a multifunctional transmembrane serine protease in pathobiology

“…Members of the TTSP family are expressed in many tissues, where they participate in diverse processes, including food digestion [14], epithelial differentiation [15,16], intestinal barrier function [17][18][19], skin permeability [20][21][22], sodium homeostasis [23,24], iron metabolism [25], and vascular remodeling [26,27]. TTSP deficiencies or overexpression has been reported in patients with malnutrition [14], skin defects [28,29], intestinal disease [30], iron deficiency anemia [25], hypertension [31,32], kidney disease [33], and cancer [34]. Moreover, epithelial TTSPs in human airways have been shown to cleave and activate coronavirus spike proteins, which is essential for viral infectivity [35,36].…”

New links for meprin β within the protease web

“…Wound healing phenotypes in mice with genetic ablation of either MT1-MMP or meprin b in epidermal keratinocytes are mild [12,13], but both proteases are increased in abundance during the redifferentiation phase, whereas ADAM17 also plays important roles in keratinocyte differentiation [14]. Activities with similar functional consequences have been assigned to matriptase-1 (ST14 (suppressor of tumorigenicity 14)) [15] that is closely related and shares cleavage specificity with matriptase-2 (TMPRSS6), a major activator of membrane-anchored meprin b [4], making it a potential candidate for meprin b activation in the epidermal compartment. As a caveat, most of these studies have been performed using mouse models, whereas Werny et al could only demonstrate mutual shedding of meprin b and MT1-MMP using human proteins.…”