Proprotein convertase expression and localization in epidermis: evidence for multiple roles and substrates

Abstract

Specific proteolysis plays an important role in the terminal differentiation of keratinocytes in the epidermis and several types of proteases have been implicated in this process. The proprotein convertases (PCs) are a family of Ca2+-dependent serine proteases involved in processing and activation of several types of substrates. In this study we examined the expression and some potential substrates of PCs in epidermis. Four PCs are expressed in epidermis: furin, PACE4, PC5/6 and PC7/8. Furin is detected in two forms, either with or without the transmembrane domain, suggesting occurrence of post-translational cleavage to produce a soluble enzyme. In addition the furin active site has differential accessibility in the granular layer of the epidermis relative to the basal layer, whereas antibodies to the transmembrane domain stain both layers. These findings suggest that furin has access to different types of substrates in granular cells as opposed to basal cells. PC7/8, in contrast, is detected throughout the epidermis with antibodies to both the transmembrane and active site and no soluble form observed. A peptide PC inhibitor (dec-RVKR-CMK) inhibits cleavage of Notch-1, a receptor important in cell fate determination that is found throughout the epidermis. Profilaggrin, found in the granular layer, is specifically cleaved by furin and PACE4 in vitro at a site between the amino terminus and the first filaggrin repeat. This work suggests that the PCs play multiple roles during epidermal differentiation.

Proprotein Convertase Subtilisin/Kexin Type 7 (PCSK7) Is Essential for the Zebrafish Development and Bioavailability of Transforming Growth Factor β1a (TGFβ1a)

“…In accordance with previous reports in mammals, the zebrafish PCSK enzymes also show variation in their developmental and tissue-specific expression. Zebrafish homologs for the neuroendocrine system-specific PCSK1 and PCSK2 were particularly highly expressed in the fish neural tissues, and the homologs of previously reported ubiquitous enzymes, such as FURIN, PCSK5, and PCSK7, were found to be relatively widely expressed similarly to earlier reports using mammals (17,18,47). PCSK7 shares several common substrate molecules with PCSK5 and FURIN at least in in vitro analyses (48).…”

Furin Is a Chemokine-modifying Enzyme

“…Some PCs are specific for certain cells and tissues. In the epidermis, expression of furin, PACE4, PC5/6, and PC7/8 has been identified (35). Because the pro-protein convertase inhibitor used in our studies also inhibits other PCs, we cannot exclude the possibility that other PCs are involved in the CXCL10 processing in vivo.…”

Cleavage of the papillomavirus minor capsid protein, L2, at a furin consensus site is necessary for infection

“…However, it remains formally possible that a PC family member not expressed in these cells might be able to do so, because dec.-RVKR-cmk inhibits substrate binding to furin and related PCs (36). Keratinocytes, which are the natural host cell for PV, are known to express furin, PACE4, PC5͞6, and PC7͞8 (37). CHO cells express PC7͞8 but not PACE4 (13), whereas LoVo express PACE4 (15,23).…”