title: Colocalization of cystatin M/E and its target proteases suggests a role in terminal differentiation of human hair follicle and nail.
abstract: The cysteine protease inhibitor cystatin M/E is a key regulator of a biochemical pathway that leads to epidermal terminal differentiation by inhibition of its target proteases cathepsin L, cathepsin V, and legumain. Inhibition of cathepsin L is important in the cornification process of the skin, as we have recently demonstrated that cathepsin L is the elusive processing and activating protease for transglutaminase 3, an enzyme that is responsible for crosslinking of structural proteins in cornified envelope formation. Here, we study the localization of all players of this pathway in the human hair follicle and nail unit in order to elucidate their possible role in the biology of these epidermal appendages. We found that cathepsin L and transglutaminase 3 specifically colocalize in the hair bulb and the nail matrix, the regions that provide cells that terminally differentiate to the hair fiber and the nail plate, respectively. Furthermore, transglutaminase 3 also colocalizes with the structural proteins loricrin and involucrin, which are established transglutaminase substrates. These findings suggest that cathepsin L and transglutaminase 3 could be involved in the pathway that leads to terminal differentiation, not only in the epidermis but also in the human hair follicle and nail unit.
authors.affiliation: Department of Dermatology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Tsing
authors.initials: T
authors.lastname: Cheng
authors.forename: Ivonne M J J
authors.initials: IM
authors.lastname: van Vlijmen-Willems
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Hitomi
authors.forename: Marcel C
authors.initials: MC
authors.lastname: Pasch
authors.forename: Piet E J
authors.initials: PE
authors.lastname: van Erp
authors.forename: Joost
authors.initials: J
authors.lastname: Schalkwijk
authors.forename: Patrick L J M
authors.initials: PL
authors.lastname: Zeeuwen
mesh_terms: D056668:Cathepsin L; D002403:Cathepsins / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology*; D055332:Cystatin M / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D018859:Hair Follicle / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D009262:Nails / Q000166:cytology / Q000378:metabolism*; D011498:Protein Precursors / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D011503:Transglutaminases / Q000378:metabolism*
chemical_list: C525104:CST6 protein, human; D055332:Cystatin M; D008565:Membrane Proteins; D011498:Protein Precursors; C064554:loricrin; C032253:involucrin; C498712:TGM3 protein, human; D011503:Transglutaminases; D002403:Cathepsins; D003546:Cysteine Endopeptidases; C534281:CTSL protein, human; D056668:Cathepsin L