title: Elastase 2 is expressed in human and mouse epidermis and impairs skin barrier function in Netherton syndrome through filaggrin and lipid misprocessing.
abstract: The human epidermis serves 2 crucial barrier functions: it protects against water loss and prevents penetration of infectious agents and allergens. The physiology of the epidermis is maintained by a balance of protease and antiprotease activities, as illustrated by the rare genetic skin disease Netherton syndrome (NS), in which impaired inhibition of serine proteases causes severe skin erythema and scaling. Here, utilizing mass spectrometry, we have identified elastase 2 (ELA2), which we believe to be a new epidermal protease that is specifically expressed in the most differentiated layer of living human and mouse epidermis. ELA2 localized to keratohyalin granules, where it was found to directly participate in (pro-)filaggrin processing. Consistent with the observation that ELA2 was hyperactive in skin from NS patients, transgenic mice overexpressing ELA2 in the granular layer of the epidermis displayed abnormal (pro-)filaggrin processing and impaired lipid lamellae structure, which are both observed in NS patients. These anomalies led to dehydration, implicating ELA2 in the skin barrier defect seen in NS patients. Thus, our work identifies ELA2 as a major new epidermal protease involved in essential pathways for skin barrier function. These results highlight the importance of the control of epidermal protease activity in skin homeostasis and designate ELA2 as a major protease driving the pathogenesis of NS.
authors.affiliation: INSERM, U, Toulouse, France.
authors.forename: Chrystelle
authors.initials: C
authors.lastname: Bonnart
authors.forename: Céline
authors.initials: C
authors.lastname: Deraison
authors.forename: Matthieu
authors.initials: M
authors.lastname: Lacroix
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Uchida
authors.forename: Céline
authors.initials: C
authors.lastname: Besson
authors.forename: Aurélie
authors.initials: A
authors.lastname: Robin
authors.forename: Anaïs
authors.initials: A
authors.lastname: Briot
authors.forename: Marie
authors.initials: M
authors.lastname: Gonthier
authors.forename: Laurence
authors.initials: L
authors.lastname: Lamant
authors.forename: Pierre
authors.initials: P
authors.lastname: Dubus
authors.forename: Bernard
authors.initials: B
authors.lastname: Monsarrat
authors.forename: Alain
authors.initials: A
authors.lastname: Hovnanian
mesh_terms: D000818:Animals; D003594:Cytoplasmic Granules / Q000201:enzymology / Q000235:genetics; D004817:Epidermis / Q000201:enzymology* / Q000473:pathology; D000091344:Filaggrin Proteins; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007381:Intermediate Filament Proteins / Q000235:genetics / Q000378:metabolism*; D007633:Keratins / Q000235:genetics / Q000378:metabolism; D050356:Lipid Metabolism; D051379:Mice; D008822:Mice, Transgenic; D056770:Netherton Syndrome / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D012697:Serine Endopeptidases / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins; C001500:keratohyalin; D007633:Keratins; D012697:Serine Endopeptidases; C117309:pancreatic elastase II