{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSPINK5 encodes the serine protease inhibitor LEKTI, a multidomain protein that is central to skin differentiation and barrier homeostasis. LEKTI is synthesized as a high molecular‐weight precursor, which is rapidly processed by furin into a series of bioactive fragments. These fragments exert selective inhibitory activities against a subset of serine proteases, most notably the kallikreins (KLK5, KLK7, and KLK14), whose precise regulation is critical for orderly desquamation. Disruption of this finely tuned proteolytic balance, as seen in loss‐of‐function mutations in SPINK5, underlies the pathogenesis of Netherton syndrome, a severe autosomal recessive ichthyosis with characteristic hair defects and atopic features."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMechanistic studies have demonstrated that LEKTI fragments bind their protease targets rapidly and irreversibly, a process modulated by epidermal pH gradients that govern the release of proteolytic activity in the superficial stratum corneum. In addition to the exquisite domain‐specific inhibition of kallikreins, animal and cell‐based models confirm that defective LEKTI expression culminates in unrestrained proteolysis of desmosomal components and impaired barrier function, while secondary compensatory mechanisms are elicited to partially restore homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn parallel, genetic studies have highlighted that SPINK5 variants not only cause monogenic disorders such as Netherton syndrome but are also associated with common atopic conditions including atopic dermatitis and asthma. These investigations, through the analysis of polymorphisms and genotype–phenotype correlations, indicate that even subtle disruptions in LEKTI expression or processing can modulate local inflammatory responses, alter immunoglobulin E levels, and influence the severity of cutaneous barrier defects. Such associations underscore the multifactorial contribution of SPINK5 to overall barrier integrity and immunological homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "21"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMore recent work has expanded our understanding of SPINK5 function by uncovering alternative splicing mechanisms and additional protease targets that further diversify LEKTI’s activities. These studies reveal that distinct LEKTI isoforms may differentially regulate proteolytic cascades—not only by inhibiting epidermal kallikreins but also by interacting with enzymes such as mesotrypsin and caspase 14—and implicate LEKTI in broader signaling pathways including Wnt/β‐catenin. Functional assays in transgenic models and keratinocyte culture systems demonstrate that aberrant LEKTI processing contributes to desmosomal instability and chronic inflammation, thereby reinforcing a link between protease dysregulation, barrier dysfunction, and the pathogenesis of atopic as well as neoplastic conditions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "22", "end_ref": "46"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Celine Deraison, Chrystelle Bonnart, Frederic Lopez, et al. "}, {"type": "b", "children": [{"type": "t", "text": "LEKTI fragments specifically inhibit KLK5, KLK7, and KLK14 and control desquamation through a pH-dependent interaction."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Biol Cell (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1091/mbc.e07-02-0124"}], "href": "https://doi.org/10.1091/mbc.e07-02-0124"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17596512"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17596512"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Emmanuelle Bitoun, Alessia Micheloni, Laurence Lamant, et al. "}, {"type": "b", "children": [{"type": "t", "text": "LEKTI proteolytic processing in human primary keratinocytes, tissue distribution and defective expression in Netherton syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddg247"}], "href": "https://doi.org/10.1093/hmg/ddg247"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12915442"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12915442"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Nahoko Komatsu, Minoru Takata, Norio Otsuki, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Elevated stratum corneum hydrolytic activity in Netherton syndrome suggests an inhibitory regulation of desquamation by SPINK5-derived peptides."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Invest Dermatol (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1046/j.0022-202x.2001.01663.x"}], "href": "https://doi.org/10.1046/j.0022-202x.2001.01663.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11874482"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11874482"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Emmanuelle Bitoun, Stéphane Chavanas, Alan D Irvine, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Association of SPINK5 gene polymorphisms with atopic dermatitis in the Japanese population."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Br J Dermatol (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1046/j.1365-2133.2003.05243.x"}], "href": "https://doi.org/10.1046/j.1365-2133.2003.05243.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12752122"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12752122"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Jean-Pierre Hachem, Fredrik Wagberg, Matthias Schmuth, et al. 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