{"doi":"10.1016/j.jid.2022.08.054","title":"Keratin 75 Is a Component of the LINC Complex and Has an Essential Role in Mediating the SOX2 Rapid Healing Response during Wound Repair","abstract":"The wound healing process relies on the proper execution and regulation of signaling pathways and transcriptional regulators to properly coordinate the wound healing response (Eming et al., 2014Eming S.A. Martin P. Tomic-Canic M. Wound repair and regeneration: mechanisms, signaling, and translation.Sci Transl Med. 2014; 6: 265sr6Crossref PubMed Scopus (1428) Google Scholar). Although epithelial lining tissues have a remarkable ability for tissue repair, the efficiency of such repair varies depending on the tissue considered (Iglesias-Bartolome et al., 2018Iglesias-Bartolome R. Uchiyama A. Molinolo A.A. Abusleme L. Brooks S.R. Callejas-Valera J.L. et al.Transcriptional signature primes human oral mucosa for rapid wound healing.Sci Transl Med. 2018; 10eaap8798Crossref PubMed Scopus (83) Google Scholar). For example, wounds of the oral mucosa heal more effectively than wounds of the skin (Iglesias-Bartolome et al., 2018Iglesias-Bartolome R. Uchiyama A. Molinolo A.A. Abusleme L. Brooks S.R. Callejas-Valera J.L. et al.Transcriptional signature primes human oral mucosa for rapid wound healing.Sci Transl Med. 2018; 10eaap8798Crossref PubMed Scopus (83) Google Scholar). Recently, our laboratory performed a comparative analysis on human oral and cutaneous skin wounds and determined that a wound-activated transcriptional network regulated by the transcription factor SOX2 establishes a network that primes the oral epithelium for rapid wound repair (Iglesias-Bartolome et al., 2018Iglesias-Bartolome R. Uchiyama A. Molinolo A.A. Abusleme L. Brooks S.R. Callejas-Valera J.L. et al.Transcriptional signature primes human oral mucosa for rapid wound healing.Sci Transl Med. 2018; 10eaap8798Crossref PubMed Scopus (83) Google Scholar). Reprogramming of cutaneous skin by SOX2 corresponded to increased expression of several wound-activated keratin genes, including keratin (K)6 gene K6, gene K16, and gene K17 at baseline before wounding, further showing priming of cutaneous skin for rapid wound healing (Iglesias-Bartolome et al., 2018Iglesias-Bartolome R. Uchiyama A. Molinolo A.A. Abusleme L. Brooks S.R. Callejas-Valera J.L. et al.Transcriptional signature primes human oral mucosa for rapid wound healing.Sci Transl Med. 2018; 10eaap8798Crossref PubMed Scopus (83) Google Scholar; Uchiyama et al., 2019Uchiyama A. Nayak S. Graf R. Cross M. Hasneen K. Gutkind J.S. et al.SOX2 epidermal overexpression promotes cutaneous wound healing via activation of EGFR/MEK/ERK signaling mediated by EGFR ligands.J Invest Dermatol. 2019; 139: 1809-1820.e8Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar). In addition to the wound-activated keratin genes, we found that SOX2 corresponded to increased expression of K75, a hair follicle type II keratin, in human oral mucosa and mouse models of rapid wound healing (Supplementary Figure S1), suggesting a role for this keratin in the SOX2-mediated rapid healing response. In addition to its role as a hair keratin gene, we identified K75 to be secreted by ameloblast cells to form dental enamel (Yang et al., 2019Yang X. Yamazaki H. Yamakoshi Y. Duverger O. Morasso M.I. Beniash E. Trafficking and secretion of keratin 75 by ameloblasts in vivo.J Biol Chem. 2019; 294: 18475-18487Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar) and to be an essential component of the enamel organic matrix (Chiba et al., 2019Chiba R. Okubo M. Yamamoto R. Saito M.M. Kobayashi S. Beniash E. et al.Porcine keratin 75 in developing enamel.J Oral Biosci. 2019; 61: 163-172Crossref PubMed Scopus (1) Google Scholar; Duverger et al., 2014Duverger O. Ohara T. Shaffer J.R. Donahue D. Zerfas P. Dullnig A. et al.Hair keratin mutations in tooth enamel increase dental decay risk.J Clin Invest. 2014; 124: 5219-5224Crossref PubMed Scopus (34) Google Scholar). Sequence variations in K75 had been previously shown to be directly correlated with defects in mouse hair shafts (Liu et al., 2016Liu Y. Snedecor E.R. Zhang X. Xu Y. Huang L. 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