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HHD is characterized by impaired epidermal cell\u2010to\u2010cell adhesion and defective keratinocyte growth\/differentiation. The mechanism by which mutant ATP2C1 causes HHD is unknown and current treatments for affected individuals do not address the underlying defects and are ineffective. Notch signalling is a direct determinant of keratinocyte growth and differentiation. We found that loss of ATP2C1 leads to impaired Notch1 signalling, thus deregulation of the Notch signalling response is therefore likely to contribute to HHD manifestation. NOTCH1 is a transmembrane receptor and upon ligand binding, the\u00a0intracellular domain (NICD) translocates to the nucleus activating its target genes. In the context of HHD, we found that loss of ATP2C1 function promotes upregulation of the active NOTCH1 protein (NICD\u2010Val1744). Here, deeply exploring this aspect, we observed that NOTCH1 activation is not associated with the transcriptional enhancement of its targets. Moreover, in agreement with these results, we found a cytoplasmic localization of NICD\u2010Val1744. We have also observed that ATP2C1\u2010loss is associated with the degradation of NICD\u2010Val1744 through the lysosomal\/proteasome pathway. These results show that ATP2C1\u2010loss could promote a mechanism by which NOTCH1 is endocytosed and degraded by the cell membrane. The deregulation of this phenomenon, finely regulated in physiological conditions, could in HHD lead to the deregulation of NOTCH1 with alteration of skin homeostasis and disease manifestation.<\/jats:p>","DOI":"10.1111\/exd.14769","type":"journal-article","created":{"date-parts":[[2023,2,15]],"date-time":"2023-02-15T07:51:36Z","timestamp":1676447496000},"page":"787-798","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Loss of <scp>ATP2C1<\/scp> function promotes trafficking and degradation of <scp>NOTCH1<\/scp>: Implications for Hailey\u2010Hailey disease"],"prefix":"10.1111","volume":"32","author":[{"given":"Azzurra","family":"Zonfrilli","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine Sapienza University of Rome  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Truglio","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine Sapienza University of Rome  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Simeone","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine Sapienza University of Rome  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Pelullo","sequence":"additional","affiliation":[{"name":"CLN2S\u2010Center for Life Nano\u2010 &amp; Neuro\u2010Sciences Istituto Italiano di Tecnologia  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0872-185X","authenticated-orcid":false,"given":"Valeria","family":"De\u00a0Turris","sequence":"additional","affiliation":[{"name":"CLN2S\u2010Center for Life Nano\u2010 &amp; Neuro\u2010Sciences Istituto Italiano di Tecnologia  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dario","family":"Benelli","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine Sapienza University of Rome  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saula","family":"Checquolo","sequence":"additional","affiliation":[{"name":"Department of Medico\u2010Surgical Sciences and Biotechnology Sapienza University of Rome  Latina Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Bellavia","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine Sapienza University of Rome  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rocco","family":"Palermo","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine Sapienza University of Rome  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Uccelletti","sequence":"additional","affiliation":[{"name":"Department of Biology and Biotechnology \u201cC. 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