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The most frequent mutation is F508del. This mutation leads to a misfolded CFTR protein quickly degraded via ubiquitination in the endoplasmic reticulum. Although preventing ubiquitination stabilizes the protein, functionality is not restored due to impaired plasma membrane transport. However, inhibiting the ubiquitination process can improve the effectiveness of correctors which act as chemical chaperones, facilitating F508del CFTR trafficking to the plasma membrane. Previous studies indicate a crosstalk between SUMOylation and ubiquitination in the regulation of CFTR. In this study, we investigated the potential of inhibiting SUMOylation to increase the effects of correctors and enhance the rescue of the F508del mutant across various cell models. In the widely used CFBE41o-cell line expressing F508del-CFTR, inhibiting SUMOylation substantially boosted F508del expression, thereby increasing the efficacy of correctors. Interestingly, this outcome did not result from enhanced stability of the mutant channel, but rather from augmented cytomegalovirus (CMV) promoter-mediated gene expression of F508del-CFTR. Notably, CFTR regulated by endogenous promoters in multiple cell lines or patient cells was not influenced by SUMOylation inhibitors.<\/jats:p>","DOI":"10.3390\/ijms25042302","type":"journal-article","created":{"date-parts":[[2024,2,15]],"date-time":"2024-02-15T05:55:59Z","timestamp":1707976559000},"page":"2302","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["SUMOylation Inhibition Enhances Protein Transcription under CMV Promoter: A Lesson from a Study with the F508del-CFTR Mutant"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9540-8145","authenticated-orcid":false,"given":"Christian","family":"Borgo","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9217-9404","authenticated-orcid":false,"given":"Claudio","family":"D\u2019Amore","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valeria","family":"Capurro","sequence":"additional","affiliation":[{"name":"UOC Genetica Medica, IRCCS Istituto Giannina Gaslini, Via Gerolamo Gaslini 5, 16147 Genova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3761-1916","authenticated-orcid":false,"given":"Valeria","family":"Tomati","sequence":"additional","affiliation":[{"name":"UOC Genetica Medica, IRCCS Istituto Giannina Gaslini, Via Gerolamo Gaslini 5, 16147 Genova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5161-1720","authenticated-orcid":false,"given":"Nicoletta","family":"Pedemonte","sequence":"additional","affiliation":[{"name":"UOC Genetica Medica, IRCCS Istituto Giannina Gaslini, Via Gerolamo Gaslini 5, 16147 Genova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4659-1873","authenticated-orcid":false,"given":"Valentina","family":"Bosello Travain","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, University of Padova, 35131 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3448-6048","authenticated-orcid":false,"given":"Mauro","family":"Salvi","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1992","DOI":"10.1056\/NEJMra043184","article-title":"Cystic Fibrosis","volume":"352","author":"Rowe","year":"2005","journal-title":"N. 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