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Mol. Biosci."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> Loss of function mutation in <jats:italic>FLG<\/jats:italic> is the major genetic risk factor for atopic dermatitis (AD) and other allergic manifestations. Presently, little is known about the cellular turnover and stability of profilaggrin, the protein encoded by <jats:italic>FLG<\/jats:italic>. Since ubiquitination directly regulates the cellular fate of numerous proteins, their degradation and trafficking, this process could influence the concentration of filaggrin in the skin.<\/jats:p><jats:p><jats:bold>Objective:<\/jats:bold> To determine the elements mediating the interaction of profilaggrin with the ubiquitin-proteasome system (i.e., degron motifs and ubiquitination sites), the features responsible for its stability, and the effect of nonsense and frameshift mutations on profilaggrin turnover.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> The effect of inhibition of proteasome and deubiquitinases on the level and modifications of profilaggrin and processed products was assessed by immunoblotting. Wild-type profilaggrin sequence and its mutated variants were analysed <jats:italic>in silico<\/jats:italic> using the DEGRONOPEDIA and Clustal Omega tool.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> Inhibition of proteasome and deubiquitinases stabilizes profilaggrin and its high molecular weight of presumably ubiquitinated derivatives. <jats:italic>In silico<\/jats:italic> analysis of the sequence determined that profilaggrin contains 18 known degron motifs as well as multiple canonical and non-canonical ubiquitination-prone residues. <jats:italic>FLG<\/jats:italic> mutations generate products with increased stability scores, altered usage of the ubiquitination marks, and the frequent appearance of novel degrons, including those promoting C-terminus-mediated degradation routes.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> The proteasome is involved in the turnover of profilaggrin, which contains multiple degrons and ubiquitination-prone residues. <jats:italic>FLG<\/jats:italic> mutations alter those key elements, affecting the degradation routes and the mutated products\u2019 stability.<\/jats:p>","DOI":"10.3389\/fmolb.2023.1105678","type":"journal-article","created":{"date-parts":[[2023,5,2]],"date-time":"2023-05-02T05:00:01Z","timestamp":1683003601000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["In silico analysis of the profilaggrin sequence indicates alterations in the stability, degradation route, and intracellular protein fate in filaggrin null mutation carriers"],"prefix":"10.3389","volume":"10","author":[{"given":"Argho Aninda","family":"Paul","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia A.","family":"Szulc","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian","family":"Kobiela","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara J.","family":"Brown","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wojciech","family":"Pokrzywa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danuta","family":"Gutowska-Owsiak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,5,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"400","DOI":"10.1038\/nrc2657","article-title":"P21 in cancer: Intricate networks and multiple activities","volume":"9","author":"Abbas","year":"2009","journal-title":"Nat. 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