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Nevertheless, its primary functions in human signaling remain unclear due to the limited identification of direct substrates. Here, we investigated the interaction between RNF213 and caveolin-1 (Cav-1), a small scaffolding protein vital for caveolae formation and the regulation of a plethora of cellular processes. Cav-1 specifically binds within the two functional AAA+ domains of RNF213 in an ATP-dependent manner, highlighting the influence of cellular energy status on this interaction. Consequently, RNF213 ubiquitinates Cav-1 at several N-terminal lysine residues through K48 and K63 linkages, although several Moyamoya disease-associated RNF213 mutations greatly reduce this polyubiquitination. Moreover, RNF213 activity inhibits phosphorylation of a key regulatory residue of Cav-1, as RNF213 knockdown under oxidative stress markedly enhances Cav-1 Tyr14 phosphorylation and modifies nitric oxide bioavailability in endothelial cells. Collectively, our results indicate that RNF213 functions as a molecular switch modulating Cav-1 signaling based on RNF213 functionality and cellular conditions. These findings offer new insights into vascular pathogenesis and the vast signal pathways along the RNF213\u2013Cav-1 axis.<\/jats:p>","DOI":"10.3390\/cells14110775","type":"journal-article","created":{"date-parts":[[2025,5,25]],"date-time":"2025-05-25T20:39:36Z","timestamp":1748205576000},"page":"775","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["RNF213 Acts as a Molecular Switch for Cav-1 Ubiquitination and Phosphorylation in Human Cells"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2451-5634","authenticated-orcid":false,"given":"Jungmi","family":"Choi","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Biosciences, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryoichi","family":"Inoue","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biosciences, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-3515-173X","authenticated-orcid":false,"given":"Yuki","family":"Masuo","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biosciences, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukiko","family":"Shimizu","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biosciences, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhiro","family":"Sonomura","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8536-8653","authenticated-orcid":false,"given":"Minsoo","family":"Kim","sequence":"additional","affiliation":[{"name":"Laboratory of Integrative Molecular Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5664-6869","authenticated-orcid":false,"given":"Hatasu","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, Tsu 514-8507, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7319-123X","authenticated-orcid":false,"given":"Kouji H.","family":"Harada","sequence":"additional","affiliation":[{"name":"Department of Health and Environmental Sciences, Graduate School of Medicine, Kyoto University, Kyoto 606-8601, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6346-3999","authenticated-orcid":false,"given":"Yohei","family":"Mineharu","sequence":"additional","affiliation":[{"name":"Department of Artificial Intelligence in Healthcare and Medicine, Kyoto University, Kyoto 606-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akio","family":"Koizumi","sequence":"additional","affiliation":[{"name":"Institute of Public Health, Kyoto Hokenkai Foundation, Kyoto 616-8149, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tohru","family":"Tezuka","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biosciences, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan"},{"name":"Laboratory of Integrative Molecular Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-4096-8677","authenticated-orcid":false,"given":"Shohab","family":"Youssefian","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biosciences, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1038\/jhg.2010.132","article-title":"A genome-wide association study identifies RNF213 as the first Moyamoya disease gene","volume":"56","author":"Kamada","year":"2011","journal-title":"J. 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