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Mol. Life Sci."],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Cystic fibrosis (CF) is a monogenic disorder caused by mutations in the CFTR gene, which encodes a cAMP-regulated anion channel at the apical plasma membrane (PM) of epithelial cells. CFTR modulators have recently been approved as effective therapies for folding-defective mutations, including the most common variant, F508del. However, no clinically effective treatments are available for nonsense mutations such as G542X, the second most frequent CF-causing mutation. Translational readthrough-inducing drugs (TRIDs), such as G418, can suppress premature termination codons (PTCs) and partially restore full-length CFTR expression, but their therapeutic efficacy remains limited. Notably, combining TRIDs with CFTR modulators enhances functional rescue, suggesting that the restored full-length CFTR may be targeted by protein quality control (QC) pathways. Here, we investigated the QC mechanisms responsible for degrading TRID-induced full-length CFTR proteins harboring nonsense mutations. We identified the E3 ubiquitin ligases RNF5, RNF185, and RFFL as key regulators of CFTR turnover. Among these, RFFL played a particularly critical role in peripheral QC, targeting TRID-induced full-length CFTR for ubiquitination and degradation. Knockdown (KD) of RFFL markedly reduced CFTR ubiquitination, stabilized mature CFTR at the PM, and significantly enhanced functional rescue when TRIDs were combined with CFTR modulators. Enhanced CFTR channel activity confirmed that the stabilized proteins were functional. These findings indicate that RFFL-mediated degradation restricts the therapeutic benefit of TRID-based approaches. Targeting RFFL therefore represents a promising strategy to boost the efficacy of combination therapies involving TRIDs and CFTR modulators, offering new opportunities for the treatment of CF patients carrying nonsense CFTR mutations.<\/jats:p>","DOI":"10.1007\/s00018-026-06114-3","type":"journal-article","created":{"date-parts":[[2026,2,21]],"date-time":"2026-02-21T20:52:36Z","timestamp":1771707156000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["RFFL-mediated protein quality control limits functional rescue of TRID-CFTR modulator combination therapy for cystic fibrosis nonsense mutations"],"prefix":"10.1007","volume":"83","author":[{"given":"Hazuki","family":"Tateishi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukako","family":"Doi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuka","family":"Kamada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5175-2224","authenticated-orcid":false,"given":"Tsukasa","family":"Okiyoneda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,21]]},"reference":[{"key":"6114_CR1","doi-asserted-by":"publisher","first-page":"1859","DOI":"10.1001\/jama.2023.8120","volume":"329","author":"T Ong","year":"2023","unstructured":"Ong T, Ramsey BW (2023) Cystic fibrosis: a review. 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