{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T21:02:53Z","timestamp":1785445373016,"version":"3.56.0"},"reference-count":46,"publisher":"National Academy of Sciences","issue":"42","license":[{"start":{"date-parts":[[2024,10,10]],"date-time":"2024-10-10T00:00:00Z","timestamp":1728518400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"HHS | NIH | National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R01GM138845"],"award-info":[{"award-number":["R01GM138845"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"HHS | NIH | National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R35GM152086"],"award-info":[{"award-number":["R35GM152086"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,10,15]]},"abstract":"<jats:p>The cotranslational misfolding of the cystic fibrosis transmembrane conductance regulator chloride channel (CFTR) plays a central role in the molecular basis of CF. The misfolding of the most common CF variant (\u0394F508) remodels both the translational regulation and quality control of CFTR. Nevertheless, it is unclear how the misassembly of the nascent polypeptide may directly influence the activity of the translation machinery. In this work, we identify a structural motif within the CFTR transcript that stimulates efficient \u22121 ribosomal frameshifting and triggers the premature termination of translation. Though this motif does not appear to impact the interactome of wild-type CFTR, silent mutations that disrupt this RNA structure alter the association of nascent \u0394F508 CFTR with numerous translation and quality control proteins. Moreover, disrupting this RNA structure enhances the functional gating of the \u0394F508 CFTR channel at the plasma membrane and its pharmacological rescue by the CFTR modulators contained in the CF drug Trikafta. The effects of the RNA structure on \u0394F508 CFTR appear to be attenuated in the absence of the ER membrane protein complex, which was previously found to modulate ribosome collisions during \u201cpreemptive quality control\u201d of a misfolded CFTR homolog. Together, our results reveal that ribosomal frameshifting selectively modulates the assembly, function, and pharmacological rescue of a misfolded CFTR variant. These findings suggest that interactions between the nascent chain, quality control machinery, and ribosome may dynamically modulate ribosomal frameshifting in order to tune the processivity of translation in response to cotranslational misfolding.<\/jats:p>","DOI":"10.1073\/pnas.2414768121","type":"journal-article","created":{"date-parts":[[2024,10,10]],"date-time":"2024-10-10T11:54:56Z","timestamp":1728561296000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":8,"title":["Ribosomal frameshifting selectively modulates the assembly, function, and pharmacological rescue of a misfolded CFTR variant"],"prefix":"10.1073","volume":"121","author":[{"given":"Patrick J.","family":"Carmody","sequence":"first","affiliation":[{"name":"Department of Chemistry, Indiana University Bloomington, Bloomington, IN 47401"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francis J.","family":"Roushar","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Indiana University Bloomington, Bloomington, IN 47401"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Austin","family":"Tedman","sequence":"additional","affiliation":[{"name":"The James Tarpo Junior and Margaret Tarpo Department of Chemistry, Purdue University, West Lafayette, IN 47907"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35233"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madeline","family":"Herwig","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Vanderbilt University, Nashville, TN 37240"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minsoo","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Vanderbilt University, Nashville, TN 37240"},{"name":"Program in Chemical and Physical Biology, Vanderbilt University, Nashville, TN 37240"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eli F.","family":"McDonald","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Vanderbilt University, Nashville, TN 37240"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Noguera","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Indiana University Bloomington, Bloomington, IN 47401"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3278-3711","authenticated-orcid":false,"given":"Jennifer","family":"Wong-Roushar","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Indiana University Bloomington, Bloomington, IN 47401"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jon-Luc","family":"Poirier","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Indiana University Bloomington, Bloomington, IN 47401"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan B.","family":"Zelt","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Indiana University Bloomington, Bloomington, IN 47401"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben T.","family":"Pockrass","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Indiana University Bloomington, Bloomington, IN 47401"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew G.","family":"McKee","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Indiana University Bloomington, Bloomington, IN 47401"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles P.","family":"Kuntz","sequence":"additional","affiliation":[{"name":"The James Tarpo Junior and Margaret Tarpo Department of Chemistry, Purdue University, West Lafayette, IN 47907"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. 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