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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,4,29]]},"abstract":"<jats:p>Cystic fibrosis (CF) is a lethal genetic disorder caused by variants in CF transmembrane conductance regulator (CFTR). Many variants are treatable with correctors, which enhance the folding and trafficking of CFTR. However, approximately 3% of persons with CF harbor poorly responsive variants. Here, we used affinity purification mass spectrometry proteomics to profile the protein homeostasis (proteostasis) changes of CFTR variants during correction to assess modulated interactions with protein folding and maturation pathways. Responsive variant interactions converged on similar proteostasis pathways during correction. In contrast, poorly responsive variants subtly diverged, revealing a partial restoration of protein quality control surveillance and partial correction. Computational structural modeling showed that corrector VX-445 failed to confer enough NBD1 stability to poor responders. NBD1 secondary stabilizing mutations rescued poorly responsive variants, revealing structural vulnerabilities in NBD1 required for treating poor responders. Our study provides a framework for discerning the underlying protein quality control and structural defects of CFTR variants not reached with existing drugs to expand therapeutics to all susceptible CFTR variants.<\/jats:p>","DOI":"10.1073\/pnas.2418407122","type":"journal-article","created":{"date-parts":[[2025,4,22]],"date-time":"2025-04-22T13:36:04Z","timestamp":1745328964000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":8,"title":["Proteostasis landscapes of cystic fibrosis variants reveal drug response vulnerability"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0572-330X","authenticated-orcid":false,"given":"Eli Fritz","family":"McDonald","sequence":"first","affiliation":[{"name":"Department of Chemistry, Vanderbilt University","place":["Nashville"]},{"name":"Center for Structural Biology, Vanderbilt University","place":["Nashville"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9854-2999","authenticated-orcid":false,"given":"Minsoo","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Vanderbilt University","place":["Nashville"]},{"name":"Chemical and Physical Biology Program, Vanderbilt University","place":["Nashville"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9654-6611","authenticated-orcid":false,"suffix":"III","given":"John A.","family":"Olson","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Vanderbilt University","place":["Nashville"]},{"name":"Chemical and Physical Biology Program, Vanderbilt University","place":["Nashville"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8945-193X","authenticated-orcid":false,"given":"Jens","family":"Meiler","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Vanderbilt University","place":["Nashville"]},{"name":"Center for Structural Biology, Vanderbilt University","place":["Nashville"]},{"name":"Department of Pharmacology, Vanderbilt University","place":["Nashville"]},{"name":"Institute for Drug Discovery, Leipzig University","place":["Leipzig, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4363-6116","authenticated-orcid":false,"given":"Lars","family":"Plate","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Vanderbilt University","place":["Nashville"]},{"name":"Department of Biological Sciences, Vanderbilt University","place":["Nashville"]},{"name":"Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center","place":["Nashville"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2025,4,22]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e14-04-0935"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1021\/acschembio.3c00310"},{"key":"e_1_3_4_3_2","unstructured":"Vertex Pharmaceuticals Incorporated Who TRIKAFTA\u00ae is For? 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