Proteostasis landscapes of cystic fibrosis variants reveal drug response vulnerability

• 成果类型: Article
• 署名作者: McDonald, Eli Fritz; Kim, Minsoo; Olson, John A.; Meiler, Jens; Plate, Lars
• 署名单位: Vanderbilt University; Vanderbilt University; Vanderbilt University; Vanderbilt University; Leipzig University; Vanderbilt University; Vanderbilt University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14066
• DOI: 10.1073/pnas.2418407122
• 发表日期: 2025-04-29
• 关键词: transmembrane conductance regulator; nucleotide-binding domain; quality-control; human cftr; degradation; rescue; f508del-cftr; identification; temperature; mechanism

摘要

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 reached with existing drugs to expand therapeutics to all susceptible CFTR variants.