Ribosomal frameshifting selectively modulates the assembly, function, and pharmacological rescue of a misfolded CFTR variant

• 成果类型: Article
• 署名作者: Carmody, Patrick J.; Roushar, Francis J.; Tedman, Austin; Wang, Wei; Herwig, Madeline; Kim, Minsoo; McDonald, Eli F.; Noguera, Karen; Wong-Roushar, Jennifer; Poirier, Jon-Luc; Zelt, Nathan B.; Pockrass, Ben T.; McKee, Andrew G.; Kuntz, Charles P.; Raju, S. Vamsee; Plate, Lars; Penn, Wesley D.; Schlebach, Jonathan P.
• 署名单位: Indiana University System; Indiana University Bloomington; Purdue University System; Purdue University; University of Alabama System; University of Alabama Birmingham; Vanderbilt University; Vanderbilt University; Vanderbilt University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14379
• DOI: 10.1073/pnas.2414768121
• 发表日期: 2024-10-15
• 关键词: ccr5 messenger-rna; cystic-fibrosis; upf1

摘要

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 (OF508) 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 -1 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 OF508 CFTR with numerous translation and quality control proteins. Moreover, disrupting this RNA structure enhances the functional gating of the OF508 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 OF508 CFTR appear to be attenuated in the absence of the ER membrane protein complex, which was previously found to modulate ribosome collisions during preemptive quality control 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.