Evidence map›Paper›PMID 39091758›Full record

ArticlebioRxiv : the preprint server for biology2024

Ribosomal Frameshifting Selectively Modulates the Assembly, Function, and Pharmacological Rescue of a Misfolded CFTR Variant.

Patrick Carmody, Francis J Roushar, Austin Tedman, Wei Wang, Madeline Herwig, Minsoo Kim, Eli F McDonald, Karen Noguera, Jennifer Wong-Roushar, Jon-Luc Poirier and 8 more

Abstract readPreprint
PubMed Full text at PMC Publisher
In one paragraph

Article in bioRxiv : the preprint server for biology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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0cells of the map it votes in
0citing papers in PubMed
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1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

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Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

18 authors.

Patrick CarmodyDepartment of Chemistry, Indiana University Bloomington, Bloomington, IN, USA 47401.
Francis J RousharDepartment of Chemistry, Indiana University Bloomington, Bloomington, IN, USA 47401.
Austin TedmanThe James Tarpo Jr. and Margaret Tarpo Department of Chemistry, Purdue University, West Lafayette, IN, USA 47907.
Wei WangDepartment of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA 35233.
Madeline HerwigDepartment of Chemistry, Vanderbilt University, Nashville, TN, USA 37240.
Minsoo KimDepartment of Chemistry, Vanderbilt University, Nashville, TN, USA 37240.
Eli F McDonaldDepartment of Chemistry, Vanderbilt University, Nashville, TN, USA 37240.
Karen NogueraDepartment of Chemistry, Indiana University Bloomington, Bloomington, IN, USA 47401.
Jennifer Wong-RousharDepartment of Chemistry, Indiana University Bloomington, Bloomington, IN, USA 47401.
Jon-Luc PoirierDepartment of Chemistry, Indiana University Bloomington, Bloomington, IN, USA 47401.
Nathan B ZeltDepartment of Chemistry, Indiana University Bloomington, Bloomington, IN, USA 47401.
Ben T PockrassDepartment of Chemistry, Indiana University Bloomington, Bloomington, IN, USA 47401.
Andrew G McKeeDepartment of Chemistry, Indiana University Bloomington, Bloomington, IN, USA 47401.
Charles P KuntzThe James Tarpo Jr. and Margaret Tarpo Department of Chemistry, Purdue University, West Lafayette, IN, USA 47907.
S Vamsee RajuDepartment of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA 35233.
Lars PlateDepartment of Chemistry, Vanderbilt University, Nashville, TN, USA 37240.
Wesley D PennDepartment of Chemistry, Indiana University Bloomington, Bloomington, IN, USA 47401.
Jonathan P SchlebachThe James Tarpo Jr. and Margaret Tarpo Department of Chemistry, Purdue University, West Lafayette, IN, USA 47907.ORCID 0000-0003-0955-7633

Funding

Stimulation of Ribosomal Frameshifting by Cotranslational Membrane Protein Folding and MisfoldingR01GM138845 · NIGMS · TRUSTEES OF INDIANA UNIVERSITY · PI SCHLEBACH, JONATHAN PATRICK · 2021 to 2024
$1.2M
NIGMS NIH HHS R01 GM138845
6 · The paper itself

Abstract

The cotranslational misfolding of the cystic fibrosis transmembrane conductance regulator chloride channel (CFTR) plays a central role in the molecular basis of cystic fibrosis (CF). The misfolding of the most common CF variant (ΔF508) 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 ΔF508 CFTR with numerous translation and quality control proteins. Moreover, disrupting this RNA structure enhances the functional gating of the ΔF508 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 ΔF508 CFTR appear to be attenuated in the absence of the ER membrane protein complex (EMC), 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 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.

Identifiers

PMID39091758
PMCPMC11290997

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.