PXD039773

PXD039773 is an original dataset announced via ProteomeXchange.

Title	Elexacaftor/VX-445-mediated CFTR interactome remodeling reveals differential correction driven by mutation-specific translational dynamics
Description	Cystic fibrosis (CF) is one of the most prevalent lethal genetic diseases with over 2000 identified genetic variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Pharmacological chaperones such as Lumacaftor (VX-809), Tezacaftor (VX-661) and Elexacaftor (VX-445) treat mutation-induced defects by stabilizing CFTR and are called correctors. These correctors improve proper folding and thus facilitate processing and trafficking to increase the amount of functional CFTR on the cell surface. Yet, CFTR variants display differential responses to each corrector. Here, we report variants P67L and L206W respond similarly to VX-809 but divergently to VX-445 with P67L exhibiting little rescue when treated with VX-445. We investigate the underlying cellular mechanisms of how CFTR biogenesis is altered by correctors in these variants. Affinity purification-mass spectrometry (AP-MS) multiplexed with isobaric Tandem Mass Tags (TMT) was used to quantify CFTR protein-protein interaction changes between variants P67L and L206W. VX-445 facilitates unique proteostasis factor interactions especially in translation, folding, and degradation pathways in a CFTR variant-dependent manner. A number of these interacting proteins knocked down by siRNA, such as ribosomal subunit proteins, moderately rescued fully glycosylated P67L. Importantly, these knock-downs sensitize P67L to VX-445 and further enhance the correction of this variant. Our results provide a better understanding of VX-445 biological mechanism of action and reveal cellular targets that may sensitize unresponsive CFTR variants to known and available correctors.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_09:05:16.713.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Jonathan Davies
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2023-02-01 05:16:36	ID requested
1	2023-09-18 13:23:12	announced
⏵ 2	2023-11-14 09:05:24	announced	2023-11-14: Updated project metadata.

Kim M, McDonald EF, Sabusap CMP, Timalsina B, Joshi D, Hong JS, Rab A, Sorscher EJ, Plate L, Elexacaftor/VX-445-mediated CFTR interactome remodeling reveals differential correction driven by mutation-specific translational dynamics. J Biol Chem, 299(10):105242(2023) [pubmed]

submitter keyword: AP-MS, Elexacaftor,CF, CFTR, Trikafta, Interactomics

Lars Plate
contact affiliation	Departments of Chemistry, Biological Sciences, Pathology, Microbiology and Immunology, Vanderbilt University
contact email	lars.plate@vanderbilt.edu
lab head
Jonathan Davies
contact affiliation	Vanderbilt University
contact email	jonathan.p.davies@vanderbilt.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD039773
     1. Label: PRIDE project
     2. Name: Elexacaftor/VX-445-mediated CFTR interactome remodeling reveals differential correction driven by mutation-specific translational dynamics