PXD016095

PXD016095 is an original dataset announced via ProteomeXchange.

Title	Chronic intermittent autophagy inhibition ameliorates Bag3-dependent cardiomyopathy
Description	Mutations in the Hsp70 co-chaperone Bcl2-associated athanogene 3 (Bag3) result in myofibrillar myopathy and pediatric hypertrophic cardiomyopathy (pHCM) in human patients, but the pathological mechanisms underlying Bag3 dysfunction in the developing heart have remained unclear. Here we show that conditional ablation of Bag3 in cardiomyocytes (CMs) results in progressive cardiomyopathy accompanied by increased autophagic flux and autophagosome accumulation in the early post-natal period. Autophagy inhibition via acute administration of chloroquine (CQ) results in transient accumulation of cardiac proteins in the detergent-insoluble fraction, implying a role for autophagy in the degradation of unfolded proteins in the absence of Bag3 co-chaperone activity. Exacerbated autophagy in Bag3 deficient CMs leads to decreased soluble levels of proteins involved in cardiac contraction and conduction, including the gap junction protein connexin 43 (Cx43). Importantly, chronic CQ treatment during the early post-natal period results in a significant amelioration of the pathological phenotype, with recovered contractile performances and restoration of soluble levels of autophagy-targeted proteins. We therefore conclude that loss of Bag3 in CMs leads to autophagic flux exacerbation and that CQ treatment is relevant to therapeutic strategies for Bag3-dependent pHCM patients.
HostingRepository	PRIDE
AnnounceDate	2024-06-05
AnnouncementXML	Submission_2024-06-05_08:44:23.385.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Johannes Graumann
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	monohydroxylated residue; acetylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2019-10-31 04:22:41	ID requested
⏵ 1	2024-06-05 08:44:23	announced

10.1016/J.YJMCC.2024.06.001;

curator keyword: Biological

submitter keyword: Chloroquine, Cx43, Bag3, Pediatric Hypertrophic Cardiomyopathy (pHCM),Autophagy, Protein Quality Control

Johnny Kim
contact affiliation	Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research
contact email	johnny.kim@mpi-bn.mpg.de
lab head
Johannes Graumann
contact affiliation	Institute of Translational Proteomics, Faculty of Medicine, Philipps-Universität Marburg
contact email	johannes.graumann@uni-marburg.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD016095
     1. Label: PRIDE project
     2. Name: Chronic intermittent autophagy inhibition ameliorates Bag3-dependent cardiomyopathy