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RPL3L Mutant Heart Cells LFQ MS.

ABSTRACT: Mutations in the tissue-specific ribosomal protein RPL3L lead to infant dilated cardiomyopathy. The current project aims to understand the mechanistic details of disease progression using in vivo biopsies from transplanted heart of patient with RPL3L mutations as well as engineered AC16 cell lines that express the same and other RPL3L variants containing a C-terminal HA tag. The files consist of two datasets from human left ventricle (LV) and human AC16 cells, respectively. The human LV samples are two technical replicates from the same biopsy. The AC16 cell samples are immunoprecipitations of HA-tagged RPL3L in nuclear extracts.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cardiovascular System

SUBMITTER: Rajesh Soni

LAB HEAD: Xuebing Wu

PROVIDER: PXD066450 | Pride | 2025-11-15

REPOSITORIES: Pride

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			Action	DRS
	MM1225-ProteinGroups.xlsx	Xlsx
	MM1272_MM1225.zip	Other

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Project description:Background: Extracellular matrix remodeling mechanisms are understudied in cardiac development and congenital heart defects. Two similar matrix-degrading metalloproteases, ADAMTS1 and ADAMTS5, are extensively co-expressed during mouse cardiac development. The mouse mutants of each have mild cardiac anomalies, but their combined genetic inactivation is precluded by tight linkage. We coupled Adamts1 inactivation with pharmacologic ADAMTS5 blockade to uncover stage-specific cooperative roles and mechanisms in mouse cardiac development. Methods: ADAMTS5 blockade was achieved in Adamts1 null mouse embryos using an activity-blocking monoclonal antibody during distinct developmental windows covering myocardial compaction or cardiac septation and outflow tract rotation. Synchrotron imaging, RNA in situ hybridization, immunofluorescence microscopy and electron microscopy were used to determine the impact on cardiac development and compared to Gpc6 and ADAMTS-cleavage resistant mouse mutants. Mass spectrometry-based N-terminomics was used to identify relevant substrates. Results: Combined inactivation of ADAMTS1 and ADAMTS5 prior to 12.5 days of gestation led to dramatic accumulation of versican-rich cardiac jelly and inhibited formation of compact and trabecular myocardium, which we also observed in mice with ADAMTS cleavage-resistant versican. Subsequently, combined knockout impaired outflow tract development and ventricular septal closure, generating a tetralogy of Fallot-like defect independently of versican proteolysis. N-terminomics of combined ADAMTS knockout and wild-type hearts identified a cleaved glypican-6 peptide only in the wild-type and showed that ADAMTS1 and ADAMTS5 each cleaved glypican-6. Paradoxically, ADAMTS1 and ADAMTS5 inactivated hearts lacked glypican-6 despite unaltered Gpc6 transcription. Gpc6-/- mice demonstrated similar rotational defects as the combined ADAMTS knockout and both had reduced Hedgehog signaling. Conclusions: ADAMTS1 and ADAMTS5 ensure proper cardiac development via cleavage of distinct proteoglycans, each with independent roles in cardiac development. Whereas versican clearance in cardiac jelly is required for proper ventricular cardiomyogenesis, glypican-6 cleavage may activate/stabilize this cell-surface proteoglycan which is required for Hedgehog signaling during outflow tract development.

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RPL3L Mutant Heart Cells LFQ MS.

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