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The Caveolin3 complex stabilizes functional surface expression of the Lactate-Proton Shuttle McT1 but not the sodium channel Nav1.5 in cardiomyocytes - Part 2: Ratiometric Proximity Proteomics

ABSTRACT: Caveolin3 variants were associated with action potential prolongation. As Caveolin1 was recently identified in cardiomyocytes, we hypothesize that conserved isoform-specific protein interactions underlie human loss-of-function variants. To analyze the Caveolin1 and Caveolin3 interactome, we developed unbiased live-cell proteomic and isoform-specific mass spectrometry techniques. We demonstrate the functional relevance and pathogenic mechanism of a novel Caveolin3 interactor in gene-edited human iPSC-cardiomyocyte models.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Heart, Cardiac Muscle Cell

DISEASE(S): Cardiovascular System Disease

SUBMITTER: Christof Lenz

LAB HEAD: Christof Lenz

PROVIDER: PXD019398 | Pride | 2022-10-30

REPOSITORIES: Pride

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Project description:Ineffective hematopoiesis is a hallmark of myelodysplastic syndromes (MDS). Hematopoietic alterations in MDS patients strictly correlate with microenvironment dysfunctions, eventually affecting also the mesenchymal stromal cells (MSCs) compartment. Stromal cells are indeed epigenetically reprogrammed to cooperate with leukemic cells and propagate the disease as "tumor unit"; therefore, changes on MSCs epigenetic profile might contribute to the hematopoietic perturbations typical of MDS. Here, we unveil that the histone variant macroH2A1 (mH2A1) regulates the crosstalk between epigenetics and inflammation in MDS-MSCs, potentially affecting their hematopoietic support ability. We show that the mH2A1 splicing isoform mH2A1.1 accumulates in MDS-MSCs, correlating with the expression of the Toll-like receptor 4 (TLR4), an important pro-tumor activator of MSC phenotype associated to a pro-inflammatory behavior. MH2A1.1-TLR4 axis was further investigated in HS-5 stromal cells after ectopic mH2A1.1 overexpression (mH2A1.1-OE). Proteomic data confirmed the activation of a pro-inflammatory signature associated to TLR4 and nuclear factor kappa B (NFkB) activation. Moreover, mH2A1.1-OE proteomic profile identified several upregulated proteins associated to DNA and histones hypermethylation, including S-adenosylhomocysteine hydrolase, a strong inhibitor of DNA methyltransferase and of the methyl donor S-adenosyl-methionine (SAM). HPLC analysis confirmed higher SAM/SAH ratio along with a metabolic reprogramming. Interestingly, an increased LDHA nuclear localization was detected both in mH2A1.1-OE cells and MDS-MSCs, probably depending on MSC inflammatory phenotype. Finally, coculturing healthy mH2A1-OE MSCs with CD34+ cells, we found a significant reduction in the number of CD34+ cells, which was reflected in a decreased number of colony forming units (CFU -Cs). These results suggest a key role of mH2A1.1 in driving the crosstalk between epigenetic signaling, inflammation and cell metabolism networks in MDS-MSCs.

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The Caveolin3 complex stabilizes functional surface expression of the Lactate-Proton Shuttle McT1 but not the sodium channel Nav1.5 in cardiomyocytes - Part 2: Ratiometric Proximity Proteomics

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