Dataset Information

Bidirectional regulation of HDAC5 by mAKAP? signalosomes in cardiac myocytes.

ABSTRACT: Class IIa histone deacetylases (HDACs) are transcriptional repressors whose nuclear export in the cardiac myocyte is associated with the induction of pathological gene expression and cardiac remodeling. Class IIa HDACs are regulated by multiple, functionally opposing post-translational modifications, including phosphorylation by protein kinase D (PKD) that promotes nuclear export and phosphorylation by protein kinase A (PKA) that promotes nuclear import. We have previously shown that the scaffold protein muscle A-kinase anchoring protein ? (mAKAP?) orchestrates signaling in the cardiac myocyte required for pathological cardiac remodeling, including serving as a scaffold for both PKD and PKA. We now show that mAKAP? is a scaffold for HDAC5 in cardiac myocytes, forming signalosomes containing HDAC5, PKD, and PKA. Inhibition of mAKAP? expression attenuated the phosphorylation of HDAC5 by PKD and PKA in response to ?- and ?-adrenergic receptor stimulation, respectively. Importantly, disruption of mAKAP?-HDAC5 anchoring prevented the induction of HDAC5 nuclear export by ?-adrenergic receptor signaling and PKD phosphorylation. In addition, disruption of mAKAP?-PKA anchoring prevented the inhibition by ?-adrenergic receptor stimulation of ?-adrenergic-induced HDAC5 nuclear export. Together, these data establish that mAKAP? signalosomes serve to bidirectionally regulate the nuclear-cytoplasmic localization of class IIa HDACs. Thus, the mAKAP? scaffold serves as a node in the myocyte regulatory network controlling both the repression and activation of pathological gene expression in health and disease, respectively.

SUBMITTER: Dodge-Kafka KL

PROVIDER: S-EPMC5940533 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Bidirectional regulation of HDAC5 by mAKAPβ signalosomes in cardiac myocytes.

Dodge-Kafka Kimberly L KL Gildart Moriah M Li Jinliang J Thakur Hrishikesh H Kapiloff Michael S MS

Journal of molecular and cellular cardiology 20180306

Class IIa histone deacetylases (HDACs) are transcriptional repressors whose nuclear export in the cardiac myocyte is associated with the induction of pathological gene expression and cardiac remodeling. Class IIa HDACs are regulated by multiple, functionally opposing post-translational modifications, including phosphorylation by protein kinase D (PKD) that promotes nuclear export and phosphorylation by protein kinase A (PKA) that promotes nuclear import. We have previously shown that the scaffol ...[more]

PMID: 29522762

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Project description:The molecular mechanisms of Trypanosoma cruzi induced cardiac fibrosis remains to be elucidated. Primary human cardiomyoctes (PHCM) exposed to invasive T. cruzi trypomastigotes were used for transcriptome profiling and downstream bioinformatic analysis to determine fibrotic-associated genes regulated early during infection process (0 to 120 minutes). The identification of early molecular host responses to T. cruzi infection can be exploited to delineate important molecular signatures that can be used for the classification of Chagasic patients at risk of developing heart disease. Our results show distinct gene network architecture with multiple gene networks modulated by the parasite with an incline towards progression to a fibrogenic phenotype. Early during infection, T. cruzi significantly upregulated transcription factors including activator protein 1 (AP1) transcription factor network components (including FOSB, FOS and JUNB), early growth response proteins 1 and 3 (EGR1, EGR3), and cytokines/chemokines (IL5, IL6, IL13, CCL11), which have all been implicated in the onset of fibrosis. The changes in our selected genes of interest did not all start at the same time point. The transcriptome microarray data, validated by quantitative Real-Time PCR, was also confirmed by immunoblotting and customized Enzyme Linked Immunosorbent Assays (ELISA) array showing significant increases in the protein expression levels of fibrogenic EGR1, SNAI1 and IL 6. Furthermore, phosphorylated SMAD2/3 which induces a fibrogenic phenotype is also upregulated accompanied by an increased nuclear translocation of JunB. Pathway analysis of the validated genes and phospho-proteins regulated by the parasite provides the very early fibrotic interactome operating when T. cruzi comes in contact with PHCM. The interactome architecture shows that the parasite induces both TGF-? dependent and independent fibrotic pathways, providing an early molecular foundation for Chagasic cardiomyopathy. Examining the very early molecular events of T. cruzi cellular infection may provide disease biomarkers which will aid clinicians in patient assessment and identification of patient subpopulation at risk of developing Chagasic cardiomyopathy.

Dataset Information

Bidirectional regulation of HDAC5 by mAKAP? signalosomes in cardiac myocytes.

Publications

Bidirectional regulation of HDAC5 by mAKAPβ signalosomes in cardiac myocytes.

Similar Datasets

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