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E-C coupling structural protein junctophilin-2 encodes a stress-adaptive transcription regulator

ABSTRACT: E-C coupling structural protein junctophilin-2 encodes a stress-adaptive transcription regulator

PROVIDER: PRJNA497729 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8082330.fastq.gz	Fastqsanger.gz
	SRR8082340_1.fastq.gz	Fastqsanger.gz
	SRR8082340_2.fastq.gz	Fastqsanger.gz
	SRR8082331.fastq.gz	Fastqsanger.gz
	SRR8082341_1.fastq.gz	Fastqsanger.gz

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E-C coupling structural protein junctophilin-2 encodes a stress-adaptive transcription regulator

Project description:This SuperSeries is composed of the SubSeries listed below.

2019-01-31 | GSE121547 | GEO

E-C coupling structural protein junctophilin-2 encodes a stress-adaptive transcription regulator.

Project description:Junctophilin-2 (JP2) is a structural protein required for normal excitation-contraction (E-C) coupling. After cardiac stress, JP2 is cleaved by the calcium ion-dependent protease calpain, which disrupts the E-C coupling ultrastructural machinery and drives heart failure progression. We found that stress-induced proteolysis of JP2 liberates an N-terminal fragment (JP2NT) that translocates to the nucleus, binds to genomic DNA, and controls expression of a spectrum of genes in cardiomyocytes. Transgenic overexpression of JP2NT in mice modifies the transcriptional profile, resulting in attenuated pathological remodeling in response to cardiac stress. Conversely, loss of nuclear JP2NT function accelerates stress-induced development of hypertrophy and heart failure in mutant mice. These data reveal a self-protective mechanism in failing cardiomyocytes that transduce mechanical information (E-C uncoupling) into salutary transcriptional reprogramming in the stressed heart.

| S-EPMC6336677 | biostudies-literature

Junctophilin-2 Regulates Store-Operated Calcium Entry to Drive Cardiac Fibroblast Activation, Fibrotic Repair, and Angiogenesis After Myocardial Infarction

Project description:Calcium homeostasis in cardiac fibroblasts (CFs) are thought to play a critical role in myocardial repair and remodeling following injury. Junctophilin-2 (JP2) is a structural protein known to regulate intracellular calcium signaling and excitation-contraction coupling in cardiomyocytes. However, the role of JP2 in CF biology remains unexplored. To investigate the functional role of JP2 in CFs, we transduced primary CFs with adenoviruses expressing GFP, JP2, or a JP2 targetting shRNA and determined differentially expressed genes via RNA-sequencing. JP2 overepression and silencing had opposite effects on the expression of genes associated with fibrosis, migration, and cell division.

2025-06-23 | GSE287096 | GEO

Preventing Site-specific Calpain Proteolysis of Junctophilin-2 Protects Against Stress-induced E-C Uncoupling and Heart Failure

Project description:Junctophilin-2 (JP2) is an essential component of the excitation-contraction coupling apparatus in cardiomyocytes and becomes proteolytically cleaved in response to stress. We previously mapped the primary calpain cleavage site to JP2 residues 565-566 using in vitro assays. To determine whether this site is responsible for JP2 cleavage in vivo, we generated calpain resistant JP2 (JP2CR) knock-in mice lacking this site. We find JP2 is not cleaved in JP2CR mice during pressure overload stress resulting in better cardiac outcomes and an attenuated transcriptional response relative to wildtype mice.

2024-08-01 | GSE235601 | GEO

Gene Therapy with the N-terminus of Junctophilin-2 Improves Hypertrophy and Heart Failure in Mice

Project description:Our previous work found a variety of cardiac stresses initiate site-specific cleavage of junctophilin-2 (JP2), an essential component of the E-C coupling apparatus, producing a 75-kDa N-terminal fragment (JP2NT) which unexpectedly translocates into cardiomyocyte nuclei and functions as a transcriptional repressor. We also determined that transgenic overexpression of JP2NT in cardiomyocytes attenuates pressure-overload induced hypertrophy and heart failure by blunting the induction of maladaptive transcripts. To test whether JP2NT could be utilized by gene therapy approaches for treating heart failure, we developed cardiotropic adeno-associated GFP and JP2NT expressing viruses for testing in a preclinical model of heart failure. Our results show that the transcriptional and pathological changes from pressure overload can be reduced through viral expression of JP2NT once hypertrophy and heart failure has already begun.

2022-09-06 | GSE189475 | GEO

Calpain Cleavage of Junctophilin-2 generates a Spectrum of Calcium-dependent Cleavage Products and DNA-rich NT1-Fragment Domains in Cardiomyocytes

Project description:Calpains are calcium (Ca2+) activated neutral proteases that are involved in several essential signaling pathways. One Calpain-specific proteolytic target is Junctophilin-2 (JP2), an important structural protein of Ca2+ release units required for the excitation-contraction coupling in cardiomyocytes. While downregulation of JP2 by Calpain cleavage in mouse models of heart failure has been reported previously, the precise molecular identity of the Calpain cleavage sites and the (patho-) physiological roles of the JP2 proteolytic products remain controversial. We systematically analyzed the JP2 cleavage fragments as function of Calpain-1 versus Calpain-2 proteolytic activities, revealing that both Calpain isoforms preferentially cleave mouse JP2 at R565 but subsequently also at three additional secondary Calpain cleavage sites. We identified the Calpain-specific primary cleavage products not only in mouse but also in human iPSC-derived cardiomyocytes (hiPSC-CMs). Knockout of RyR2 in hiPSC-CMs destabilized JP2 resulting in an increase of the Calpain-specifc cleavage fragments. The primary N-terminal cleavage product (NT1) accumulated in the nucleus of mouse and human cardiomyocytes in a Ca2+ dependent manner, closely associated with DNA-rich chromosomal regions, where NT1 is proposed to function as a cardioprotective transcriptional regulator in heart failure. Taken together, our data suggest that stabilizing NT1 by preventing secondary cleavage events by Calpain and other proteases could be an important therapeutic target for future studies.

2022-08-12 | PXD031321 | Pride

Calpain Cleavage of Junctophilin-2 generates a Spectrum of Calcium-dependent Cleavage Products and DNA-rich NT1-Fragment Domains in Cardiomyocytes - PRM Dataset

Project description:Calpains are calcium (Ca2+) activated neutral proteases that are involved in several essential signaling pathways. One Calpain-specific proteolytic target is Junctophilin-2 (JP2), an important structural protein of Ca2+ release units required for the excitation-contraction coupling in cardiomyocytes. While downregulation of JP2 by Calpain cleavage in mouse models of heart failure has been reported previously, the precise molecular identity of the Calpain cleavage sites and the (patho-) physiological roles of the JP2 proteolytic products remain controversial. We systematically analyzed the JP2 cleavage fragments as function of Calpain-1 versus Calpain-2 proteolytic activities, revealing that both Calpain isoforms preferentially cleave mouse JP2 at R565, but subsequently also at three additional secondary Calpain cleavage sites. We identified the Calpain-specific primary cleavage products not only in mouse but also in human iPSC-derived cardiomyocytes (hiPSC-CMs). Knockout of RyR2 in hiPSC-CMs destabilized JP2 resulting in an increase of the Calpain-specifc cleavage fragments. The primary N-terminal cleavage product (NT1) accumulated in the nucleus of mouse and human cardiomyocytes in a Ca2+ dependent manner, closely associated with DNA-rich chromosomal regions, where NT1 is proposed to function as a cardioprotective transcriptional regulator in heart failure. Taken together, our data suggest that stabilizing NT1 by preventing secondary cleavage events by Calpain and other proteases could be an important therapeutic target for future studies.

2022-08-12 | PXD031424 | Pride

Bipolar and schizophrenia risk gene AKAP11 encodes an autophagy receptor coupling the regulation of PKA kinase network homeostasis to synaptic transmission

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Structural mechanism underlying primary and secondary coupling between GPCRs and the Gi/o family

Project description:G protein-coupled receptors (GPCRs) are the largest receptor superfamily that can propagate various extracellular stimulus into cells by coupling with heterotrimeric G proteins. G proteins are divided into four families, Gs, Gi/o, Gq/11 and G12/13, which are responsible for the transduction of discrete downstream signaling pathways. Interestingly, one receptor can couple to more than one G protein subtype with different coupling efficiency or kinetics; coupling with the highest efficiency and/or kinetics is known as ‘primary coupling’ whereas the one with lower efficiency and/or slower kinetics is known as ‘secondary coupling’. Due to its significance in human physiology, there has been a great effort to elucidate the precise mechanism of GPCR-G protein coupling, however, the complex nature of GPCR and G protein interaction raises more unanswered questions. Here, we utilized hydrogen/deuterium exchange mass spectrometry (HDX-MS) to understand the molecular mechanism underlying primary and secondary Gi/o coupling using muscarinic acetylcholine receptor type 2 (M2R) and β2-adrenergic receptor (β2AR) as the primary and secondary Gi/o-coupling receptors, respectively. Results showed the engagement of the distal C-terminus of Gi/o with the receptor differentiates primary and secondary Gi/o couplings. In addition, the interaction between the intracellular loop 2 (ICL2) of the receptor and Gi/o in primary Gi/o coupling is not as critical as in primary Gs coupling.

2020-07-02 | PXD019367 | Pride

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Project description:Adaptive Structural Variants Contributing to Human Brain Development Revealed by 1,026 Rhesus Macaque Genomes

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