Uncovering New Functions of CSN6 in Cardiac Desmosomal Biology and Disease
揭示 CSN6 在心脏桥粒生物学和疾病中的新功能
基本信息
- 批准号:9754240
- 负责人:
- 金额:$ 39.38万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-08-01 至 2022-07-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdultArrhythmogenic Right Ventricular DysplasiaAutomobile DrivingBehaviorBindingBiochemicalBiological AssayBiologyBiopsyCOPS5 geneCardiacCardiac MyocytesCellsComplexComputer SimulationConnexin 43DataDefectDesmosomesDiseaseElectrophysiology (science)ExhibitsFamilyGeneticHealthHeartHeart DiseasesHumanIn VitroIntercellular JunctionsInterruptionInterventionKnock-in MouseKnock-outKnockout MiceLeftLinkMediatingModelingMolecularMolecular AnalysisMusMutationMyocardiumPathway interactionsPatientsPatternPharmacologyPhenotypePhysiologicalPlayProteinsProteomicsRoleStructureSudden DeathTestingTherapeuticTissuesUbiquitinUbiquitinationYeastsbasecDNA Librarydesmoplakineffective therapyin vivoinduced pluripotent stem cellinherited cardiomyopathyinhibitor/antagonistinsightmembermouse modelnovelplakophilin 2protein degradationsmall hairpin RNAsudden cardiac deathyeast two hybrid system
项目摘要
Abstract
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic-based heart disease leading to sudden
cardiac death in young people. ARVC is termed a “disease of the desmosome” as 40% of ARVC harbor
mutations and/or loss of desmosomal components. However, the mechanisms that control desmosomal
protein levels and function in health and disease are undefined. We identified CSN6, which is subunit 6 of the
COP9 signalosome family, in a yeast-two-hybrid screen as a novel desmosomal (desmoplakin, DSP)
interacting protein in the adult human heart. Traditional functions of the CSN complex are to “turn off”
ubiquitination mediated protein degradation via de-neddylation; however, the role for CSN6 in the heart is
undefined. We believe that CSN6 uniquely protects the cardiac desmosome from degradation and its loss
accelerates desmosome destruction as (i) CSN6 co-localizes to desmosomal junctions, (ii) CSN6 co-
immunoprecipitates with desmosomal proteins and (iii) hearts from novel cardiac-specific CSN6 knockout
(CSN6-cKO) mice display selective loss of desmosomal protein levels (and its primary target, connexin43).
CSN6 loss is a trigger for ARVC as CSN6-cKO mice exhibit sudden death and cardiac disease features
associated with a biventricular form of ARVC, similar to our classic biventricular (DSP-cKO) model of ARVC.
CSN6 and DSP-cKO hearts both selectively display underlying hyper-accumulation of protein degradation
machinery at the cell junction, specifically linking CSN6 pathways to the desmosome. CSN6 pathways are
relevant to human ARVC as (i) CSN6 levels are down-regulated in ARVC hiPSC-derived cardiac cells that
exhibit striking desmosomal defects and arrhythmogenic behavior and (ii) CSN6 localization is lost from cell
junctions in a cardiac biopsy from an ARVC patient harboring desmosomal (DSP (R315C) and plakophilin-2
(PKP2 IVS10-1 G>C) mutations. Yeast and in silico modeling assays reveal that this DSP R315C mutation is
sufficient to abrogate DSP binding to CSN6. However, CSN6 also associates with PKP2, suggesting that the
PKP2 mutation may also play a role in these mechanisms (two-hit hypothesis). In terms of the CSN6-
desmosomal complex, our data suggests that other CSNs may compartmentalize (“subcomplex”) with CSN6 at
the desmosome and their localization may be dependent on CSN6. We hypothesize that CSN6 targets an
enzymatically active CSN subcomplex to the cardiac desmosome to protect desmosomes from degradation via
neddylation, and dysregulation of this mechanism triggers ARVC. We aim to: (i) define the CSN6 subcomplex
members, which protect the desmosome from degradation in cardiomyocytes, (ii) determine the effects of
inhibiting the underlying hyper-accumulated protein degradation in cardiac-specific CSN6 and DSP knockout
mice and (iii) understand the role of the desmosome-CSN6 interaction by characterizing two novel knockin
mouse models that harbor human ARVC-associated desmosomal mutations that interrupt binding to CSN6.
摘要
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Farah Sheikh其他文献
Farah Sheikh的其他文献
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{{ truncateString('Farah Sheikh', 18)}}的其他基金
Determinants of Arrhythmogenic Risk In Arrhythmogenic Cardiomyopathies and Mitral Valve Prolapse
致心律失常性心肌病和二尖瓣脱垂的致心律失常风险的决定因素
- 批准号:
10853894 - 财政年份:2022
- 资助金额:
$ 39.38万 - 项目类别:
Uncovering Molecular Targets for Arrhythmogenic Cardiomyopathy Therapeutics
发现致心律失常性心肌病治疗的分子靶点
- 批准号:
10588199 - 财政年份:2022
- 资助金额:
$ 39.38万 - 项目类别:
Uncovering New Functions of CSN6 in Cardiac Desmosomal Biology and Disease
揭示 CSN6 在心脏桥粒生物学和疾病中的新功能
- 批准号:
10220119 - 财政年份:2018
- 资助金额:
$ 39.38万 - 项目类别:
Uncovering New Functions of CSN6 in Cardiac Desmosomal Biology and Disease
揭示 CSN6 在心脏桥粒生物学和疾病中的新功能
- 批准号:
9973231 - 财政年份:2018
- 资助金额:
$ 39.38万 - 项目类别:
The molecular mechanisms underlying arrhythmogenic right ventricular dysplasia/cardiomyopathy
致心律失常性右心室发育不良/心肌病的分子机制
- 批准号:
9036430 - 财政年份:2009
- 资助金额:
$ 39.38万 - 项目类别:
The molecular mechanisms underlying arrhythmogenic right ventricular dysplasia/cardiomyopathy
致心律失常性右心室发育不良/心肌病的分子机制
- 批准号:
9244060 - 财政年份:2009
- 资助金额:
$ 39.38万 - 项目类别:
The molecular mechanisms underlying arrhythmogenic right ventricular dysplasia/ca
致心律失常性右心室发育不良/ca的分子机制
- 批准号:
7795808 - 财政年份:2009
- 资助金额:
$ 39.38万 - 项目类别:
The molecular mechanisms underlying arrhythmogenic right ventricular dysplasia/ca
致心律失常性右心室发育不良/ca的分子机制
- 批准号:
8121311 - 财政年份:2009
- 资助金额:
$ 39.38万 - 项目类别:
The molecular mechanisms underlying arrhythmogenic right ventricular dysplasia/ca
致心律失常性右心室发育不良/ca的分子机制
- 批准号:
8041043 - 财政年份:2009
- 资助金额:
$ 39.38万 - 项目类别:
The molecular mechanisms underlying arrhythmogenic right ventricular dysplasia/cardiomyopathy
致心律失常性右心室发育不良/心肌病的分子机制
- 批准号:
8884263 - 财政年份:2009
- 资助金额:
$ 39.38万 - 项目类别:
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