Dysfunction of the ubiquitin-proteasome system (UPS) and autophagy, two main intracellular proteolytic pathways, have been observed in a variety of heart diseases and implicated in the genesis of congestive heart failure (CHF), the final common pathway for virtually all heart diseases and afflicting the life of millions of Americans. The COP9 signalosome (CSN) is an evolutionarily conserved protein complex consisting of 8 unique subunits (CSN1 ~ CSN8). In the preceding competitive cycle, we have discovered that the Csn8/CSN is required for not only UPS-mediated proteolysis but also autophagy to exert their protein quality control roles in mouse hearts. Perinatal cardiomyocyte-restricted CSN subunit 8 knockout (CR-Csn8KO) causes primarily massive cardiomyocyte (CM) necrosis in intact mice and this is preceded by impairment in the autophagic- lysosomal pathway and accompanied by UPS malfunction. The CR-Csn8KO mice develop dilated cardiomyopathy and die of CHF prematurely. Building upon these exciting novel findings, we propose to decipher the molecular mechanisms by which Csn8/CSN regulates the autophagic-lysosomal pathway and cardiomyocyte survival in the heart. Using a combination of innovative genetic manipulations and pharmacological interrogations in intact mice, we will pursue three specific aims to test the central hypothesis that Csn8/CSN promotes AM via Rab7 and facilitates PQC in CMs, thereby promoting CM survival by suppressing the RIP1/RIP3-mediated necrosis pathway.
Specific aim 1 defines molecular mechanisms by which Csn8/CSN promotes autophagy. This will test the hypothesis that Csn8/CSN regulates autophagosome maturation (AM) via Rab7.
Specific aim 2 investigates the pathophysiological significance of autophagic activation by proteasome inhibition. This is to test the hypothesis that proteasome functional insufficiency (PFI) activates cardiac autophagy and this activation compensates for protein quality control impairment caused by PFI.
Specific aim 3 tests the hypotheses that impaired AM compromises the degradation of proteasome substrates and that the duo-impairment in the UPS and autophagy triggers CM necrosis via the RIP1-RIP3 mediated pathway. The completion of this research is expected to significantly improve our understanding on how protein quality control and degradation pathways in the heart are coordinately regulated, especially by the CSN, which will facilitate the search for new strategies to prevent and/or more effectively treat CHF, a leading cause of death and disability in the US.

Public Health Relevance

Congestive heart failure is the final common pathway of virtually all heart disease and is the most expensive single diagnosis in US health care. It is a highly lethal and disabling syndrome. Despite recent advances in its clinical management, it remains the leading cause of death in the US. This research project will help improve our understanding on the molecular mechanisms underlying the progression of various heart diseases to congestive heart failure, which will ultimately facilitate the search for new measures to prevent or more effectively treat this common and yet life-threatening disorder.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL085629-06A1
Application #
8310341
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Evans, Frank
Project Start
2006-07-01
Project End
2016-02-28
Budget Start
2012-04-15
Budget End
2013-02-28
Support Year
6
Fiscal Year
2012
Total Cost
$360,938
Indirect Cost
$110,938
Name
University of South Dakota
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
929930808
City
Vermillion
State
SD
Country
United States
Zip Code
57069
Wu, Penglong; Yuan, Xun; Li, Faqian et al. (2017) Myocardial Upregulation of Cathepsin D by Ischemic Heart Disease Promotes Autophagic Flux and Protects Against Cardiac Remodeling and Heart Failure. Circ Heart Fail 10:
Abdullah, Ammara; Eyster, Kathleen M; Bjordahl, Travis et al. (2017) Murine Myocardial Transcriptome Analysis Reveals a Critical Role of COPS8 in the Gene Expression of Cullin-RING Ligase Substrate Receptors and Redox and Vesicle Trafficking Pathways. Front Physiol 8:594
Pan, Bo; Zhang, Hanming; Cui, Taixing et al. (2017) TFEB activation protects against cardiac proteotoxicity via increasing autophagic flux. J Mol Cell Cardiol 113:51-62
Wang, Xuejun (2017) Vascular Spasm: A Newly Unraveled Cause for Cardiovascular Adversity of Proteasome Inhibition. EBioMedicine 21:51-52
Reihe, Casey A; Pekas, Nickolas; Wu, Penglong et al. (2017) Systemic inhibition of neddylation by 3-day MLN4924 treatment regime does not impair autophagic flux in mouse hearts and brains. Am J Cardiovasc Dis 7:134-150
Li, Jie; Ma, Wenxia; Yue, Guihua et al. (2017) Cardiac proteasome functional insufficiency plays a pathogenic role in diabetic cardiomyopathy. J Mol Cell Cardiol 102:53-60
Liao, Yuning; Liu, Ningning; Hua, Xianliang et al. (2017) Proteasome-associated deubiquitinase ubiquitin-specific protease 14 regulates prostate cancer proliferation by deubiquitinating and stabilizing androgen receptor. Cell Death Dis 8:e2585
Zhao, Chong; Chen, Xin; Yang, Changshan et al. (2017) Repurposing an antidandruff agent to treating cancer: zinc pyrithione inhibits tumor growth via targeting proteasome-associated deubiquitinases. Oncotarget 8:13942-13956
Hou, Ning; Wen, Ying; Yuan, Xun et al. (2017) Activation of Yap1/Taz signaling in ischemic heart disease and dilated cardiomyopathy. Exp Mol Pathol 103:267-275
Huang, Hongbiao; Guo, Mingxing; Liu, Ningning et al. (2017) Bilirubin neurotoxicity is associated with proteasome inhibition. Cell Death Dis 8:e2877

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