Aberrant protein aggregation is essential for a mutant desmin to impair the proteolytic function of the ubiquitin-proteasome system in cardiomyocytes.
Aberrant protein aggregates in cardiomyocytes are frequently observed in many forms of cardiomyopathies and are often associated with impairment of proteolytic function of the ubiquitin-proteasome system (UPS). However, a causal relationship between mutant desmin (MT-des) induced aberrant protein aggregation and UPS impairment has not been established. The present study has tested the causal relationship. In cultured neonatal rat ventricular myocytes, modest overexpression of a human (cardio)myopathy-linked MT-des protein led to formation of desmin-positive aggregates and inhibited UPS proteolytic function in cardiomyocytes in a dose-dependent manner. Prevention or reduction of aberrant protein aggregation by co-expression of a heat shock protein (Hsp), alphaB-crystallin or inducible Hsp70, or by treatment of Congo red prevented and/or significantly attenuated the induction of UPS malfunction by MT-des. These findings prove for the first time that aberrant protein aggregation is not only sufficient but also required for MT-des to impair UPS proteolytic function in cardiomyocytes.
Cardiovascular Research Institute-South Dakota Health Research Foundation, University of South Dakota School of Medicine and Sioux Valley Hospitals and Health System, Sioux Falls SD 57105, USA.
Jinbao
J
Liu
Mingxin
M
Tang
Ruben
R
Mestril
Xuejun
X
Wang
D000818:Animals; D000831:Animals, Newborn; D009202:Cardiomyopathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D003893:Desmin / Q000235:genetics / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis / Q000235:genetics; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology; D006801:Humans; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D051381:Rats; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism*; D038203:alpha-Crystallin B Chain / Q000096:biosynthesis / Q000235:genetics
C059215:CRYAB protein, human; D003893:Desmin; D018840:HSP70 Heat-Shock Proteins; D011994:Recombinant Proteins; D025801:Ubiquitin; D038203:alpha-Crystallin B Chain; D046988:Proteasome Endopeptidase Complex