Evolutionarily conserved intercalated disc protein Tmem65 regulates cardiac conduction and connexin 43 function

Parveen Sharma, Cynthia Abbasi, Savo Lazic, Allen C. T. Teng, Dingyan Wang, Nicole Dubois, Vladimir Ignatchenko, Victoria Wong, Jun Liu, Toshiyuki Araki, Malte Tiburcy, Cameron Ackerley, Wolfram H. Zimmermann, Robert Hamilton, Yu Sun, Peter P. Liu, Gordon Keller, Igor Stagljar, Ian C. Scott, Thomas Kislinger () and Anthony O. Gramolini ()
Additional contact information
Parveen Sharma: University of Toronto, Toronto General Hospital Research Institute
Cynthia Abbasi: University of Toronto, Toronto General Hospital Research Institute
Savo Lazic: University of Toronto
Allen C. T. Teng: University of Toronto, Toronto General Hospital Research Institute
Dingyan Wang: University of Toronto, Toronto General Hospital Research Institute
Nicole Dubois: McEwen Centre for Regenerative Medicine, University Health Network
Vladimir Ignatchenko: Princess Margaret Cancer Centre, University Health Network
Victoria Wong: Donnelly Centre,, University of Toronto
Jun Liu: Advanced Micro and Nanosystems Laboratory, University of Toronto
Toshiyuki Araki: Princess Margaret Cancer Centre, University Health Network
Malte Tiburcy: Institute of Pharmacology, University Medical Center Göttingen and DZHK (German Center for Cardiovascular Research) partner site Göttingen
Cameron Ackerley: The Hospital for Sick Children
Wolfram H. Zimmermann: Institute of Pharmacology, University Medical Center Göttingen and DZHK (German Center for Cardiovascular Research) partner site Göttingen
Robert Hamilton: The Hospital for Sick Children
Yu Sun: Advanced Micro and Nanosystems Laboratory, University of Toronto
Peter P. Liu: Toronto General Hospital, University Health Network
Gordon Keller: McEwen Centre for Regenerative Medicine, University Health Network
Igor Stagljar: Donnelly Centre,, University of Toronto
Ian C. Scott: University of Toronto
Thomas Kislinger: Princess Margaret Cancer Centre, University Health Network
Anthony O. Gramolini: University of Toronto, Toronto General Hospital Research Institute

Nature Communications, 2015, vol. 6, issue 1, 1-13

Abstract: Abstract Membrane proteins are crucial to heart function and development. Here we combine cationic silica-bead coating with shotgun proteomics to enrich for and identify plasma membrane-associated proteins from primary mouse neonatal and human fetal ventricular cardiomyocytes. We identify Tmem65 as a cardiac-enriched, intercalated disc protein that increases during development in both mouse and human hearts. Functional analysis of Tmem65 both in vitro using lentiviral shRNA-mediated knockdown in mouse cardiomyocytes and in vivo using morpholino-based knockdown in zebrafish show marked alterations in gap junction function and cardiac morphology. Molecular analyses suggest that Tmem65 interaction with connexin 43 (Cx43) is required for correct localization of Cx43 to the intercalated disc, since Tmem65 deletion results in marked internalization of Cx43, a shorter half-life through increased degradation, and loss of Cx43 function. Our data demonstrate that the membrane protein Tmem65 is an intercalated disc protein that interacts with and functionally regulates ventricular Cx43.

Date: 2015
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DOI: 10.1038/ncomms9391

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