Calpain cleavage of Junctophilin-2 generates a spectrum of calcium-dependent cleavage products and DNA-rich NT1-fragment domains in cardiomyocytes

2022 | journal article; research paper. A publication with affiliation to the University of Göttingen.

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​Calpain cleavage of Junctophilin-2 generates a spectrum of calcium-dependent cleavage products and DNA-rich NT1-fragment domains in cardiomyocytes​
Weninger, G.; Pochechueva, T.; El Chami, D.; Luo, X.; Kohl, T. ; Brandenburg, S.   & Urlaub, H.  et al.​ (2022) 
Scientific Reports12(1).​ DOI: 

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Weninger, Gunnar; Pochechueva, Tatiana; El Chami, Dana; Luo, Xiaojing; Kohl, Tobias ; Brandenburg, Sören ; Urlaub, Henning ; Guan, Kaomei ; Lenz, Christof ; Lehnart, Stephan Elmar 
Calpains are calcium-activated neutral proteases involved in the regulation of key signaling pathways. Junctophilin-2 (JP2) is a Calpain-specific proteolytic target and essential structural protein inside Ca 2+ release units required for excitation-contraction coupling in cardiomyocytes. While downregulation of JP2 by Calpain cleavage in heart failure has been reported, 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 at three additional secondary Calpain cleavage sites. Moreover, we identified the Calpain-specific primary cleavage products for the first time in human iPSC-derived cardiomyocytes. Knockout of RyR2 in hiPSC-cardiomyocytes destabilized JP2 resulting in an increase of the Calpain-specific cleavage fragments. The primary N-terminal cleavage product NT 1 accumulated in the nucleus of mouse and human cardiomyocytes in a Ca 2+ -dependent manner, closely associated with euchromatic chromosomal regions, where NT 1 is proposed to function as a cardio-protective transcriptional regulator in heart failure. Taken together, our data suggest that stabilizing NT 1 by preventing secondary cleavage events by Calpain and other proteases could be an important therapeutic target for future studies.
Issue Date
Scientific Reports 
SFB 1190: Transportmaschinen und Kontaktstellen zellulärer Kompartimente 
SFB 1190 | P03: Erhaltung und funktionelle Kopplung von ER-Kontakten mit der Plasmamembran 
SFB 1190 | Z02: Massenspektrometrie-basierte Proteomanalyse 
EXC 2067: Multiscale Bioimaging 
SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz 
SFB 1002 | A09: Lokale molekulare Nanodomänen-Regulation der kardialen Ryanodin-Rezeptor-Funktion 
Working Group
RG Lehnart (Cellular Biophysics and Translational Cardiology Section) 
External URL
Deutsche Forschungsgemeinschaft
Deutsches Zentrum für Herz-Kreislaufforschung
Herzzentrum Göttingen
Open-Access-Publikationsfonds 2022



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