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

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Beitragende

  • Gunnar Weninger - , University of Göttingen, Columbia University (Autor:in)
  • Tatiana Pochechueva - , University of Göttingen (Autor:in)
  • Dana El Chami - , University of Göttingen (Autor:in)
  • Xiaojing Luo - , Institut für Pharmakologie und Toxikologie (Autor:in)
  • Tobias Kohl - , University of Göttingen, Deutsches Zentrum für Herz-Kreislaufforschung (DZHK) (Autor:in)
  • Sören Brandenburg - , University of Göttingen, Deutsches Zentrum für Herz-Kreislaufforschung (DZHK) (Autor:in)
  • Henning Urlaub - , University of Göttingen, Max-Planck-Institut für Multidisziplinäre Naturwissenschaften (Autor:in)
  • Kaomei Guan - , Institut für Pharmakologie und Toxikologie (Autor:in)
  • Christof Lenz - , University of Göttingen, Max-Planck-Institut für Multidisziplinäre Naturwissenschaften (Autor:in)
  • Stephan E. Lehnart - , University of Göttingen, Deutsches Zentrum für Herz-Kreislaufforschung (DZHK) (Autor:in)

Abstract

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 Ca2+ 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 NT1 accumulated in the nucleus of mouse and human cardiomyocytes in a Ca2+-dependent manner, closely associated with euchromatic chromosomal regions, where NT1 is proposed to function as a cardio-protective transcriptional regulator in heart failure. Taken together, our data suggest that stabilizing NT1 by preventing secondary cleavage events by Calpain and other proteases could be an important therapeutic target for future studies.

Details

OriginalspracheEnglisch
Aufsatznummer10387
Seitenumfang17
FachzeitschriftScientific reports
Jahrgang12
Ausgabenummer1
PublikationsstatusVeröffentlicht - Dez. 2022
Peer-Review-StatusJa

Externe IDs

PubMed 35725601
WOS 000838090200013

Schlagworte

ASJC Scopus Sachgebiete

Schlagwörter

  • Determinants, Expression, Heart, Prediction, Proteins, Proteolysis, Sequences, Specificity, Myocytes, Cardiac/metabolism, DNA/metabolism, Calpain/metabolism, Mice, Knockout, Calcium/metabolism, Animals, Membrane Proteins/metabolism, Heart Failure, Mice