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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., et al. (2022). Calpain cleavage of Junctophilin-2 generates a spectrum of calcium-dependent cleavage products and DNA-rich NT1-fragment domains in cardiomyocytes. Scientific Reports, 12: 10387. doi:10.1038/s41598-022-14320-9.

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 Creators:
Weninger, G., Author
Pochechueva, T., Author
El Chami, D., Author
Luo, X., Author
Kohl, T., Author
Brandenburg, S., Author
Urlaub, H.1, Author           
Guan, K., Author
Lenz, C.1, Author           
Lehnart, S. E., Author
Affiliations:
1Research Group of Bioanalytical Mass Spectrometry, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society, ou_3350290              

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 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.

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Language(s): eng - English
 Dates: 2022-06-202022
 Publication Status: Published in print
 Pages: 17
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: DOI: 10.1038/s41598-022-14320-9
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Project name : This project was funded by Deutsche Forschun- gsgemeinschaft (DFG) collaborative research units SFB1002 to SEL, SB and CL (project A09 supporting GW), and through SFB1190 to SEL (project P03) and to HU (project Z02); and was supported under Germany’s Excel- lence Strategy (EXC2067/1-390729940). KG was funded by Deutsche Forschungsgemeinschaft (GU 595/3-1).
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Title: Scientific Reports
  Abbreviation : Sci. Rep.
Source Genre: Journal
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Publ. Info: London, UK : Nature Publishing Group
Pages: 17 Volume / Issue: 12 Sequence Number: 10387 Start / End Page: - Identifier: ISSN: 2045-2322
CoNE: https://pure.mpg.de/cone/journals/resource/2045-2322