Neprilysins regulate muscle contraction and heart function via cleavage of SERCA-inhibitory micropeptides

Ronja Schiemann, Annika Buhr, Eva Cordes, Stefan Walter, Jürgen J. Heinisch, Paola Ferrero, Hendrik Milting, Achim Paululat and Heiko Meyer ()
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Ronja Schiemann: Osnabrück University
Annika Buhr: Osnabrück University
Eva Cordes: Osnabrück University
Stefan Walter: Center of Cellular Nanoanalytics Osnabrück - CellNanOs
Jürgen J. Heinisch: Center of Cellular Nanoanalytics Osnabrück - CellNanOs
Paola Ferrero: Center for Cardiovascular Research - CONICET/National University of La Plata
Hendrik Milting: University of Bochum, Erich & Hanna Klessmann-Institute for Cardiovascular Research and Development
Achim Paululat: Osnabrück University
Heiko Meyer: Osnabrück University

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract Muscle contraction depends on strictly controlled Ca2+ transients within myocytes. A major player maintaining these transients is the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase, SERCA. Activity of SERCA is regulated by binding of micropeptides and impaired expression or function of these peptides results in cardiomyopathy. To date, it is not known how homeostasis or turnover of the micropeptides is regulated. Herein, we find that the Drosophila endopeptidase Neprilysin 4 hydrolyzes SERCA-inhibitory Sarcolamban peptides in membranes of the sarcoplasmic reticulum, thereby ensuring proper regulation of SERCA. Cleavage is necessary and sufficient to maintain homeostasis and function of the micropeptides. Analyses on human Neprilysin, sarcolipin, and ventricular cardiomyocytes indicates that the regulatory mechanism is evolutionarily conserved. By identifying a neprilysin as essential regulator of SERCA activity and Ca2+ homeostasis in cardiomyocytes, these data contribute to a more comprehensive understanding of the complex mechanisms that control muscle contraction and heart function in health and disease.

Date: 2022
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DOI: 10.1038/s41467-022-31974-1

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