Title:	Neprilysins regulate muscle contraction and heart function via cleavage of SERCA-inhibitory micropeptides
Authors:	Schiemann, Ronja Buhr, Annika Cordes, Eva Walter, Stefan Heinisch, Jürgen J. Ferrero, Paola Milting, Hendrik Paululat, Achim Meyer, Heiko
ORCID of the author:	https://orcid.org/0000-0002-5037-9560 https://orcid.org/0000-0003-4197-4285 https://orcid.org/0000-0002-5582-642X https://orcid.org/0000-0002-8845-6859 https://orcid.org/0000-0002-3304-4523 https://orcid.org/0000-0003-2011-2467
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.
Citations:	Schiemann, R., Buhr, A., Cordes, E. et al. Neprilysins regulate muscle contraction and heart function via cleavage of SERCA-inhibitory micropeptides. Nat Commun 13, 4420 (2022).
URL:	https://doi.org/10.48693/322 https://osnadocs.ub.uni-osnabrueck.de/handle/ds-202305048979
Subject Keywords:	Calcium signalling; Cardiovascular biology; Peptides; Proteases
Issue Date:	29-Jul-2022
License name:	Attribution 4.0 International
License url:	http://creativecommons.org/licenses/by/4.0/
Type of publication:	Einzelbeitrag in einer wissenschaftlichen Zeitschrift [Article]
Appears in Collections:	FB05 - Hochschulschriften Open-Access-Publikationsfonds

This item is licensed under a Creative Commons License