The Membrane-Bound Notch Regulator Mnr Supports Notch Cleavage and Signaling Activity in <i>Drosophila melanogaster</i>

The Notch signaling pathway is pivotal to cellular differentiation. Activation of this pathway involves proteolysis of the Notch receptor and the release of the biologically active Notch intracellular domain, acting as a transcriptional co-activator of Notch target genes. While the regulation of Not...

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Autores principales:	Anja C. Nagel, Dominik Müller, Mirjam Zimmermann, Anette Preiss
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	cell–cell communication Notch cleavage γ-secretase membrane-bound Notch regulator Mnr Notch Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/ff86cd4a37364b038af7dcab4331854b
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spelling	oai:doaj.org-article:ff86cd4a37364b038af7dcab4331854b2021-11-25T16:53:38ZThe Membrane-Bound Notch Regulator Mnr Supports Notch Cleavage and Signaling Activity in <i>Drosophila melanogaster</i>10.3390/biom111116722218-273Xhttps://doaj.org/article/ff86cd4a37364b038af7dcab4331854b2021-11-01T00:00:00Zhttps://www.mdpi.com/2218-273X/11/11/1672https://doaj.org/toc/2218-273XThe Notch signaling pathway is pivotal to cellular differentiation. Activation of this pathway involves proteolysis of the Notch receptor and the release of the biologically active Notch intracellular domain, acting as a transcriptional co-activator of Notch target genes. While the regulation of Notch signaling dynamics at the level of ligand–receptor interaction, endocytosis, and transcriptional regulation has been well studied, little is known about factors influencing Notch cleavage. We identified EP555 as a suppressor of the Notch antagonist Hairless (H). EP555 drives expression of CG32521 encoding membrane-bound proteins, which we accordingly rename <i>membrane-bound Notch regulator</i> (<i>mnr</i>). Within the signal-receiving cell, upregulation of Mnr stimulates Notch receptor activation, whereas a knockdown reduces it, without apparent influence on ligand–receptor interaction. We provide evidence that Mnr plays a role in γ-secretase-mediated intramembrane cleavage of the Notch receptor. As revealed by a fly-eye-based reporter system, γ-secretase activity is stimulated by the overexpression of Mnr, and is inhibited by its knockdown. We conclude that Mnr proteins support Notch signaling activity by fostering the cleavage of the Notch receptor. With Mnr, we identified a membrane-bound factor directly augmenting Notch intra-membrane processing, thereby acting as a positive regulator of Notch signaling activity.Anja C. NagelDominik MüllerMirjam ZimmermannAnette PreissMDPI AGarticlecell–cell communicationNotch cleavageγ-secretasemembrane-bound Notch regulatorMnrNotchMicrobiologyQR1-502ENBiomolecules, Vol 11, Iss 1672, p 1672 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	cell–cell communication Notch cleavage γ-secretase membrane-bound Notch regulator Mnr Notch Microbiology QR1-502
spellingShingle	cell–cell communication Notch cleavage γ-secretase membrane-bound Notch regulator Mnr Notch Microbiology QR1-502 Anja C. Nagel Dominik Müller Mirjam Zimmermann Anette Preiss The Membrane-Bound Notch Regulator Mnr Supports Notch Cleavage and Signaling Activity in <i>Drosophila melanogaster</i>
description	The Notch signaling pathway is pivotal to cellular differentiation. Activation of this pathway involves proteolysis of the Notch receptor and the release of the biologically active Notch intracellular domain, acting as a transcriptional co-activator of Notch target genes. While the regulation of Notch signaling dynamics at the level of ligand–receptor interaction, endocytosis, and transcriptional regulation has been well studied, little is known about factors influencing Notch cleavage. We identified EP555 as a suppressor of the Notch antagonist Hairless (H). EP555 drives expression of CG32521 encoding membrane-bound proteins, which we accordingly rename <i>membrane-bound Notch regulator</i> (<i>mnr</i>). Within the signal-receiving cell, upregulation of Mnr stimulates Notch receptor activation, whereas a knockdown reduces it, without apparent influence on ligand–receptor interaction. We provide evidence that Mnr plays a role in γ-secretase-mediated intramembrane cleavage of the Notch receptor. As revealed by a fly-eye-based reporter system, γ-secretase activity is stimulated by the overexpression of Mnr, and is inhibited by its knockdown. We conclude that Mnr proteins support Notch signaling activity by fostering the cleavage of the Notch receptor. With Mnr, we identified a membrane-bound factor directly augmenting Notch intra-membrane processing, thereby acting as a positive regulator of Notch signaling activity.
format	article
author	Anja C. Nagel Dominik Müller Mirjam Zimmermann Anette Preiss
author_facet	Anja C. Nagel Dominik Müller Mirjam Zimmermann Anette Preiss
author_sort	Anja C. Nagel
title	The Membrane-Bound Notch Regulator Mnr Supports Notch Cleavage and Signaling Activity in <i>Drosophila melanogaster</i>
title_short	The Membrane-Bound Notch Regulator Mnr Supports Notch Cleavage and Signaling Activity in <i>Drosophila melanogaster</i>
title_full	The Membrane-Bound Notch Regulator Mnr Supports Notch Cleavage and Signaling Activity in <i>Drosophila melanogaster</i>
title_fullStr	The Membrane-Bound Notch Regulator Mnr Supports Notch Cleavage and Signaling Activity in <i>Drosophila melanogaster</i>
title_full_unstemmed	The Membrane-Bound Notch Regulator Mnr Supports Notch Cleavage and Signaling Activity in <i>Drosophila melanogaster</i>
title_sort	membrane-bound notch regulator mnr supports notch cleavage and signaling activity in <i>drosophila melanogaster</i>
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/ff86cd4a37364b038af7dcab4331854b
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The Membrane-Bound Notch Regulator Mnr Supports Notch Cleavage and Signaling Activity in <i>Drosophila melanogaster</i>

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