title: Acetylation-dependent regulation of endothelial Notch signalling by the SIRT1 deacetylase.
abstract: Notch signalling is a key intercellular communication mechanism that is essential for cell specification and tissue patterning, and which coordinates critical steps of blood vessel growth. Although subtle alterations in Notch activity suffice to elicit profound differences in endothelial behaviour and blood vessel formation, little is known about the regulation and adaptation of endothelial Notch responses. Here we report that the NAD(+)-dependent deacetylase SIRT1 acts as an intrinsic negative modulator of Notch signalling in endothelial cells. We show that acetylation of the Notch1 intracellular domain (NICD) on conserved lysines controls the amplitude and duration of Notch responses by altering NICD protein turnover. SIRT1 associates with NICD and functions as a NICD deacetylase, which opposes the acetylation-induced NICD stabilization. Consequently, endothelial cells lacking SIRT1 activity are sensitized to Notch signalling, resulting in impaired growth, sprout elongation and enhanced Notch target gene expression in response to DLL4 stimulation, thereby promoting a non-sprouting, stalk-cell-like phenotype. In vivo, inactivation of Sirt1 in zebrafish and mice causes reduced vascular branching and density as a consequence of enhanced Notch signalling. Our findings identify reversible acetylation of the NICD as a molecular mechanism to adapt the dynamics of Notch signalling, and indicate that SIRT1 acts as rheostat to fine-tune endothelial Notch responses.
authors.affiliation: Institute for Cardiovascular Regeneration, Centre of Molecular Medicine, Goethe University, D-60590 Frankfurt, Germany.
authors.forename: Virginia
authors.initials: V
authors.lastname: Guarani
authors.forename: Gianluca
authors.initials: G
authors.lastname: Deflorian
authors.forename: Claudio A
authors.initials: CA
authors.lastname: Franco
authors.forename: Marcus
authors.initials: M
authors.lastname: Krüger
authors.forename: Li-Kun
authors.initials: LK
authors.lastname: Phng
authors.forename: Katie
authors.initials: K
authors.lastname: Bentley
authors.forename: Louise
authors.initials: L
authors.lastname: Toussaint
authors.forename: Franck
authors.initials: F
authors.lastname: Dequiedt
authors.forename: Raul
authors.initials: R
authors.lastname: Mostoslavsky
authors.forename: Mirko H H
authors.initials: MHH
authors.lastname: Schmidt
authors.forename: Barbara
authors.initials: B
authors.lastname: Zimmermann
authors.forename: Ralf P
authors.initials: RP
authors.lastname: Brandes
authors.forename: Marina
authors.initials: M
authors.lastname: Mione
authors.forename: Christoph H
authors.initials: CH
authors.lastname: Westphal
authors.forename: Thomas
authors.initials: T
authors.lastname: Braun
authors.forename: Andreas M
authors.initials: AM
authors.lastname: Zeiher
authors.forename: Holger
authors.initials: H
authors.lastname: Gerhardt
authors.forename: Stefanie
authors.initials: S
authors.lastname: Dimmeler
authors.forename: Michael
authors.initials: M
authors.lastname: Potente
mesh_terms: D000107:Acetylation; D000818:Animals; D042783:Endothelial Cells / Q000166:cytology / Q000201:enzymology*; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D020868:Gene Silencing; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009154:Mutation; D051881:Receptor, Notch1 / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D056564:Sirtuin 1 / Q000235:genetics* / Q000378:metabolism*; D015027:Zebrafish / Q000196:embryology / Q000235:genetics
chemical_list: D051881:Receptor, Notch1; D051880:Receptors, Notch; D056564:Sirtuin 1