Article (Scientific journals)
Acetylation-dependent regulation of endothelial Notch signalling by the SIRT1 deacetylase.
Guarani, Virginia; Deflorian, Gianluca; Franco, Claudio A et al.
2011In Nature, 473 (7346), p. 234-8
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Keywords :
Acetylation; Animals; Endothelial Cells/cytology/enzymology; Gene Expression Regulation; Gene Knockout Techniques; Gene Silencing; HEK293 Cells; Humans; Mice; Mutation; Receptor, Notch1/metabolism; Receptors, Notch/metabolism; Signal Transduction/physiology; Sirtuin 1/genetics/metabolism; Zebrafish/embryology/genetics
Abstract :
[en] 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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Guarani, Virginia
Deflorian, Gianluca
Franco, Claudio A
Kruger, Marcus
Phng, Li*-Kun
Bentley, Katie
Toussaint, Louise ;  Université de Liège - ULiège > Chimie et bio-industries > Centre de Bio. Fond. - Section de Biologie cell. et moléc.
Dequiedt, Franck  ;  Université de Liège - ULiège > GIGA-R > Laboratoire de signalisation et d'interaction protéiques
Mostoslavsky, Raul
Schmidt, Mirko H H
Zimmermann, Barbara
Brandes, Ralf P
Mione, Marina
Westphal, Christoph H
Braun, Thomas
Zeiher, Andreas M
Gerhardt, Holger
Dimmeler, Stefanie
Potente, Michael
More authors (9 more) Less
Language :
English
Title :
Acetylation-dependent regulation of endothelial Notch signalling by the SIRT1 deacetylase.
Publication date :
2011
Journal title :
Nature
ISSN :
0028-0836
eISSN :
1476-4687
Publisher :
Nature Publishing Group, Basingstoke, United Kingdom
Volume :
473
Issue :
7346
Pages :
234-8
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 09 June 2011

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