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Published 5 July 2004. doi:10.1083/jcb.200310098
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 166, Number 1, 73-83
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Article

 Monoubiquitination and endocytosis direct {gamma}-secretase cleavage of activated Notch receptor

Neetu Gupta-Rossi, Emmanuelle Six, Odile LeBail, Frédérique Logeat, Patricia Chastagner, Annie Olry, Alain Israël, and Christel Brou

Unité de Biologie Moléculaire de l'Expression Génique, URA 2582, CNRS, Institut Pasteur, 75724 Paris Cedex 15, France

Address correspondence to Christel Brou, Unité de Biologie Moléculaire de l'Expression Génique, URA 2582, CNRS, Institut Pasteur, 25 rue du Dr. Roux, 75724 Paris Cedex 15, France. Tel.: (33) 1-40-61-30-38. Fax: (33) 1-40-61-30-40. email: cbrou{at}pasteur.fr


Abstract
Activation of mammalian Notch receptor by its ligands induces TNF{alpha}-converting enzyme–dependent ectodomain shedding, followed by intramembrane proteolysis due to presenilin (PS)-dependent {gamma}-secretase activity. Here, we demonstrate that a new modification, a monoubiquitination, as well as clathrin-dependent endocytosis, is required for {gamma}-secretase processing of a constitutively active Notch derivative, {Delta}E, which mimics the TNF{alpha}-converting enzyme–processing product. PS interacts with this modified form of {Delta}E, {Delta}Eu. We identified the lysine residue targeted by the monoubiquitination event and confirmed its importance for activation of Notch receptor by its ligand, Delta-like 1. We propose a new model where monoubiquitination and endocytosis of Notch are a prerequisite for its PS-dependent cleavage, and discuss its relevance for other {gamma}-secretase substrates.

Key Words: Notch; presenilins; endocytosis; ubiquitin; {gamma}-secretase

Abbreviations used in this paper: APP, amyloid ß precursor protein; CY3-Tf, CY3-labeled transferrin; ICv, intracellular domain of Notch1; PS, presenilin; TACE, TNF{alpha}-converting enzyme; TM, transmembrane; WT, wild type.


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