Gupta-Rossi Neetu, Six Emmanuelle, LeBail Odile, Logeat Frédérique, Chastagner Patricia, Olry Annie, Israël Alain, Brou Christel
Unité de Biologie Moléculaire de l'Expression Génique, URA 2582, CNRS, Institut Pasteur, 25 rue du Dr. Roux, 75724 Paris Cedex 15, France.
J Cell Biol. 2004 Jul 5;166(1):73-83. doi: 10.1083/jcb.200310098.
Activation of mammalian Notch receptor by its ligands induces TNFalpha-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, DeltaE, which mimics the TNFalpha-converting enzyme-processing product. PS interacts with this modified form of DeltaE, DeltaEu. 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.
哺乳动物Notch受体被其配体激活后，会诱导肿瘤坏死因子α转化酶（TNFα-converting enzyme，TACE）依赖性的胞外域脱落，随后由于早老素（PS）依赖性的γ-分泌酶活性而发生膜内蛋白水解。在此，我们证明，一种新的修饰——单泛素化，以及网格蛋白依赖性内吞作用，对于组成型激活的Notch衍生物DeltaE的γ-分泌酶加工是必需的，DeltaE模拟了TACE加工产物。PS与这种修饰形式的DeltaE，即DeltaEu相互作用。我们鉴定了单泛素化事件所靶向的赖氨酸残基，并证实了其对于Notch受体被其配体Delta样1激活的重要性。我们提出了一个新模型，其中Notch的单泛素化和内吞作用是其PS依赖性切割的前提条件，并讨论了其与其他γ-分泌酶底物的相关性。
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