Monoubiquitination and endocytosis direct gamma-secretase cleavage of activated Notch receptor.
Monoubiquitination and endocytosis direct gamma-secretase cleavage of activated Notch receptor.
复制标题
DOI：
10.1083/jcb.200310098
复制
发表时间：
2004-07-05
影响因子：
7.8
通讯作者：
Brou, Christel
中科院分区：
文献类型：
--
作者：
Gupta-Rossi, Neetu;Six, Emmanuelle;LeBail, Odile;Logeat, Frederique;Chastagner, Patricia;Olry, Annie;Israel, Alain;Brou, Christel
哺乳动物Notch受体被其配体激活会诱导TNFα转换酶依赖性胞外域脱落，随后由于早老素（PS）依赖性γ分泌酶活性而导致膜内蛋白水解。在这里，我们证明了一种新的修饰，即单泛素化以及网格蛋白依赖性内吞作用，是γ-分泌酶加工组成型活性Notch衍生物ΔE所必需的，ΔE模拟了TNFα转换酶加工产物。 PS 与 ΔE、ΔEu 的这种修饰形式相互作用。我们鉴定了单泛素化事件所针对的赖氨酸残基，并证实了其对于通过其配体 Delta-like 1 激活 Notch 受体的重要性。我们提出了一种新模型，其中 Notch 的单泛素化和内吞作用是其 PS 依赖性裂解的先决条件，并讨论了其与其他 γ-分泌酶底物的相关性。
Activation of mammalian Notch receptor by its ligands induces TNFα-converting enzyme–dependent ectodomain shedding, followed by intramembrane proteolysis due to presenilin (PS)-dependent γ-secretase activity. Here, we demonstrate that a new modification, a monoubiquitination, as well as clathrin-dependent endocytosis, is required for γ-secretase processing of a constitutively active Notch derivative, ΔE, which mimics the TNFα-converting enzyme–processing product. PS interacts with this modified form of ΔE, ΔEu. 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 γ-secretase substrates.