Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
J Cell Biol. 2011 Dec 12;195(6):1005-15. doi: 10.1083/jcb.201104146.
The Notch signaling pathway defines a conserved mechanism that regulates cell fate decisions in metazoans. Signaling is modulated by a broad and multifaceted genetic circuitry, including members of the endocytic machinery. Several individual steps in the endocytic pathway have been linked to the positive or negative regulation of the Notch receptor. In seeking genetic elements involved in regulating the endosomal/lysosomal degradation of Notch, mediated by the molecular synergy between the ubiquitin ligase Deltex and Kurtz, the nonvisual β-arrestin in Drosophila, we identified Shrub, a core component of the ESCRT-III complex as a key modulator of this synergy. Shrub promotes the lysosomal degradation of the receptor by mediating its delivery into multivesicular bodies (MVBs). However, the interplay between Deltex, Kurtz, and Shrub can bypass this path, leading to the activation of the receptor. Our analysis shows that Shrub plays a pivotal rate-limiting step in late endosomal ligand-independent Notch activation, depending on the Deltex-dependent ubiquitinylation state of the receptor. This activation mode of the receptor emphasizes the complexity of Notch signal modulation in a cell and has significant implications for both development and disease.
Notch 信号通路定义了一种保守的机制，调节后生动物细胞命运的决定。信号受到广泛而复杂的遗传电路的调节，包括内吞作用机制的成员。内吞作用途径的几个单独步骤已与 Notch 受体的正或负调节相关联。在寻求参与调节由泛素连接酶 Deltex 和 Kurtz 介导的 Notch 内体/溶酶体降解的遗传元件时，通过与果蝇中非视觉β-arrestin 的分子协同作用，我们鉴定了 Shrub，它是 ESCRT-III 复合物的核心组成部分，是这种协同作用的关键调节剂。Shrub 通过将其递送至多泡体 (MVBs) 来促进受体的溶酶体降解。然而，Deltex、Kurtz 和 Shrub 之间的相互作用可以绕过这条途径，导致受体的激活。我们的分析表明，Shrub 在晚期内体配体非依赖性 Notch 激活中起着关键的限速步骤作用，这取决于受体的 Deltex 依赖性泛素化状态。这种受体的激活模式强调了 Notch 信号调节在细胞中的复杂性，并对发育和疾病都有重要意义。
