Unravelling the molecular network of Lethal (2) giant discs (Lgd) in Drosophila melanogaster.

肿瘤抑制因子 Lethal (2) 巨盘 (Lgd) 是在后生动物中保守的蛋白质家族的创始成员。人类直系同源物之一 LGD2 的突变会导致遗传性非综合征性精神发育迟滞。 Lgd 参与跨膜蛋白（例如 Notch 受体）通过内体途径的运输。我们最近在果蝇和哺乳动物细胞培养中的工作表明，Lgd 通过与其亚基 Shrub/Snf7/CHMP4 之一直接相互作用，是 ESCRT-III 复合物发挥全部活性所必需的。 ESCRT-III 是介导管腔内囊泡 (ILV) 夹入成熟内体管腔的五种复合物之一。这些 ILV 的形成对于跨膜蛋白的降解和通过激活的信号受体消除信号传导是必要的。 Lgd 在此过程中的具体作用尚不清楚。我们实验室进行的遗传筛选结果表明，ESCRT 机制完整活动所需的辅助 ESCRT 组与 Lgd 具有功能关系。酵母中辅助 ESCRT 功能的丧失会导致 ESCRT-III 复合物活性降低，正如在 Lgd 中观察到的那样。在此应用程序的框架中，我们将探讨 Lgd 与辅助 ESRT 的功能关系的本质。此外，我们将用分子筛查来补充我们进行的遗传筛查。这些实验将有助于了解进化保守的 Lgd 蛋白家族的功能。

The tumoursuppressor Lethal (2) giant discs (Lgd) is a founding member of a protein family that is conserved throughout metazoans. A mutation in one of the human orthologs, LGD2, causes an inherited form of non-syndromic mental retardation. Lgd is involved in the trafficking of transmembrane proteins, such as the Notch receptor, through the endosomal pathway. Our recent work in Drosophila and mammalian cell culture indicates that Lgd is required for the full activity of the ESCRT-III complex through direct interaction with one of its subunits Shrub/Snf7/CHMP4. ESCRT-III is one of five complexes that mediate the pinching off of intraluminal vesicles (ILVs) into the lumen of maturing endosomes. The formation of these ILVs is necessary for the degradation of transmembrane proteins and cancellation of signalling through activated signalling receptors. The exact role of Lgd during this process is not understood. The results of genetic screens performed in our lab suggest that the group of auxiliary ESCRTs, which are required for the full activity of the ESCRT machinery, have a functional relationship with Lgd. Loss of function of the auxiliary ESCRTs in yeast results in the reduction of the activity of the ESCRT-III complex, as has been observed for Lgd. In the frame of this application we will explore the nature of the functional relationship of Lgd to the auxiliary ESCRTs. Moreover, we will complement our performed genetic screens with a molecular one. These experiments will help to understand the function of the evolutionary conserved Lgd protein family.