Institute of Molecular Biochemistry, Biocenter, Medical University of Innsbruck, Innsbruck, Austria.
Institute of Cell Biology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria.
Nat Commun. 2024 Oct 26;15(1):9257. doi: 10.1038/s41467-024-53676-6.
The Golgi apparatus is essential for protein sorting, yet its quality control mechanisms are poorly understood. Here we show that the Dsc ubiquitin ligase complex uses its rhomboid pseudo-protease subunit, Dsc2, to assess the hydrophobic length of α-helical transmembrane domains (TMDs) at the Golgi. Thereby the Dsc complex likely interacts with orphaned ER and Golgi proteins that have shorter TMDs and ubiquitinates them for targeted degradation. Some Dsc substrates will be extracted by Cdc48 for endosome and Golgi associated proteasomal degradation (EGAD), while others will undergo ESCRT dependent vacuolar degradation. Some substrates are degraded by both, EGAD- or ESCRT pathways. The accumulation of Dsc substrates entails a specific increase in glycerophospholipids with shorter and asymmetric fatty acyl chains. Hence, the Dsc complex mediates the selective degradation of orphaned proteins at the sorting center of cells, which prevents their spreading across other organelles and thereby preserves cellular membrane protein and lipid composition.
高尔基氏体对于蛋白质分拣至关重要，但人们对其质量控制机制知之甚少。本文中，我们发现 Dsc 泛素连接酶复合物利用其类蛋白水解酶亚基 Dsc2 来评估 α-螺旋跨膜结构域（TMD）在高尔基氏体的疏水性长度。由此，Dsc 复合物可能与具有较短 TMD 的孤儿内质网和高尔基体蛋白相互作用，并对其进行泛素化修饰以进行靶向降解。一些 Dsc 底物将被 Cdc48 提取进行内体和高尔基体相关蛋白酶体降解（EGAD），而另一些则会通过 ESCRT 依赖性液泡降解。一些底物会通过 EGAD 或 ESCRT 途径进行降解。Dsc 底物的积累需要具有更短和不对称脂肪酸链的甘油磷脂的特异性增加。因此，Dsc 复合物在细胞的分拣中心介导了孤儿蛋白的选择性降解，从而防止它们扩散到其他细胞器，从而维持了细胞的膜蛋白和脂质组成。
