The Dsc ubiquitin ligase complex identifies transmembrane degrons to degrade orphaned proteins at the Golgi
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, particularly the rhomboid pseudo-protease subunit, Dsc2, assesses the hydrophobic length of -helical transmembrane domains (TMDs) at the Golgi. Thereby the Dsc complex interacts with orphaned ER and Golgi proteins that have shorter TMDs and ubiquitinates them for targeted degradation. Some Dsc substrates will be K63 polyubiquitinated for ESCRT dependent vacuolar degradation or K48 polyubiquitinated for endosome and Golgi associated proteasomal degradation (EGAD). Other Dsc substrates are exclusively extracted by Cdc48 for EGAD. 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 thus preserves cellular membrane protein and lipid composition.