biostudies-literatureWeyer YAustrian Science Fund FWFFonds National de la Recherche LuxembourgFonds National de la Recherche Luxembourg (National Research Fund)Lipotype lipidomics excellence awardEC | Horizon 2020 Framework ProgrammeEC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)9257https://www.ebi.ac.uk/biostudies/studies/S-EPMC11513148biostudies-literatureUnknown15(1)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 asymmeNature communicationsThe Dsc ubiquitin ligase complex identifies transmembrane degrons to degrade orphaned proteins at the Golgi.PMC1151314884768110.55776/DOC821357182610.55776/P3216110.55776/P3490710.55776/P36187Weyer YWiderin MALiedl KRPurwar AWeys STeis DSchwabl SIRuepp ASarg BDunzendorfer-Matt TMutsters NJMSchmidt OKremser LSiegmann KTettamanti MGNiedrist VTang XfalseThe 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 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 asymme2024-01-01T00:00:00Z2024 Oct2026-07-15T17:37:34.569Z2025-04-06T14:25:56.738ZS-EPMC115131483946195810.1038/s41467-024-53676-6