The Dsc ubiquitin ligase complex identifies transmembrane degrons to degrade orphaned proteins at the Golgi

Yannick Weyer, Sinead I. Schwabl, Xuechen Tang, Astha Purwar, Konstantin Siegmann, Angela Ruepp, Theresia Dunzendorfer-Matt, Michael A. Widerin, Veronika Niedrist, Noa J. M. Mutsters, Maria G. Tettamanti, Sabine Weys, Bettina Sarg, Leopold Kremser, Klaus R. Liedl, Oliver Schmidt and David Teis ()
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Yannick Weyer: Medical University of Innsbruck
Sinead I. Schwabl: Medical University of Innsbruck
Xuechen Tang: University of Innsbruck
Astha Purwar: Medical University of Innsbruck
Konstantin Siegmann: Medical University of Innsbruck
Angela Ruepp: Medical University of Innsbruck
Theresia Dunzendorfer-Matt: Medical University of Innsbruck
Michael A. Widerin: Medical University of Innsbruck
Veronika Niedrist: Medical University of Innsbruck
Noa J. M. Mutsters: Medical University of Innsbruck
Maria G. Tettamanti: University of Geneva
Sabine Weys: Medical University of Innsbruck
Bettina Sarg: Medical University of Innsbruck
Leopold Kremser: Medical University of Innsbruck
Klaus R. Liedl: Medical University of Innsbruck
Oliver Schmidt: Medical University of Innsbruck
David Teis: Medical University of Innsbruck

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-53676-6

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