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

Nat Commun. 2024 Oct 26;15(1):9257. doi: 10.1038/s41467-024-53676-6.

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.

MeSH terms

  • Degrons
  • Endoplasmic Reticulum / metabolism
  • Endosomal Sorting Complexes Required for Transport / metabolism
  • Glycerophospholipids / metabolism
  • Golgi Apparatus* / metabolism
  • Membrane Proteins* / genetics
  • Membrane Proteins* / metabolism
  • Protein Transport
  • Proteolysis*
  • Saccharomyces cerevisiae Proteins* / genetics
  • Saccharomyces cerevisiae Proteins* / metabolism
  • Saccharomyces cerevisiae* / genetics
  • Saccharomyces cerevisiae* / metabolism
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • Saccharomyces cerevisiae Proteins
  • Membrane Proteins
  • Endosomal Sorting Complexes Required for Transport
  • Ubiquitin-Protein Ligases
  • Glycerophospholipids