Ubiquitination of phosphatidylethanolamine in organellar membranes

Mol Cell. 2022 Oct 6;82(19):3677-3692.e11. doi: 10.1016/j.molcel.2022.08.008. Epub 2022 Aug 30.


The covalent conjugation of ubiquitin family proteins is a widespread post-translational protein modification. In the ubiquitin family, the ATG8 subfamily is exceptional because it is conjugated mainly to phospholipids. However, it remains unknown whether other ubiquitin family proteins are also conjugated to phospholipids. Here, we report that ubiquitin is conjugated to phospholipids, mainly phosphatidylethanolamine (PE), in yeast and mammalian cells. Ubiquitinated PE (Ub-PE) accumulates at endosomes and the vacuole (or lysosomes), and its level increases during starvation. Ub-PE is also found in baculoviruses. In yeast, PE ubiquitination is catalyzed by the canonical ubiquitin system enzymes Uba1 (E1), Ubc4/5 (E2), and Tul1 (E3) and is reversed by Doa4. Liposomes containing Ub-PE recruit the ESCRT components Vps27-Hse1 and Vps23 in vitro. Ubiquitin-like NEDD8 and ISG15 are also conjugated to phospholipids. These findings suggest that the conjugation to membrane phospholipids is not specific to ATG8 but is a general feature of the ubiquitin family.

Keywords: Doa4; Tul1; endosome; lysosome; phosphatidylethanolamine; phospholipids; ubiquitin; ubiquitin-like proteins; vacuole.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Endosomal Sorting Complexes Required for Transport / genetics
  • Endosomal Sorting Complexes Required for Transport / metabolism
  • Liposomes / metabolism
  • Mammals / metabolism
  • Phosphatidylethanolamines / metabolism
  • Phospholipids / metabolism
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Saccharomyces cerevisiae Proteins* / genetics
  • Saccharomyces cerevisiae Proteins* / metabolism
  • Saccharomyces cerevisiae* / genetics
  • Saccharomyces cerevisiae* / metabolism
  • Ubiquitin / metabolism
  • Ubiquitin-Conjugating Enzymes / genetics
  • Ubiquitin-Conjugating Enzymes / metabolism
  • Ubiquitination


  • Endosomal Sorting Complexes Required for Transport
  • Hse1 protein, S cerevisiae
  • Liposomes
  • Phosphatidylethanolamines
  • Phospholipids
  • Receptors, Cytoplasmic and Nuclear
  • Saccharomyces cerevisiae Proteins
  • Ubiquitin
  • VPS27 protein, S cerevisiae
  • Ubiquitin-Conjugating Enzymes