Spongiform neurodegeneration-associated E3 ligase Mahogunin ubiquitylates TSG101 and regulates endosomal trafficking

Mol Biol Cell. 2007 Apr;18(4):1129-42. doi: 10.1091/mbc.e06-09-0787. Epub 2007 Jan 17.

Abstract

A null mutation in the gene encoding the putative E3 ubiquitin-protein ligase Mahogunin causes spongiform neurodegeneration, a recessively transmitted prion-like disease in mice. However, no substrates of Mahogunin have been identified, and the cellular role of Mahogunin is unknown. Here, we report the identification of TSG101, a key component of the endosomal sorting complex required for transport (ESCRT)-I, as a specific Mahogunin substrate. We find that Mahogunin interacts with the ubiquitin E2 variant (UEV) domain of TSG101 via its PSAP motif and that it catalyzes monoubiquitylation of TSG101 both in vivo and in vitro. Depletion of Mahogunin by small interfering RNAs in mammalian cells disrupts endosome-to-lysosome trafficking of epidermal growth factor receptor, resulting in prolonged activation of a downstream signaling cascade. Our findings support a role for Mahogunin in a proteasome-independent ubiquitylation pathway and suggest a link between dysregulation of endosomal trafficking and spongiform neurodegeneration.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Cells, Cultured
  • DNA-Binding Proteins / metabolism*
  • Endosomal Sorting Complexes Required for Transport
  • Endosomes / metabolism*
  • ErbB Receptors / metabolism
  • Humans
  • Lysosomes / metabolism
  • Molecular Sequence Data
  • Nerve Degeneration / metabolism*
  • Prion Diseases / metabolism
  • Protein Transport
  • Rats
  • Signal Transduction
  • Transcription Factors / metabolism*
  • Ubiquitin / metabolism
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • DNA-Binding Proteins
  • Endosomal Sorting Complexes Required for Transport
  • Transcription Factors
  • Tsg101 protein
  • Ubiquitin
  • MGRN1 protein, human
  • Ubiquitin-Protein Ligases
  • ErbB Receptors