Journal
MOLECULAR BIOLOGY OF THE CELL
Volume 18, Issue 4, Pages 1129-1142Publisher
AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E06-09-0787
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Funding
- NIA NIH HHS [R01 AG021489, AG-021489] Funding Source: Medline
- NINDS NIH HHS [F31 NS054597-02, R01 NS050650, NS-047199, R01 NS047575, NS-050650, F31 NS054597-01, R01 NS047199, F31 NS054597, NS-047575] Funding Source: Medline
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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.
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