Spongiform Neurodegeneration-associated E3 Ligase Mahogunin Ubiquitylates TSG101 and Regulates Endosomal Trafficking

• Type of Material: Article
• Authors: Bong Yoon Kim, Emory University; James A. Olzmann, Emory University; Gregory S. Barsh, Stanford University; Lih-Shen Chin, Emory University; Lian Li, Emory University
• Language: English
• Date: 2007-04
• Publisher: The American Society for Cell Biology
• Publication Version: Final Published Version
• Copyright Statement: © 2007 by The American Society for Cell Biology
• Final Published Version (URL): http://www.molbiolcell.org/content/18/4/1129
• Title of Journal or Parent Work: Molecular Biology of the Cell
• Volume: 18
• Issue: 4
• Start Page: 1129
• End Page: 1142
• Research Categories: Health Sciences, Pharmacology; Health Sciences, General

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.