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MBC in Press, published online ahead of print January 17, 2007
Mol. Biol. Cell 10.1091/mbc.E06-09-0787

A more recent version of this article appeared on April 1, 2007
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Submitted on September 6, 2006
Revised on December 29, 2006
Accepted on January 5, 2007

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

Bong Yoon Kim,*{dagger} James A. Olzmann,*{dagger} Gregory S. Barsh,{ddagger} Lih-Shen Chin,* and Lian Li*

*Department of Pharmacology, Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA 30322; {ddagger}Department of Genetics and Pediatrics, Stanford University School of Medicine, Stanford, CA 94305

Monitoring Editor: Jennifer Lippincott-Schwartz

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-1 (ESCRT-1), as a specific Mahogunin substrate. We find that Mahogunin interacts with the ubiquitin E2 variant (UEV) domain of TSG101 via its PSAP motif, and catalyzes monoubiquitylation of TSG101 both in vivo and in vitro. Depletion of Mahogunin by siRNAs in mammalian cells disrupts endosome-to-lysosome trafficking of epidermal growth factor receptor (EGFR), resulting in prolonged activation of a downstream signaling cascade. Our findings support a role for Mahogunin in a proteasome-independent ubiquitination pathway and suggest a link between dysregulation of endosomal trafficking and spongiform neurodegeneration.

{dagger}These authors contributed equally to this work.

Address correspondence to: Lih-Shen Chin (chinl{at}pharm.emory.edu) or Lian Li (lianli{at}pharm.emory.edu)




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