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Vol. 18, Issue 5, 1683-1692, May 2007

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Troyer Syndrome Protein Spartin Is Mono-Ubiquitinated and Functions in EGF Receptor Trafficking

Joanna C. Bakowska^*, Henri Jupille^*, Parvin Fatheddin^*, Rosa Puertollano, and Craig Blackstone^*

*Cellular Neurology Unit, National Institute of Neurological Disorders and Stroke, and Laboratory of Cell Biology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892

Submitted September 18, 2006; Revised January 30, 2007; Accepted February 16, 2007
Monitoring Editor: Sandra Lemmon

Troyer syndrome is an autosomal recessive hereditary spastic paraplegia caused by mutation in the spartin (SPG20) gene, which encodes a widely expressed protein of unknown function. This mutation results in premature protein truncation and thus might signify a loss-of-function disease mechanism. In this study, we have found that spartin is mono-ubiquitinated and functions in degradation of the epidermal growth factor receptor (EGFR). Upon EGF stimulation, spartin translocates from the cytoplasm to the plasma membrane and colocalizes with internalized EGF-Alexa. Knockdown of spartin by small interfering RNA decreases the rate of EGFR degradation and also affects EGFR internalization, recycling, or both. Furthermore, overexpression of spartin results in a prominent decrease in EGFR degradation. Taken together, our data suggest that spartin is involved in the intracellular trafficking of EGFR and that impaired endocytosis may underlie the pathogenesis of Troyer syndrome.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Address correspondence to: Craig Blackstone (blackstc{at}ninds.nih.gov) or Joanna C. Bakowska (bakowskj{at}ninds.nih.gov)

Abbreviations used: EGFR, epidermal growth factor receptor; ESCRT, endosomal sorting complex required for transport; FRAP, fluorescence recovery after photobleaching; GST, glutathione S-transferase; HA, hemagglutinin; HSP, hereditary spastic paraplegia; MIT, contained within microtubule-interacting and trafficking molecules; Vps4DN, Vps4-A^E228Q; YFP, yellow fluorescence protein.

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