title: Troyer syndrome protein spartin is mono-ubiquitinated and functions in EGF receptor trafficking.
abstract: 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.
authors.affiliation: Cellular Neurology Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Joanna C
authors.initials: JC
authors.lastname: Bakowska
authors.forename: Henri
authors.initials: H
authors.lastname: Jupille
authors.forename: Parvin
authors.initials: P
authors.lastname: Fatheddin
authors.forename: Rosa
authors.initials: R
authors.lastname: Puertollano
authors.forename: Craig
authors.initials: C
authors.lastname: Blackstone
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D048868:Adaptor Proteins, Signal Transducing; D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins; D002460:Cell Line; D018076:DNA, Complementary / Q000235:genetics; D004705:Endocytosis; D056827:Endosomal Sorting Complexes Required for Transport; D011992:Endosomes / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D015870:Gene Expression; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D011506:Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015419:Spastic Paraplegia, Hereditary / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D013577:Syndrome; D025801:Ubiquitin / Q000378:metabolism; D025262:Vacuolar Proton-Translocating ATPases; D033921:Vesicular Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001426:Bacterial Proteins; D002135:Calcium-Binding Proteins; D018797:Cell Cycle Proteins; D018076:DNA, Complementary; C486206:EPS15 protein, human; D056827:Endosomal Sorting Complexes Required for Transport; D047908:Intracellular Signaling Peptides and Proteins; D008164:Luminescent Proteins; D010750:Phosphoproteins; D011506:Proteins; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; C464787:SPART protein, human; D025801:Ubiquitin; D033921:Vesicular Transport Proteins; C054562:yellow fluorescent protein, Bacteria; D066246:ErbB Receptors; D000251:Adenosine Triphosphatases; D025262:Vacuolar Proton-Translocating ATPases; D000074183:ATPases Associated with Diverse Cellular Activities; C490305:VPS4A protein, human