title: Spastin couples microtubule severing to membrane traffic in completion of cytokinesis and secretion.
abstract: Mutations in the gene encoding the microtubule (MT)-severing protein spastin are the most common cause of hereditary spastic paraplegia, a genetic condition in which axons of the corticospinal tracts degenerate. We show that not only does endogenous spastin colocalize with MTs, but that it is also located on the early secretory pathway, can be recruited to endosomes and is present in the cytokinetic midbody. Spastin has two main isoforms, a 68 kD full-length isoform and a 60 kD short form. These two isoforms preferentially localize to different membrane traffic pathways with 68 kD spastin being principally located at the early secretory pathway, where it regulates endoplasmic reticulum-to-Golgi traffic. Sixty kiloDalton spastin is the major form recruited to endosomes and is also present in the midbody, where its localization requires the endosomal sorting complex required for transport-III-interacting MIT domain. Loss of midbody MTs accompanies the abscission stage of cytokinesis. In cells lacking spastin, a MT disruption event that normally accompanies abscission does not occur and abscission fails. We suggest that this event represents spastin-mediated MT severing. Our results support a model in which membrane traffic and MT regulation are coupled through spastin. This model is relevant in the axon, where there also is co-ordinated MT regulation and membrane traffic.
authors.affiliation: Department of Medical Genetics and Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
authors.forename: James W
authors.initials: JW
authors.lastname: Connell
authors.forename: Catherine
authors.initials: C
authors.lastname: Lindon
authors.forename: J Paul
authors.initials: JP
authors.lastname: Luzio
authors.forename: Evan
authors.initials: E
authors.lastname: Reid
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D048749:Cytokinesis; D004721:Endoplasmic Reticulum / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism*; D008970:Molecular Weight; D009154:Mutation / Q000235:genetics; D021381:Protein Transport; D055571:Secretory Pathway; D000074181:Spastin
chemical_list: D007527:Isoenzymes; D000251:Adenosine Triphosphatases; D000074181:Spastin; C400283:SPAST protein, human