title: Role of Ostm1 Cytosolic Complex with Kinesin 5B in Intracellular Dispersion and Trafficking.
abstract: In humans and in mice, mutations in the Ostm1 gene cause the most severe form of osteopetrosis, a major bone disease, and neuronal degeneration, both of which are associated with early death. To gain insight into Ostm1 function, we first investigated by sequence and biochemical analysis an immature 34-kDa type I transmembrane Ostm1 protein with a unique cytosolic tail. Mature Ostm1 is posttranslationally processed and highly N-glycosylated and has an apparent mass of ∼60 kDa. Analysis the subcellular localization of Ostm1 showed that it is within the endoplasmic reticulum, trans-Golgi network, and endosomes/lysosomes. By a wide protein screen under physiologic conditions, several novel cytosolic Ostm1 partners were identified and validated, for which a direct interaction with the kinesin 5B heavy chains was demonstrated. These results determined that Ostm1 is part of a cytosolic scaffolding multiprotein complex, imparting an adaptor function to Ostm1. Moreover, we uncovered a role for the Ostm1/KIF5B complex in intracellular trafficking and dispersion of cargos from the endoplasmic reticulum to late endosomal/lysosomal subcellular compartments. These Ostm1 molecular and cellular functions could elucidate all of the pathophysiologic mechanisms underlying the wide phenotypic spectrum of Ostm1-deficient mice.
authors.affiliation: Laboratory of Cellular Interactions and Development, Clinical Research Institute of Montreal, Montreal, Québec, Canada Département de Médecine, Université de Montréal, Montréal, Québec, Canada Department of Medicine, Division of Experimental Medicine, McGill University, Montréal, Québec, Canada.
authors.forename: Subramanya N M
authors.initials: SN
authors.lastname: Pandruvada
authors.affiliation: Laboratory of Cellular Interactions and Development, Clinical Research Institute of Montreal, Montreal, Québec, Canada Département de Médecine, Université de Montréal, Montréal, Québec, Canada Department of Medicine, Division of Experimental Medicine, McGill University, Montréal, Québec, Canada.
authors.forename: Janie
authors.initials: J
authors.lastname: Beauregard
authors.affiliation: Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, Montreal, Québec, Canada.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Benjannet
authors.affiliation: Laboratory of Cellular Interactions and Development, Clinical Research Institute of Montreal, Montreal, Québec, Canada Département de Médecine, Université de Montréal, Montréal, Québec, Canada Department of Medicine, Division of Experimental Medicine, McGill University, Montréal, Québec, Canada.
authors.forename: Monica
authors.initials: M
authors.lastname: Pata
authors.affiliation: Laboratory of Neuropeptide Structure and Metabolism, Clinical Research Institute of Montreal, Montreal, Québec, Canada.
authors.forename: Claude
authors.initials: C
authors.lastname: Lazure
authors.affiliation: Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, Montreal, Québec, Canada.
authors.forename: Nabil G
authors.initials: NG
authors.lastname: Seidah
authors.affiliation: Laboratory of Cellular Interactions and Development, Clinical Research Institute of Montreal, Montreal, Québec, Canada Département de Médecine, Université de Montréal, Montréal, Québec, Canada Department of Medicine, Division of Experimental Medicine, McGill University, Montréal, Québec, Canada vacherj@ircm.qc.ca.
authors.forename: Jean
authors.initials: J
authors.lastname: Vacher
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D017173:Caenorhabditis elegans; D002460:Cell Line; D002522:Chlorocebus aethiops; D003600:Cytosol / Q000737:chemistry / Q000378:metabolism*; D004331:Drosophila melanogaster; D057809:HEK293 Cells; D006801:Humans; D016547:Kinesins / Q000737:chemistry / Q000378:metabolism*; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D016415:Sequence Alignment; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000378:metabolism*; D015027:Zebrafish
chemical_list: C488101:KIF5B protein, human; D008565:Membrane Proteins; C489946:OSTM1 protein, human; C509143:OSTM1 protein, mouse; D044767:Ubiquitin-Protein Ligases; C475469:Kif5b protein, mouse; D016547:Kinesins