Role of Ostm1 Cytosolic Complex with Kinesin 5B in Intracellular Dispersion and Trafficking

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...

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Published in:Molecular and cellular biology 2016-02, Vol.36 (3), p.507-521
Main Authors: Pandruvada, Subramanya N. M., Beauregard, Janie, Benjannet, Suzanne, Pata, Monica, Lazure, Claude, Seidah, Nabil G., Vacher, Jean
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Caenorhabditis elegans
Cell Line
Cercopithecus aethiops
COS Cells
Cytosol - chemistry
Cytosol - metabolism
Drosophila melanogaster
HEK293 Cells
Humans
Kinesin - chemistry
Kinesin - metabolism
Membrane Proteins - chemistry
Membrane Proteins - metabolism
Mice
Molecular Sequence Data
Protein Processing, Post-Translational
Protein Transport
Sequence Alignment
Ubiquitin-Protein Ligases - chemistry
Ubiquitin-Protein Ligases - metabolism
Zebrafish
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Summary: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.
ISSN:1098-5549
0270-7306
1098-5549
DOI:10.1128/MCB.00656-15