title: Myosin Vb mediates Cu+ export in polarized hepatocytes.
abstract: The cellular machinery responsible for Cu(+)-stimulated delivery of the Wilson-disease-associated protein ATP7B to the apical domain of hepatocytes is poorly understood. We demonstrate that myosin Vb regulates the Cu(+)-stimulated delivery of ATP7B to the apical domain of polarized hepatic cells, and that disruption of the ATP7B-myosin Vb interaction reduces the apical surface expression of ATP7B. Overexpression of the myosin Vb tail, which competes for binding of subapical cargos to myosin Vb bound to subapical actin, disrupted the surface expression of ATP7B, leading to reduced cellular Cu(+) export. The myosin-Vb-dependent targeting step occurred in parallel with hepatocyte-like polarity. If the myosin Vb tail was expressed acutely in cells just prior to the establishment of polarity, it appeared as part of an intracellular apical compartment, centered on γ-tubulin. ATP7B became selectively arrested in this compartment at high [Cu(+)] in the presence of myosin Vb tail, suggesting that these compartments are precursors of donor-acceptor transfer stations for apically targeted cargos of myosin Vb. Our data suggest that reduced hepatic Cu(+) clearance in idiopathic non-Wilsonian types of disease might be associated with the loss of function of myosin Vb.
authors.affiliation: Department of Cell Biology, Johns Hopkins University, Baltimore, MD 21205, USA arnabatiicb@gmail.com.
authors.forename: Arnab
authors.initials: A
authors.lastname: Gupta
authors.affiliation: Department of Cell Biology, Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Schell
authors.affiliation: Department of Physiology, Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Ashima
authors.initials: A
authors.lastname: Bhattacharjee
authors.affiliation: Department of Physiology, Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Lutsenko
authors.affiliation: Department of Cell Biology, Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Ann L
authors.initials: AL
authors.lastname: Hubbard
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D016764:Cell Polarity; D003300:Copper / Q000378:metabolism*; D000073840:Copper-Transporting ATPases; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D006527:Hepatolenticular Degeneration / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000166:cytology / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism*; D024701:Myosin Type V / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport
chemical_list: D027682:Cation Transport Proteins; C505832:MYO5B protein, human; D003300:Copper; D000251:Adenosine Triphosphatases; D024701:Myosin Type V; D018995:Myosin Heavy Chains; C000612464:ATP7B protein, human; D000073840:Copper-Transporting ATPases
keywords: ATP7B; Apical; Cu+; Endosome; Hepatocyte; Myosin; Trafficking
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