title: UNC-45A Is a Nonmuscle Myosin IIA Chaperone Required for NK Cell Cytotoxicity via Control of Lytic Granule Secretion.
abstract: NK cell's killing is a tightly regulated process under the control of specific cytoskeletal proteins. This includes Wiskott-Aldrich syndrome protein, Wiskott-Aldrich syndrome protein-interacting protein, cofilin, Munc13-4, and nonmuscle myosin IIA (NMIIA). These proteins play a key role in controlling NK-mediated cytotoxicity either via regulating the attachment of lytic granules to the actin-based cytoskeleton or via promoting the cytoskeletal reorganization that is requisite for lytic granule release. UNC-45A is a highly conserved member of the UNC-45/CRO1/She4p family of proteins that act as chaperones for both conventional and nonconventional myosin. Although we and others have shown that in lower organisms and in mammalian cells NMIIA-associated functions, such as cytokinesis, cell motility, and organelle trafficking, are dependent upon the presence of UNC-45A, its role in NK-mediated functions is largely unknown. In this article, we describe UNC-45A as a key regulator of NK-mediated cell toxicity. Specifically we show that, in human NK cells, UNC-45A localize at the NK cell immunological synapse of activated NK cells and is part of the multiprotein complex formed during NK cell activation. Furthermore, we show that UNC-45A is disposable for NK cell immunological synapse formation and lytic granules reorientation but crucial for lytic granule exocytosis. Lastly, loss of UNC-45A leads to reduced NMIIA binding to actin, suggesting that UNC-45A is a crucial component in regulating human NK cell cytoskeletal dynamics via promoting the formation of actomyosin complexes.
authors.affiliation: Department of Obstetrics, Gynecology and Women's Heath, University of Minnesota Twin Cities, Minneapolis, MN 55455;
authors.forename: Yoshie
authors.initials: Y
authors.lastname: Iizuka
authors.affiliation: Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN 55455;
authors.forename: Frank
authors.initials: F
authors.lastname: Cichocki
authors.affiliation: Department of Obstetrics, Gynecology and Women's Heath, University of Minnesota Twin Cities, Minneapolis, MN 55455;
authors.forename: Andrew
authors.initials: A
authors.lastname: Sieben
authors.affiliation: Department of Life Sciences and Biotechnology, University of Ferrara, 44121 Ferrara, Italy; and.
authors.forename: Fabio
authors.initials: F
authors.lastname: Sforza
authors.affiliation: Department of Neuroscience, University of Minnesota, Minneapolis, MN 55455.
authors.forename: Razaul
authors.initials: R
authors.lastname: Karim
authors.affiliation: Department of Obstetrics, Gynecology and Women's Heath, University of Minnesota Twin Cities, Minneapolis, MN 55455;
authors.forename: Kathleen
authors.initials: K
authors.lastname: Coughlin
authors.affiliation: Department of Obstetrics, Gynecology and Women's Heath, University of Minnesota Twin Cities, Minneapolis, MN 55455;
authors.forename: Rachel
authors.initials: R
authors.lastname: Isaksson Vogel
authors.affiliation: Department of Life Sciences and Biotechnology, University of Ferrara, 44121 Ferrara, Italy; and.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Gavioli
authors.affiliation: Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN 55455;
authors.forename: Valarie
authors.initials: V
authors.lastname: McCullar
authors.affiliation: Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN 55455;
authors.forename: Todd
authors.initials: T
authors.lastname: Lenvik
authors.affiliation: Department of Neuroscience, University of Minnesota, Minneapolis, MN 55455.
authors.forename: Michael
authors.initials: M
authors.lastname: Lee
authors.affiliation: Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN 55455;
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Miller
authors.affiliation: Department of Obstetrics, Gynecology and Women's Heath, University of Minnesota Twin Cities, Minneapolis, MN 55455; mbazzaro@umn.edu.
authors.forename: Martina
authors.initials: M
authors.lastname: Bazzaro
mesh_terms: D051339:Actin Depolymerizing Factors / Q000276:immunology / Q000378:metabolism; D000199:Actins / Q000276:immunology / Q000378:metabolism; D001693:Biological Transport, Active / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D003599:Cytoskeleton / Q000276:immunology / Q000378:metabolism; D005089:Exocytosis / Q000502:physiology*; D005260:Female; D006801:Humans; D054992:Immunological Synapses / Q000276:immunology / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology* / Q000378:metabolism; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism; D024507:Nonmuscle Myosin Type IIA / Q000276:immunology* / Q000378:metabolism; D022142:Secretory Vesicles / Q000276:immunology* / Q000378:metabolism
chemical_list: D051339:Actin Depolymerizing Factors; D000199:Actins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C507969:UNC13D protein, human; C509158:UNC45A protein, human; D024507:Nonmuscle Myosin Type IIA