title: Rapid lytic granule convergence to the MTOC in natural killer cells is dependent on dynein but not cytolytic commitment.
abstract: Natural killer cells are lymphocytes specialized to participate in host defense through their innate ability to mediate cytotoxicity by secreting the contents of preformed secretory lysosomes (lytic granules) directly onto a target cell. This form of directed secretion requires the formation of an immunological synapse and occurs stepwise with actin reorganization preceding microtubule-organizing center (MTOC) polarization to the synapse. Because MTOC polarization to the synapse is required for polarization of lytic granules, we attempted to define their interrelationship. We found that compared with the time required for MTOC polarization, lytic granules converged to the MTOC rapidly. The MTOC-directed movement of lytic granules was independent of actin and microtubule reorganization, dependent on dynein motor function, occurred before MTOC polarization, and did not require a commitment to cytotoxicity. This defines a novel paradigm for rapid MTOC-directed transport as a prerequisite for directed secretion, one that may prepare, but not commit cells for precision secretory function.
authors.affiliation: Department of Pediatrics and Physiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Ashley N
authors.initials: AN
authors.lastname: Mentlik
authors.forename: Keri B
authors.initials: KB
authors.lastname: Sanborn
authors.forename: Erika L
authors.initials: EL
authors.lastname: Holzbaur
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Orange
mesh_terms: D000199:Actins / Q000378:metabolism; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D003594:Cytoplasmic Granules / Q000378:metabolism*; D003602:Cytotoxicity, Immunologic; D004398:Dyneins / Q000378:metabolism*; D006801:Humans; D007694:Killer Cells, Natural / Q000166:cytology* / Q000378:metabolism*; D018613:Microscopy, Confocal; D022101:Microtubule-Organizing Center / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014404:Tubulin / Q000235:genetics / Q000378:metabolism
chemical_list: D000199:Actins; D015703:Antigens, CD; D011993:Recombinant Fusion Proteins; D014404:Tubulin; D004398:Dyneins
references.citation: J Cell Biol. 1991 Dec;115(6):1639-50
references.pmid: 1836789
references.citation: J Cell Biol. 1997 Oct 20;139(2):469-84
references.pmid: 9334349
references.citation: J Cell Biol. 1991 Dec;115(5):1309-18
references.pmid: 1835460
references.citation: Immunity. 2009 Jul 17;31(1):99-109
references.pmid: 19592272
references.citation: J Exp Med. 2003 Aug 4;198(3):469-74
references.pmid: 12885870
references.citation: Immunity. 2009 Oct 16;31(4):621-31
references.pmid: 19833087
references.citation: Biol Bull. 2000 Jun;198(3):357-66
references.pmid: 10897449
references.citation: Proc Natl Acad Sci U S A. 2003 Jun 24;100(13):7767-72
references.pmid: 12802007
references.citation: Proc Natl Acad Sci U S A. 2006 Oct 3;103(40):14883-8
references.pmid: 16990435
references.citation: Mol Biol Cell. 2003 Apr;14(4):1405-17
references.pmid: 12686597
references.citation: Immunity. 2009 Oct 16;31(4):632-42
references.pmid: 19833088
references.citation: Nature. 1997 Sep 4;389(6646):81-5
references.pmid: 9288971
references.citation: Immunity. 2001 Nov;15(5):751-61
references.pmid: 11728337
references.citation: J Cell Biol. 2008 Sep 8;182(5):951-62
references.pmid: 18779373
references.citation: J Exp Med. 2005 Oct 3;202(7):1001-12
references.pmid: 16203869
references.citation: Immunity. 2007 Feb;26(2):177-90
references.pmid: 17306570
references.citation: J Immunol. 2001 Oct 15;167(8):4358-67
references.pmid: 11591760
references.citation: Nat Rev Immunol. 2008 Sep;8(9):713-25
references.pmid: 19172692
references.citation: Biophys J. 2006 Jan 1;90(1):318-27
references.pmid: 16214870
references.citation: Nat Cell Biol. 2000 Jan;2(1):20-4
references.pmid: 10620802
references.citation: J Cell Biol. 1987 Sep;105(3):1253-65
references.pmid: 3308906
references.citation: Cell. 1987 Oct 23;51(2):309-18
references.pmid: 2959372
references.citation: Nature. 2006 Sep 28;443(7110):462-5
references.pmid: 17006514
references.citation: J Exp Med. 2007 Oct 1;204(10):2285-91
references.pmid: 17875677
references.citation: Proc Natl Acad Sci U S A. 1995 Feb 28;92(5):1634-8
references.pmid: 7878030
references.citation: Annu Rev Cell Dev Biol. 2003;19:469-91
references.pmid: 14570578
references.citation: J Immunol. 1982 Dec;129(6):2816-25
references.pmid: 6890568
references.citation: Proc Natl Acad Sci U S A. 1982 Dec;79(23):7489-93
references.pmid: 6984191
references.citation: J Immunol. 2009 Jun 1;182(11):6969-84
references.pmid: 19454694
references.citation: Proc Natl Acad Sci U S A. 1997 Oct 28;94(22):12180-5
references.pmid: 9342383
references.citation: Proc Natl Acad Sci U S A. 2006 Jul 5;103(27):10346-10351
references.pmid: 16801532
references.citation: Proc Natl Acad Sci U S A. 2006 Apr 11;103(15):5741-5
references.pmid: 16585530
references.citation: J Immunol. 1984 Dec;133(6):2972-8
references.pmid: 6092461
references.citation: Cell Motil Cytoskeleton. 1997;38(4):397-409
references.pmid: 9415381
references.citation: Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14151-6
references.pmid: 14612578
references.citation: J Exp Med. 2007 Oct 1;204(10):2305-20
references.pmid: 17785506
references.citation: Neuron. 2002 May 30;34(5):715-27
references.pmid: 12062019
references.citation: Nature. 2006 Feb 16;439(7078):875-8
references.pmid: 16382238
references.citation: J Immunol. 2004 Sep 15;173(6):3653-9
references.pmid: 15356110
references.citation: J Cell Sci. 1993 Jan;104 ( Pt 1):151-62
references.pmid: 8449993
references.citation: Nat Immunol. 2008 Aug;9(8):887-97
references.pmid: 18587398
references.citation: J Exp Med. 1999 Nov 15;190(10):1505-16
references.pmid: 10562324