Rapid Lytic Granule Convergence to the MTOC in Natural Killer Cells is Dependent on Dynein but Not Cytolytic Commitment

Overview

Journal Mol Biol Cell

Specialties Cell Biology
Molecular Biology

Date 2010 May 7

PMID 20444980

Citations 98

Authors

Ashley N Mentlik

Keri B Sanborn

Erika L Holzbaur

Jordan S Orange

Affiliations

Soon will be listed here.

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.

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References

Gill S, Schroer T, Szilak I, Steuer E, Sheetz M, Cleveland D . Dynactin, a conserved, ubiquitously expressed component of an activator of vesicle motility mediated by cytoplasmic dynein. J Cell Biol. 1991; 115(6):1639-50. PMC: 2289205. DOI: 10.1083/jcb.115.6.1639. View

Burkhardt J, Echeverri C, Nilsson T, Vallee R . Overexpression of the dynamitin (p50) subunit of the dynactin complex disrupts dynein-dependent maintenance of membrane organelle distribution. J Cell Biol. 1997; 139(2):469-84. PMC: 2139801. DOI: 10.1083/jcb.139.2.469. View

Schroer T, Sheetz M . Two activators of microtubule-based vesicle transport. J Cell Biol. 1991; 115(5):1309-18. PMC: 2289226. DOI: 10.1083/jcb.115.5.1309. View

Liu D, Bryceson Y, Meckel T, Vasiliver-Shamis G, Dustin M, Long E . Integrin-dependent organization and bidirectional vesicular traffic at cytotoxic immune synapses. Immunity. 2009; 31(1):99-109. PMC: 2740634. DOI: 10.1016/j.immuni.2009.05.009. View

Riteau B, Barber D, Long E . Vav1 phosphorylation is induced by beta2 integrin engagement on natural killer cells upstream of actin cytoskeleton and lipid raft reorganization. J Exp Med. 2003; 198(3):469-74. PMC: 2194094. DOI: 10.1084/jem.20021995. View

Jenkins M, Tsun A, Stinchcombe J, Griffiths G . The strength of T cell receptor signal controls the polarization of cytotoxic machinery to the immunological synapse. Immunity. 2009; 31(4):621-31. PMC: 2791175. DOI: 10.1016/j.immuni.2009.08.024. View

McNamara J, Ribeiro M . The calcium dependence of pigment translocation in freshwater shrimp red ovarian chromatophores. Biol Bull. 2000; 198(3):357-66. DOI: 10.2307/1542691. View

Wulfing C, Purtic B, Klem J, Schatzle J . Stepwise cytoskeletal polarization as a series of checkpoints in innate but not adaptive cytolytic killing. Proc Natl Acad Sci U S A. 2003; 100(13):7767-72. PMC: 164662. DOI: 10.1073/pnas.1336920100. View

Combs J, Kim S, Tan S, Ligon L, Holzbaur E, Kuhn J . Recruitment of dynein to the Jurkat immunological synapse. Proc Natl Acad Sci U S A. 2006; 103(40):14883-8. PMC: 1595445. DOI: 10.1073/pnas.0600914103. View

10.

Ligon L, Shelly S, Tokito M, Holzbaur E . The microtubule plus-end proteins EB1 and dynactin have differential effects on microtubule polymerization. Mol Biol Cell. 2003; 14(4):1405-17. PMC: 153110. DOI: 10.1091/mbc.e02-03-0155. View

11.

Beal A, Anikeeva N, Varma R, Cameron T, Vasiliver-Shamis G, Norris P . Kinetics of early T cell receptor signaling regulate the pathway of lytic granule delivery to the secretory domain. Immunity. 2009; 31(4):632-42. PMC: 2778196. DOI: 10.1016/j.immuni.2009.09.004. View

12.

Presley J, Cole N, Schroer T, Hirschberg K, Zaal K, Lippincott-Schwartz J . ER-to-Golgi transport visualized in living cells. Nature. 1997; 389(6646):81-5. DOI: 10.1038/38001. View

13.

Stinchcombe J, Bossi G, Booth S, Griffiths G . The immunological synapse of CTL contains a secretory domain and membrane bridges. Immunity. 2001; 15(5):751-61. DOI: 10.1016/s1074-7613(01)00234-5. View

14.

Martin-Cofreces N, Robles-Valero J, Cabrero J, Mittelbrunn M, Gordon-Alonso M, Sung C . MTOC translocation modulates IS formation and controls sustained T cell signaling. J Cell Biol. 2008; 182(5):951-62. PMC: 2528574. DOI: 10.1083/jcb.200801014. View

15.

Bryceson Y, March M, Barber D, Ljunggren H, Long E . Cytolytic granule polarization and degranulation controlled by different receptors in resting NK cells. J Exp Med. 2005; 202(7):1001-12. PMC: 2213171. DOI: 10.1084/jem.20051143. View

16.

Gomez T, Kumar K, Medeiros R, Shimizu Y, Leibson P, Billadeau D . Formins regulate the actin-related protein 2/3 complex-independent polarization of the centrosome to the immunological synapse. Immunity. 2007; 26(2):177-90. PMC: 2836258. DOI: 10.1016/j.immuni.2007.01.008. View

17.

Vyas Y, Mehta K, Morgan M, Maniar H, Butros L, Jung S . Spatial organization of signal transduction molecules in the NK cell immune synapses during MHC class I-regulated noncytolytic and cytolytic interactions. J Immunol. 2001; 167(8):4358-67. DOI: 10.4049/jimmunol.167.8.4358. View

18.

Orange J . Formation and function of the lytic NK-cell immunological synapse. Nat Rev Immunol. 2009; 8(9):713-25. PMC: 2772177. DOI: 10.1038/nri2381. View

19.

Levi V, Serpinskaya A, Gratton E, Gelfand V . Organelle transport along microtubules in Xenopus melanophores: evidence for cooperation between multiple motors. Biophys J. 2005; 90(1):318-27. PMC: 1367030. DOI: 10.1529/biophysj.105.067843. View

20.

King S, Schroer T . Dynactin increases the processivity of the cytoplasmic dynein motor. Nat Cell Biol. 2000; 2(1):20-4. DOI: 10.1038/71338. View