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Dynamin 2 Regulates Granule Exocytosis during NK Cell-Mediated Cytotoxicity¹

Laura N. Arneson^*, Colin M. Segovis^*, Timothy S. Gomez^*,, Renee A. Schoon^*, Christopher J. Dick^*, Zhenkun Lou, Daniel D. Billadeau^2,*, and Paul J. Leibson^*

^* Department of Immunology and Division of Oncology Research, College of Medicine, Mayo Clinic, Rochester, MN 55905

NK cells are innate immune cells that can eliminate their targets through granule release. In this study, we describe a specialized role for the large GTPase Dynamin 2 (Dyn2) in the regulation of these secretory events leading to cell-mediated cytotoxicity. By modulating the expression of Dyn2 using small interfering RNA or by inhibiting its activity using a pharmacological agent, we determined that Dyn2 does not regulate conjugate formation, proximal signaling, or granule polarization. In contrast, during cell-mediated killing, Dyn2 localizes with lytic granules and polarizes to the NK cell–target interface where it regulates the final fusion of lytic granules with the plasma membrane. These findings identify a novel role for Dyn2 in the exocytic events required for effective NK cell-mediated cytotoxicity.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the National Institutes of Health (CA47752 and AI065474 to D.D.B.). D.D.B. is a Leukemia and Lymphoma Society Scholar.

² Address correspondence and reprint requests to Dr. Daniel D. Billadeau, Department of Immunology and Division of Oncology Research, Mayo Clinic College of Medicine, Rochester, MN 55905. E-mail address: billadeau.daniel{at}mayo.edu

³ Abbreviations used in this paper: MTOC, microtubule organizing center; siRNA, small interfering RNA; SNARE, soluble N-ethylmaleimide-sensitive factor attachment protein receptor; Dyn2, Dynamin 2; CMAC, 7-amino-4-chloromethylcoumarin; TPA, tetradecanoyl phorbyl myristate.

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