The Journal of Experimental Medicine
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Published online September 17, 2007
doi:10.1084/jem.20071143
The Journal of Experimental Medicine, Vol. 204, No. 10, 2285-2291
The Rockefeller University Press, 0022-1007 $30.00
© 2007 Andzelm et al.
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BRIEF DEFINITIVE REPORT

 Myosin IIA is required for cytolytic granule exocytosis in human NK cells

Milena M. Andzelm1, Xi Chen1, Konrad Krzewski1, Jordan S. Orange1,2, and Jack L. Strominger1

1 Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138
2 Children's Hospital of Philadelphia, Division of Immunology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104

CORRESPONDENCE Jack L. Strominger: jlstrom{at}fas.harvard.edu OR Jordan S. Orange: orange{at}mail.med.upenn.edu

Natural killer (NK) cell cytotoxicity involves the formation of an activating immunological synapse (IS) between the effector and target cell through which granzymes and perforin contained in lytic granules are delivered to the target cell via exocytosis. Inhibition of nonmuscle myosin II in human NK cells with blebbistatin or ML-9 impaired neither effector–target cell conjugation nor formation of a mature activating NK cell IS (NKIS; formation of an actin ring and polarization of the microtubule-organizing center and cytolytic granules to the center of the ring). However, membrane fusion of lytic granules, granzyme secretion, and NK cell cytotoxicity were all effectively blocked. Specific knockdown of the myosin IIA heavy chain by RNA interference impaired cytotoxicity, membrane fusion of lytic granules, and granzyme secretion. Thus, myosin IIA is required for a critical step between NKIS formation and granule exocytosis.

Abbreviations used: BDM, 2,3-butane-dione monoxime; cSMAC, central SMAC; IS, immunological synapse; NKIS, NK cell IS; pNK, peripheral blood NK; pSMAC, peripheral SMAC; RNAi, RNA interference; SMAC, supramolecular activation cluster; WASp, Wiskott-Aldrich syndrome protein.


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