Myosin IIA associates with NK cell lytic granules to enable their interaction with F-actin and function at the immunological synapse

Keri B. Sanborn, Gregory D. Rak, Saumya Y. Maru, Korey Demers, Analisa Difeo, John A. Martignetti, Michael R. Betts, Rémi Favier, Pinaki P. Banerjee, Jordan S. Orange

Research output: Contribution to journalArticlepeer-review

82 Scopus citations

Abstract

NK cell cytotoxicity requires the formation of an actin-rich immunological synapse (IS) with a target cell and the polarization of perforin-containing lytic granules toward the IS. Following the polarization of lytic granules, they traverse through the actin-rich IS to join the NK cell membrane in order for directed secretion of their contents to occur. We examined the role of myosin IIA as a candidate for facilitating this prefinal step in lytic NK cell IS function. Lytic granules in and derived from a human NK cell line, or ex vivo human NK cells, were constitutively associated with myosin IIA. When isolated using density gradients, myosin IIA-associated NK cell lytic granules directly bound to F-actin and the interaction was sensitive to the presence of ATP under conditions of flow. In NK cells from patients with a truncation mutation in myosin IIA, NK cell cytotoxicity, lytic granule penetration into F-actin at the IS, and interaction of isolated granules with F-actin were all decreased. Similarly, inhibition of myosin function also diminished the penetration of lytic granules into F-actin at the IS, as well as the final approach of lytic granules to and their dynamics at the IS. Thus, NK cell lytic granule-associated myosin IIA enables their interaction with actin and final transit through the actin-rich IS to the synaptic membrane, and can be defective in the context of naturally occurring human myosin IIA mutation.

Original languageEnglish
Pages (from-to)6969-6984
Number of pages16
JournalJournal of Immunology
Volume182
Issue number11
DOIs
StatePublished - 1 Jun 2009

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