Myosin IIA Associates with NK Cell Lytic Granules to Enable Their Interaction with F-Actin and Function at the Immunological Synapse

被引:80
作者
Sanborn, Keri B. [2 ]
Rak, Gregory D. [3 ]
Maru, Saumya Y.
Demers, Korey [5 ]
Difeo, Analisa [4 ]
Martignetti, John A. [4 ]
Betts, Michael R. [5 ]
Favier, Remi [6 ]
Banerjee, Pinaki P.
Orange, Jordan S. [1 ,2 ,3 ]
机构
[1] Childrens Hosp Philadelphia, Div Immunol, Abramson Res Ctr, Joseph Stokes Jr Res Inst, Philadelphia, PA 19104 USA
[2] Univ Penn, Sch Med, Immunol Grad Grp, Philadelphia, PA 19104 USA
[3] Univ Penn, Sch Med, Cell Biol & Physiol Grad Program, Philadelphia, PA 19104 USA
[4] Mt Sinai Sch Med, Dept Genet & Genom Sci, New York, NY 10029 USA
[5] Univ Penn, Dept Microbiol, Philadelphia, PA 19104 USA
[6] Armand Trousseau Childrens Hosp, Assistance Publ Hop Paris, Ctr Reference Pathol Plaquettaires, F-75012 Villejuif, France
关键词
PROTEIN-KINASE-C; NATURAL-KILLER-CELLS; HEAVY-CHAIN IIA; NONMUSCLE MYOSIN; VESICLE TRANSPORT; SMOOTH-MUSCLE; MAST-CELLS; T-CELLS; PHOSPHORYLATION; MUTATIONS;
D O I
10.4049/jimmunol.0804337
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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. The Journal of Immunology, 2009, 182: 6969-6984.
引用
收藏
页码:6969 / 6984
页数:16
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