Human microRNA-27a* targets Prf1 and GzmB expression to regulate NK-cell cytotoxicity

Abstract

Perforin (Prf1) and granzyme B (GzmB) are essential effector molecules for natural killer (NK)-cell cytotoxicity, but how Prf1 and GzmB expression is regulated during arming of NK cells is poorly defined. We show that human microRNA (miR)-27a*is a negative regulator of NKcell cytotoxicity by silencing Prf1 and GzmB expression. Human miR-27a*specifically bound to the 3′ untranslated regions of Prf1 and GzmB, down-regulating expression in both resting and activated NK cells, and it functioned as a fine-tuner for homeostasis of the net amount of the effector proteins. Consistent with miR-27a*having an inhibitory role, knockdown of miR-27a*in NK cells dramatically increased cytotoxicity in vitro and decreased tumor growth in a human tumor xenograft model. Thus, NK-cell cytotoxicity is regulated, in part, by microRNA, and modulating endogenous miR-27a*levels in NK cells represents a potential immunotherapeutic strategy.