Summary: Cryptococcus is the most important cause of fungal meningitis in immunocompromised individuals. Host defense against Cryptococcus involves direct killing by NK cells. That NK cells from HIV-infected patients fail to polarize perforin to the microbial synapse and kill C. neoformans led us to explore the mechanisms used to reposition and polarize the cytolytic granules to the synapse. Using live-cell imaging, we observed microtubule and granule movements in response to Cryptococcus that revealed a kinesin-dependent event. Eg5-kinesin bound to perforin-containing granules and was required for association with the microtubules. Inhibition of Eg5-kinesin abrogated dynein-dependent granule convergence to the MTOC and granule and MTOC polarization to the synapse and suppressed NK cell killing of Cryptococcus. In contrast, Eg5-kinesin was dispensable for tumor killing. This reveals an alternative mechanism of MTOC repositioning and granule polarization, not used in tumor cytotoxicity, in which Eg5-kinesin is required to initiate granule movement, leading to microbial killing. : The mechanisms of cytolytic granules deployment and the events leading to selective use of perforin, and not granulysin, in NK-cell-mediated killing of Cryptococcus are unknown. Ogbomo et al. demonstrate that Eg5-kinesin and dynein control these events. Eg5-kinesin activity is required to turn on dynein activity for directed cytotoxicity. Keywords: Eg5-kinesin, dynein, NK cell cytotoxicity, granule congregation, granule convergence, microtubule organizing center polarization, perforin, granulysin
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