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J Biol Chem. 2016 Mar 25;291(13):6912-22. doi: 10.1074/jbc.M115.681544. Epub 2016 Feb 11.

Ras-related C3 Botulinum Toxin Substrate (Rac) and Src Family Kinases (SFK) Are Proximal and Essential for Phosphatidylinositol 3-Kinase (PI3K) Activation in Natural Killer (NK) Cell-mediated Direct Cytotoxicity against Cryptococcus neoformans.

Author information

1
From the Departments of Microbiology, Immunology and Infectious Diseases and the Snyder Institute for Chronic Disease, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
2
From the Departments of Microbiology, Immunology and Infectious Diseases and the Snyder Institute for Chronic Disease, University of Calgary, Calgary, Alberta T2N 4N1, Canada Internal Medicine and cmody@ucalgary.ca.

Abstract

The activity of Rac in leukocytes is essential for immunity. However, its role in NK cell-mediated anti-microbial signaling remains unclear. In this study, we investigated the role of Rac in NK cell mediated anti-cryptococcal killing. We found thatCryptococcus neoformansindependently activates both Rac and SFK pathways in NK cells, and unlike in tumor killing,Cryptococcusinitiated a novel Rac → PI3K → Erk cytotoxicity cascade. Remarkably, Rac was not required for conjugate formation, despite its essential role in NK cytotoxicity againstC. neoformans Taken together, our data show that, unlike observations with tumor cells, NK cells use a novel Rac cytotoxicity pathway in conjunction with SFK, to killC. neoformans.

KEYWORDS:

Cellular signaling; Cryptococcus; Rac (Rac GTPase); Src; adhesion; fungi; natural killer cells (NK cells); phosphatidylinositide 3-kinase (PI 3-kinase)

PMID:
26867574
PMCID:
PMC4807276
DOI:
10.1074/jbc.M115.681544
[Indexed for MEDLINE]
Free PMC Article

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