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

Richard F Xiang; Danuta Stack; Shaunna M Huston; Shu Shun Li; Henry Ogbomo; Stephen K Kyei; Christopher H Mody

doi:10.1074/jbc.M115.681544

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

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

Authors

Richard F Xiang¹, Danuta Stack¹, Shaunna M Huston¹, Shu Shun Li¹, Henry Ogbomo¹, Stephen K Kyei¹, Christopher H Mody²

Affiliations

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).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Line, Tumor
Class Ia Phosphatidylinositol 3-Kinase / genetics
Class Ia Phosphatidylinositol 3-Kinase / immunology*
Cryptococcus neoformans / physiology*
Cytotoxicity, Immunologic*
Gene Expression Regulation
Host-Pathogen Interactions
Humans
Killer Cells, Natural / drug effects
Killer Cells, Natural / immunology*
Killer Cells, Natural / microbiology
Mitogen-Activated Protein Kinase 1 / genetics
Mitogen-Activated Protein Kinase 1 / immunology
Mitogen-Activated Protein Kinase 3 / genetics
Mitogen-Activated Protein Kinase 3 / immunology
Phosphorylation / drug effects
Primary Cell Culture
Pyrones / pharmacology
Quinolines / pharmacology
RAC2 GTP-Binding Protein
RNA, Small Interfering / genetics
RNA, Small Interfering / metabolism
Signal Transduction
rac GTP-Binding Proteins / antagonists & inhibitors
rac GTP-Binding Proteins / genetics
rac GTP-Binding Proteins / immunology*
rac1 GTP-Binding Protein / antagonists & inhibitors
rac1 GTP-Binding Protein / genetics
rac1 GTP-Binding Protein / immunology*
src-Family Kinases / genetics
src-Family Kinases / immunology*

Substances

EHT 1864
Pyrones
Quinolines
RAC1 protein, human
RNA, Small Interfering
Class Ia Phosphatidylinositol 3-Kinase
src-Family Kinases
MAPK1 protein, human
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
rac GTP-Binding Proteins
rac1 GTP-Binding Protein

Grants and funding

Canadian Institutes of Health Research/Canada