Interleukin 15-mediated survival of natural killer cells is determined by interactions among Bim, Noxa and Mcl-1.
Interleukin 15 (IL-15) promotes the survival of natural killer (NK) cells by preventing apoptosis through mechanisms unknown at present. Here we identify Bim, Noxa and Mcl-1 as key regulators of IL-15-dependent survival of NK cells. IL-15 suppressed apoptosis by limiting Bim expression through the kinases Erk1 and Erk2 and mechanisms dependent on the transcription factor Foxo3a, while promoting expression of Mcl-1, which was necessary and sufficient for the survival of NK cells. Withdrawal of IL-15 led to upregulation of Bim and, accordingly, both Bim-deficient and Foxo3a-/- NK cells were resistant to cytokine deprivation. Finally, IL-15-mediated inactivation of Foxo3a and cell survival were dependent on phosphotidylinositol-3-OH kinase. Thus, IL-15 regulates the survival of NK cells at multiple steps, with Bim and Noxa being key antagonists of Mcl-1, the critical survivor factor in this process.
Huntington
Nicholas D
ND
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia. nhunting@pasteur.fr
Puthalakath
Hamsa
H
Gunn
Priscilla
P
Naik
Edwina
E
Michalak
Ewa M
EM
Smyth
Mark J
MJ
Tabarias
Hyacinth
H
Degli-Esposti
Mariapia A
MA
Dewson
Grant
G
Willis
Simon N
SN
Motoyama
Noboru
N
Huang
David C S
DC
Nutt
Stephen L
SL
Tarlinton
David M
DM
Strasser
Andreas
A
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins / Q000276:immunology / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D002470:Cell Survival / Q000276:immunology; D005434:Flow Cytometry; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D015151:Immunoblotting; D019409:Interleukin-15 / Q000276:immunology / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism*; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000276:immunology / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000276:immunology / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011518:Proto-Oncogene Proteins / Q000276:immunology / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000276:immunology / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D019409:Interleukin-15; C579094:Mcl1 protein, mouse; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; C408009:Pmaip1 protein, mouse; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D019869:Phosphatidylinositol 3-Kinases; D048052:Mitogen-Activated Protein Kinase 3