Interleukin 15-mediated survival of natural killer cells is determined by interactions among Bim, Noxa and Mcl-1

Huntington, ND; Puthalakath, H; Gunn, P; Naik, E; Michalak, EM; Smyth, MJ; Tabarias, H; Degli-Esposti, MA; Dewson, G; Willis, SN; Motoyama, N; Huang, DCS; Nutt, SL; Tarlinton, DM; Strasser, A

Author(s): Huntington, ND; Puthalakath, H; Gunn, P; Naik, E; Michalak, EM; Smyth, MJ; Tabarias, H; Degli-Esposti, MA; Dewson, G; Willis, SN; Motoyama, N; Huang, DCS; Nutt, SL; Tarlinton, DM; Strasser, A;
Details: Publication Year 2007-08,Volume 8,Issue #8,Page 856-863
Journal Title: NATURE IMMUNOLOGY
Publication Type: Journal Article
Abstract: 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.
Publisher: NATURE PUBLISHING GROUP
Keywords: FORKHEAD TRANSCRIPTION FACTOR; FAMILY-MEMBER BIM; BCL-2 FAMILY; BH3-ONLY PROTEINS; LYMPHOID DEVELOPMENT; APOPTOTIC RESPONSES; DEFICIENT MICE; FACTOR FKHR-L1; B-CELL; HOMEOSTASIS
Publisher's Version: https://doi.org/10.1038/ni1487
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2007-08-01 12:00:00