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

Nicholas D. Huntington; Hamsa Puthalakath; Priscilla Gunn; Edwina Naik; Ewa M. Michalak; Mark J. Smyth; Hyacinth Tabarias; Mariapia A. Degli-Esposti; Grant Dewson; Simon N. Willis; Noboru Motoyama; David C.S. Huang; Stephen L. Nutt; David M. Tarlinton; Andreas Strasser

doi:10.1038/ni1487

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

Nicholas D. Huntington, Hamsa Puthalakath, Priscilla Gunn, Edwina Naik, Ewa M. Michalak, Mark J. Smyth, Hyacinth Tabarias, Mariapia A. Degli-Esposti, Grant Dewson, Simon N. Willis, Noboru Motoyama, David C.S. Huang, Stephen L. Nutt, David M. Tarlinton, Andreas Strasser

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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.

Original language	English
Pages (from-to)	856-863
Number of pages	8
Journal	Nature Immunology
Volume	8
Issue number	8
DOIs	https://doi.org/10.1038/ni1487
Publication status	Published - 1 Aug 2007
Externally published	Yes

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Huntington, N. D., Puthalakath, H., Gunn, P., Naik, E., Michalak, E. M., Smyth, M. J., Tabarias, H., Degli-Esposti, M. A., Dewson, G., Willis, S. N., Motoyama, N., Huang, D. C. S., Nutt, S. L., Tarlinton, D. M., & Strasser, A. (2007). Interleukin 15-mediated survival of natural killer cells is determined by interactions among Bim, Noxa and Mcl-1. Nature Immunology, 8(8), 856-863. https://doi.org/10.1038/ni1487

@article{be9b7b04eb16404dada20925d7e3e719,

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

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.",

author = "Huntington, {Nicholas D.} and Hamsa Puthalakath and Priscilla Gunn and Edwina Naik and Michalak, {Ewa M.} and Smyth, {Mark J.} and Hyacinth Tabarias and Degli-Esposti, {Mariapia A.} and Grant Dewson and Willis, {Simon N.} and Noboru Motoyama and Huang, {David C.S.} and Nutt, {Stephen L.} and Tarlinton, {David M.} and Andreas Strasser",

year = "2007",

month = aug,

day = "1",

doi = "10.1038/ni1487",

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volume = "8",

pages = "856--863",

journal = "Nature Immunology",

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publisher = "Nature Publishing Group",

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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 2007, 'Interleukin 15-mediated survival of natural killer cells is determined by interactions among Bim, Noxa and Mcl-1', Nature Immunology, vol. 8, no. 8, pp. 856-863. https://doi.org/10.1038/ni1487

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T1 - Interleukin 15-mediated survival of natural killer cells is determined by interactions among Bim, Noxa and Mcl-1

AU - Huntington, Nicholas D.

AU - Puthalakath, Hamsa

AU - Gunn, Priscilla

AU - Naik, Edwina

AU - Michalak, Ewa M.

AU - Smyth, Mark J.

AU - Tabarias, Hyacinth

AU - Degli-Esposti, Mariapia A.

AU - Dewson, Grant

AU - Willis, Simon N.

AU - Motoyama, Noboru

AU - Huang, David C.S.

AU - Nutt, Stephen L.

AU - Tarlinton, David M.

AU - Strasser, Andreas

PY - 2007/8/1

Y1 - 2007/8/1

N2 - 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.

AB - 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.

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EP - 863

JO - Nature Immunology

JF - Nature Immunology

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ER -

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

Abstract

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