The eIF2 kinase GCN2 is essential for the murine immune system to adapt to amino acid deprivation by asparaginase

Piyawan Bunpo, Judy K. Cundiff, Rachel B. Reinert, Ronald Wek, Carla Aldrich, Tracy G. Anthony

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Amino acid starvation by asparaginase (ASNase) enhances phosphorylation of eukaryotic initiation factor 2 (eIF2) by general control nonderepressible 2 (GCN2) kinase, leading to reduced global mRNA translation rates. This conserves energy and allows cells time to reprogram stress-related gene expression to alleviate cell injury. This study addressed the importance of GCN2 for the immune system to adapt to amino acid starvation by ASNase. GCN2+/+ and GCN2-/- mice were injected once daily with ASNase or saline for up to 7 d. In both thymus and spleen, activation of amino acid stress response genes to ASNase, such as asparagine synthetase and CAAT enhancer binding protein homologous protein, required GCN2. ASNase reduced food intake and body weight in both genotypes, but spleen and thymus wet weights and total cell numbers in thymus, spleen, bone marrow, and mesenteric lymph nodes were less in GCN2 -/- mice treated with ASNase (genotype x ASNase, P < 0.05). In the thymus, GCN2-/- mice treated with ASNase demonstrated enhanced apoptosis and fewer cells in all subpopulations examined (CD3+, CD4-8-, CD4+8+, CD4+8-, CD4-8+) compared with GCN2+/+ mice treated with ASNase (genotype x ASNase, P < 0.05). In the spleen, GCN2 deletion magnified ASNase-induced reductions in CD4+ T cells, CD8+ T cells, CD19+ B cells, and CD11b+ leukocytes (genotype x ASNase, P < 0.05). These results indicate that loss of GCN2 enhances immunosuppression by ASNase and that this eIF2 kinase is broadly required for amino acid stress management in the immune system.

Original languageEnglish
Pages (from-to)2020-2027
Number of pages8
JournalJournal of Nutrition
Volume140
Issue number11
DOIs
StatePublished - Nov 2010

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Eukaryotic Initiation Factor-2
Asparaginase
Immune System
Phosphotransferases
Amino Acids
Thymus Gland
Spleen
Genotype
Starvation
Aspartate-Ammonia Ligase
CCAAT-Enhancer-Binding Proteins
Aminoacylation
T-Lymphocytes
Protein Biosynthesis

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Nutrition and Dietetics
  • Medicine(all)

Cite this

The eIF2 kinase GCN2 is essential for the murine immune system to adapt to amino acid deprivation by asparaginase. / Bunpo, Piyawan; Cundiff, Judy K.; Reinert, Rachel B.; Wek, Ronald; Aldrich, Carla; Anthony, Tracy G.

In: Journal of Nutrition, Vol. 140, No. 11, 11.2010, p. 2020-2027.

Research output: Contribution to journalArticle

Bunpo, Piyawan ; Cundiff, Judy K. ; Reinert, Rachel B. ; Wek, Ronald ; Aldrich, Carla ; Anthony, Tracy G. / The eIF2 kinase GCN2 is essential for the murine immune system to adapt to amino acid deprivation by asparaginase. In: Journal of Nutrition. 2010 ; Vol. 140, No. 11. pp. 2020-2027.
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