A Gnl1-dependent natural killer cell deficiency is associated with altered cell cycle and ribosomal protein gene expression and is overcome by p53 ablation

Natural Killer (NK) cells are the founding members of the innate lymphoid cell family.They are bone marrow derived effector lymphocytes that have cytotoxic and regulatory capacities which provide protection against viral infection and tumor formation.Following an N-ethyl-Nnitrosourea (ENU) induced mutagenesis screen in mice, we identified a pedigree with severe susceptibility to murine cytomegalovirus (MCMV) infection due to a loss-of-function mutation in the gene, Guanine nucleotide-binding protein-like 1 (Gnl1).The mutation introduces a premature stop codon at amino acid position 365 (mutant = Gnl1 C365X ), resulting in an NK cell deficiency.The overall objective of this study is to understand the mechanism by which mutation of GNL1 leads to NK cell deficiency.Based on the close sequence homology of GNL1 to other YRG family proteins and reports on the function of human GNL1, we hypothesize that the Gnl1 C365X mutation perturbs ribosomal protein and cell cycle gene expression, p53 activation and cell survival in NK cells.In order to address the hypothesis, we performed RNA-sequencing to identify differentially expressed genes (DEGs) between Gnl1 +/+ and Gnl1 C365X NK cells.A total of 143 DEGs were identified.Gene ontology highlighted terms associated with cell cycle, and cell cycle checkpoints.A gene set enrichment analysis (GSEA) using immunological or KEGG gene sets demonstrated a positive enrichment in cell cycle and a negative enrichment in ribosome signatures in Gnl1 C365X NK cells.Bub1, Bub1b and Plk1 were three cell cycle genes among the 143 DEGs leading the enrichment of the KEGG cell cycle pathway.Bub1, Bub1b and Plk1 contain p53 responsive elements and have been shown to interact with p53.Ribosomal transcripts were reduced in the Gnl1 C365X NK cells which could be inducing ribosomal stress to activate p53 pathways.By knocking out the cell fate gate keeper p53, we were able to rescue the MCMV susceptibility observed in Gnl1 C365X mice.Moreover, the Gnl1 C365X NK cell deficiency, caspase 3 levels, and receptor expression (KLRG1, NKG2D, Ly49H, Ly49G2 and CD122) were restored to wild-type levels.In this study, we highlight that Gnl1 C365X NK cells are undergoing p53-dependent apoptotic cell death and the NK cell deficiency is underlying the susceptibility to MCMV infection.Furthermore, our data suggests that a downregulation in ribosomal protein transcription induces p53 activation resulting in abnormal NK cell cycle, proliferation and survival.

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