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A point mutation in the linker domain of mouse STAT5A is associated with impaired NK-cell regulation


The transcription factor STAT5 is critical for peripheral NK-cell survival, proliferation, and cytotoxic function. STAT5 refers to two highly related proteins, STAT5A and STAT5B. In this study, we verified the importance of STAT5A isoform for NK cells. We characterized an incidental chemically induced W484G mutation in the Stat5a gene and found that this mutation was associated with a reduction of STAT5A protein expression. Closer examination of NK-cell subsets from Stat5a mutant mice showed marked reductions in NK-cell number and maturation. IL-15 treatment of Stat5a mutant NK cells exhibited defective induction of both STAT5 and mTOR signaling pathways and reduced expression of granzyme B and IFN-γ. Finally, we observed that Stat5a mutant mice revealed more tumor growth upon injection of RMA-S tumor cell line. Overall, our results demonstrate that the W484G mutation in the linker domain of STAT5A is sufficient to compromise STAT5A function in NK-cell homeostasis, responsiveness, and tumoricidal function.

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We would like to thank P. D’Arcy for her technical assistance on animal husbandry and injection. We are grateful to the following core facilities: the Life Science Complex Cell Vision Core Facility for flow cytometry (Mcgill University) and The Centre for Phenogenomics, Infection and Inflammation Core (Toronto, Canada),

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SC and GALT performed the experiments. SC, GALT, and SMV designed and analyzed the experiments. BC assisted with animal experiments. RE and GB performed the initial exome sequencing. SC and SMV wrote the manuscript. All authors reviewed and edited the manuscript.

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Correspondence to Silvia Marina Vidal.

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Chehboun, S., Leiva-Torres, G.A., Charbonneau, B. et al. A point mutation in the linker domain of mouse STAT5A is associated with impaired NK-cell regulation. Genes Immun 21, 136–141 (2020).

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