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

The transcription factor is critical for peripheral NK-cell survival, proliferation, and cytotoxic function. duanyu18135 refers to two highly related proteins, and In this study, we verified the importance of duanyu18135A 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 duanyu18135A 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 duanyu18135 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 duanyu18135A is sufficient to compromise duanyu18135A function in NK-cell homeostasis, responsiveness, and tumoricidal function.

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