# Hippo kinases Mst1 and Mst2 maintain NK cell homeostasis by orchestrating metabolic state and transcriptional activity

## TL;DR

This study reveals that Mst1 and Mst2 kinases are essential for maintaining NK cell homeostasis by controlling metabolism and gene activity.

## Contribution

The study identifies Mst1 and Mst2 as novel regulators of NK cell homeostasis independent of canonical Hippo signaling.

## Key findings

- Mst1/2 regulate NK cell development, survival, and function through metabolic control and quiescence.
- Mst1/2 facilitate IL-15 signaling and activate pSTAT3-TCF1 to maintain NK cell homeostasis.
- The study emphasizes the role of cellular quiescence in NK cell maturation and function.

## Abstract

Natural killer (NK) cells play a crucial role in immune response against viral infections and tumors. However, further investigation is needed to better understand the key molecules responsible for determining the fate and function of NK cells. In this study, we made an important discovery regarding the involvement of the Hippo kinases Mst1 and Mst2 as novel regulators in maintaining mouse NK cell homeostasis. The presence of high Mst1 and Mst2 (Mst1/2) activity in NK cells is essential for their proper development, survival and function in a canonical Hippo signaling independent mode. Mechanistically, Mst1/2 induce cellular quiescence by regulating the processes of proliferation and mitochondrial metabolism, thereby ensuring the development and survival of NK cells. Furthermore, Mst1/2 effectively sense IL-15 signaling and facilitate the activation of pSTAT3-TCF1, which contributes to NK cell homeostasis. Overall, our investigation highlights the crucial role of Mst1/2 as key regulators in metabolic reprogramming and transcriptional regulation for mouse NK cell survival and function, emphasizing the significance of cellular quiescence during NK cell development and functional maturation.