The Orb6-Sts5 Axis Regulates Stress Granule Formation and Heat Stress Response in Fission Yeast

Cellular response to environmental fluctuations, such as increased temperature, is crucial in promoting cell survival and plays an increasingly recognized role in cancer biology. Important cellular functions altered by heat stress are cell polarization and protein translation. Previous studies have shown that heat stress alters the dynamics of Cdc42, a key regulator of cell polarization in eukaryotes, and promotes RNP granule formation, reprogramming protein translation. The biological mechanisms underlying these vast changes are only partially known. Here, we report that conserved NDR kinase Orb6, a homologue of mammalian STK38, responds to heat stress and regulates heat stress resilience by modulating Cdc42 dynamics and promoting stress granule assembly. Also, we discovered a finely tuned mechanism whereby stress-activated MAP kinase Sty1 negatively regulates Orb6 kinase and Orb6 C-terminal phosphorylation during heat stress. Orb6 inhibition by Sty1 increases the sensitivity of the cell to heat stress in a temperature-specific manner, fostering increased stress resilience and metabolic adaptation. These observations highlight the role of NDR kinase in the process of heat adaptation and thermotolerance during environmental cell exposure to elevated temperatures. Summary statementNuclear Dbf2-related kinase Orb6 inhibition by stress-activated protein kinase Sty1 promotes heat stress resilience in a temperature specific manner.