Reg1 and Snf1 regulate stress-induced relocalization of protein phosphatase-1 to cytoplasmic granules

The compartmentalization of cellular function is achieved largely through the existence of membrane-bound organelles. However, recent work suggests a novel mechanism of compartmentalization mediated by membraneless structures that have liquid droplet-like properties and arise through phase separation. Cytoplasmic stress granules (SGs) are the best characterized and are induced by various stressors including arsenite, heat shock, and glucose deprivation. Current models suggest that SGs play an important role in protein homeostasis by mediating reversible translation attenuation. Protein phosphatase-1 (PP1) is a central cellular regulator responsible for most serine/threonine dephosphorylation. Here, we show that upon arsenite stress, PP1's catalytic subunit Glc7 relocalizes to punctate cytoplasmic granules. This altered localization requires PP1's recently described maturation pathway mediated by the multifunctional ATPase Cdc48 and PP1's regulatory subunit Ypi1. Glc7 relocalization is mediated by its regulatory subunit Reg1 and its target Snf1, the AMP-dependent protein kinase. Surprisingly, Glc7 granules are highly specific to arsenite and appear distinct from canonical SGs. Arsenite induces potent translational inhibition, and translational recovery is strongly dependent on Glc7, but independent of Glc7's well-established role in regulating eIF2 alpha. These results suggest a novel form of stress-induced cytoplasmic granule and a new mode of translational control by Glc7.

Automated summary

Cellular function is mainly differentiated through membrane-bound organelles, but recent research has shown that membraneless structures formed through phase separation can also achieve compartmentalization in liquid droplet-like properties. Arsenite-induced cytoplasmic stress granules play a significant role in protein homeostasis by regulating translation, with the catalytic subunit Glc7 of protein phosphatase-1 being involved in their formation. This stress-induced granule is highly specific to arsenite and controls translation through a new mode of translational control by Glc7, independently of its established role in regulating eIF2 alpha.