Modulation of p-eIF2α cellular levels and stress granule assembly/disassembly by trehalose

Stress granules (SGs) are an important component of cellular stress response. Compromised assembly of SGs as well as their premature or delayed disassembly affect physiology and survival of cells under stress or during recovery from stress. Consequently, abnormal turnover of SGs has been implicated in the development of various pathologies, including neurodegeneration. We found that pretreatment of cells with a natural disaccharide trehalose, a known autophagy enhancer, delays SG assembly and facilitates their premature post-stress disassembly. Mechanistically, the effect of trehalose on SGs is mediated via the p-eIF2 alpha rather than autophagosome pathway. Trehalose increases pre-stress levels of p-eIF2 alpha and its phosphatase subunits and promotes post-stress translational recovery. Upon prolonged treatment, trehalose impairs basal translation affecting production of transiently expressed proteins. Early translational recovery and SG disassembly induced by trehalose pretreatment can sensitise cells to stress and impair survival. Our study has important implications for the use of trehalose in studies of autophagic clearance of misfolded proteins and for targeting SGs as a possible therapeutic approach in neurodegenerative and other diseases.