TSC2 is a stress granule suppressor.

Stress granules (SGs) are dynamic, membrane-less ribonucleoprotein assemblies that form through liquid-liquid phase separation to prioritize stress-survival proteostasis. Through reanalysis of a Drosophila genome-wide RNAi screen, we identified a set of conserved SG suppressor genes and validated the top candidate, Tsc2, in both mouse and human cell lines. We illustrate that the complete loss of Tsc2 leads to spontaneous, canonical, and translation-dependent SGs driven by mTORC1 hyperactivation in mouse embryonic fibroblasts (MEFs). In addition, the Tsc2-deficient MEFs also sensitized to endoplasmic reticulum stress, delaying SG clearance. In human cell lines, the siRNA-mediated partial reduction of TSC2 in U2OS cells, and in human tuberous sclerosis patient fibroblasts, does not induce spontaneous SGs. Instead, the sensitivity to ER stress, translation perturbation, and delay in clearance correlate with the remaining levels of TSC2, suggesting that TSC2 functions as a threshold-dependent regulator of SG assembly. Together, our findings provide a comprehensive list of novel conserved SG regulators and establish TSC2 as a key regulator of SG dynamics.