Zinc increases stress granule formation by promoting RNA condensation

During cellular stress, mRNAs are condensed into stress granules through the action of G3BP1 and G3BP2. How intracellular conditions affect RNA-protein condensation in stress granules is still unclear. Herein, we present several observations that cells modulate intracellular zinc concentrations to reduce the direct impact of zinc on RNA condensation. We show that oxidative stress increases the intracellular labile zinc and the expression of zinc-sequestering proteins, metallothioneins. Increased intracellular zinc leads to increased stress granule formation and delays stress granule disassembly without increasing translational repression, while zinc depletion decreases stress granule formation, demonstrating that even endogenous levels of free zinc can affect granules. Mechanistically, we demonstrate how zinc promotes stress granule formation by directly stimulating RNA condensation interactions at 100× lower concentrations than magnesium. Together, these data indicate that zinc modulates RNA condensation and stress granule formation and implies an unappreciated potential role for zinc in modulating intracellular RNA structures and interactions.