Stress granules are non-membranous structures that transiently form in the 
cytoplasm during cellular stress, where they promote translational repression of 
non-essential RNAs and modulate cell signaling by sequestering key signal 
transduction proteins. These and other functions of stress granules facilitate 
an adaptive cellular response to environmental adversity. A key component of 
stress granules is the prion-related RNA-binding protein, T cell intracellular 
antigen-1 (TIA-1). Here, we report that recombinant TIA-1 undergoes rapid 
multimerization and phase separation in the presence of divalent zinc, which can 
be reversed by the zinc chelator, TPEN. Similarly, the formation and maintenance 
of TIA-1-positive stress granules in arsenite-treated cells are inhibited by 
TPEN. In addition, Zn2+ is released in cells treated with arsenite, before 
stress granule formation. These findings suggest that Zn2+ is a physiological 
ligand of TIA-1, acting as a stress-inducible second messenger to promote 
multimerization of TIA-1 and subsequent localization into stress granules.