Prion‐Like Protein LENG8‐Mediated Nucleation Drives Stress Granule Assembly

Stress granules (SGs) are highly dynamic and reversible cytoplasmic biomolecular condensates formed via liquid-liquid phase separation (LLPS) under various stresses. As inherently heterogeneous assemblies, SGs possess distinct stable cores (initial nucleation seeds), substructures, or microphases. However, the mechanisms governing the formation and heterogeneity of SG nucleation seeds, and their dynamic integration, remain largely unclear. Here, we demonstrate that LENG8 is recruited to SGs under multiple stress conditions and is indispensable for SG assembly. Upon stress exposure, nuclear LENG8 granules disassemble, enabling LENG8 to translocate into the cytoplasm and undergo LLPS to form independent initial nucleation foci distinct from canonical G3BP1/TIA1-dependent seeds. Subsequently, these LENG8-initiated foci merge into growing SGs through a direct interaction between the prion-like domain of LENG8 and TIA1, facilitating SG expansion and maturation. Depletion of LENG8 or disruption of the LENG8-TIA1 interaction markedly impairs SG formation. Using conditional Leng8 knockout mice, we further establish that LENG8 deficiency attenuates stress-induced SG assembly and increases cellular apoptosis in germ cells. Collectively, our study identifies LENG8 as a previously unrecognized SG nucleator, revealing the hierarchical assembly and integration mechanism of distinct nucleation modules during early SG biogenesis.