LOTUS-domain proteins activate Vasa to drive germ granule assembly

Abstract Germline development relies on perinuclear membraneless germ granules, yet the mechanisms underlying their assembly remain incompletely understood. Here we uncover a conserved and central role for LOTUS-domain proteins in driving germ granule assembly. In C. elegans , the LOTUS-domain protein EGGD-1/MIP-1 at sub-stoichiometric levels recruits Vasa protein GLH-1 to the nuclear periphery. Acting as a catalyst, EGGD-1 impacts the ATPase cycles of GLH-1 by preferentially binding to its open conformation, enhancing its RNA binding activities, and facilitating its transition to the closed conformation. GLH-1 in the closed state enriches mRNAs at the nuclear periphery, which enables the accumulation of RNA-binding proteins including PGL-1 and PGL-3. Using human cells, we demonstrate the LOTUS-domain protein TDRD5 similarly recruits DDX4, the human Vasa homolog, and stimulates the formation of intermitochondrial cement. Collectively, these findings reveal evolutionarily conserved stimulatory effect of LOTUS-domain protein in Vasa activity and provide a unified model for germ granule assembly across species.