POSH undergoes phase separation and co-condensation with SHANK2/3 to regulate spine development

The autism-associated proteins POSH and SHANK2/3 interact at the postsynaptic density, and POSH deficiency leads to a significant reduction in SHANK2/3 abundance at the PSD and abnormal synapse development. However, the mechanisms underlying the organization and stabilization of the POSH/SHANK2/3 complex at the PSD remain elusive. Here, we show that POSH has the ability to undergo liquid-liquid phase separation, which requires its intrinsic disordered region and SH3 domains. By interacting with POSH, SHANK2/3 can be enriched in POSH condensates and significantly enhance POSH phase separation. We show that the interaction between SHANK2/3 and POSH, and the oligomerization of SHANKs both contribute to their co-condensation, as well as to the synaptic targeting of SHANK2/3 and spine development. Therefore, this study not only demonstrates that phase separation may be a mechanism by which POSH condensates with SHANK2/3 to regulate spine development, but also provides new insights into the pathogenesis of autism.