IRSp53 promotes postsynaptic density formation and actin filament bundling

Abstract

IRSp53 is abundantly expressed at the postsynaptic densities of neuronal synapses, but its action mechanism has been poorly understood. Feng et al. demonstrate that IRSp53 is a key scaffold linker for the PSD core and pallium via promoting phase separation of the PSD assembly, and they also uncover a direct role of IRSp53 in actin modulation essential for dendritic spine development.

Abstract

IRSp53 (aka BAIAP2) is a scaffold protein that couples membranes with the cytoskeleton in actin-filled protrusions such as filopodia and lamellipodia. The protein is abundantly expressed in excitatory synapses and is essential for synapse development and synaptic plasticity, although with poorly understood mechanisms. Here we show that specific multivalent interactions between IRSp53 and its binding partners PSD-95 or Shank3 drive phase separation of the complexes in solution. IRSp53 can be enriched to the reconstituted excitatory PSD (ePSD) condensates via bridging to the core and deeper layers of ePSD. Overexpression of a mutant defective in the IRSp53/PSD-95 interaction perturbs synaptic enrichment of IRSp53 in mouse cortical neurons. The reconstituted PSD condensates promote bundled actin filament formation both in solution and on membranes, via IRSp53-mediated actin binding and bundling. Overexpression of mutants that perturb IRSp53–actin interaction leads to defects in synaptic maturation of cortical neurons. Together, our studies provide potential mechanistic insights into the physiological roles of IRSp53 in synapse formation and function.