Identification of moonlighting, extranuclear and syndapin I-related functions of EPOP in mature neurons

Revealing functions of protein components distinct from initially described context significantly advances scientific knowledge. Here, we describe functions of EPOP (Elongin BC and Polycomb repressive complex 2-associated protein) distinct from EPOP’s established involvement in epigenetic regulation of gene expression in stem cells. These moonlighting functions that take place in a different cellular compartment, with a different binding partner and in mature, postmitotic cells. In neurons, we identified an EPOP subpool that was not nuclear but cytoplasmic and interacted with the membrane-shaping protein syndapin I. EPOP hereby showed a preference for the somatodendritic compartment and was also present in dendritic spines. Syndapin I KO neurons revealed that EPOP’s extranuclear presence depended on its direct binding partner syndapin I. EPOP loss-of-function negatively impacted the density, morphology and postsynaptic-density composition of mushroom-type dendritic spines in mature hippocampal neurons and by closely phenocopying syndapin I loss-of-function phenotypes highlighted an intimate functional relationship of both components in postsynapses.