An ER-associated structure sequesters misassembled FG-rich nucleoporins to help maintain nuclear pore complex function

ABSTRACT Misassembly of nucleoporins (Nups), central components of the nuclear pore complex (NPC), leads to Nup mislocalization outside of the nuclear envelope. Here we elucidate the fate of mislocalized Nups. To impair Nup assembly, we depleted the structural component Nup98 and found that nucleo-cytoplasmic transport by NPCs remains largely intact. Under this condition, several phenylalanine-glycine-rich Nups (FG-Nups) no longer assemble at the nuclear envelope but instead accumulate at discrete puncta in the endoplasmic reticulum (ER), which we term ER foci. Formation of the foci harboring the misassembled FG-Nups requires the ER morphogenic proteins RTN3, ATL3, and LNP (also known as LNPK). Preventing accumulation of misassembled FG-Nups at the ER foci impairs NPC nucleo-cytoplasmic transport, likely by allowing the misassembled FG-Nups to reach the nuclear envelope, where they disrupt NPC function. Formation of the ER foci is dependent on the kinesin-1 motor. Our results suggest that the ER can sequester misassembled Nups to help maintain NPC function. Because Nup mislocalization is found in many age-related neurodegenerative diseases, our data should illuminate the molecular basis of these pathologic conditions.