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.
Footnotes
Author contributions
Conceptualization: M.P., E.W., L.G., B.T.; Data curation: M.P., E.W., L.G.; Formal analysis: M.P., E.W., L.G., B.T.; Funding acquisition: M.P., E.W., B.T.; Investigation: M.P., E.W., L.G., B.T.; Methodology: M.P., E.W., L.G., B.T.; Project administration: B.T.; Supervision: B.T.; Writing – original draft: M.P., E.W., B.T.; Writing – review & editing: M.P., E.W., L.G., B.T.
Funding
This work was funded by grants from the National Institutes of Health (NIH) to M.P. (F31 NS124088) and start-up funds from University of Michigan to B.T. E.W. was supported by the National Science Foundation Graduate Research Fellowship (DGE-2241144), and L.G. was supported by NIH T32 GM145470. Deposited in PMC for release after 12 months.
Data availability
All relevant data can be found within the article and its supplementary information.
