Spatial organization of ER-derived protein aggregates in the nucleus requires the Hsp70-family member BiP

Cells maintain proteostasis by sequestering misfolded proteins into deposition sites. Aggregation-prone endoplasmic reticulum (ER) proteins form membrane-bound nuclear compartments that are cleared during cell division, yet the mechanisms underlying their spatial organization remain unclear. Here, using transcriptomic and proteomic analyses, we identified the ER-localized Hsp70 chaperone BiP as a key player. Genetic depletion or chemical inhibition of BiP prevented nuclear aggregate formation, while manipulating BiP regulators perturbed the aggregate formation. BiP-driven aggregation precedes the inner nuclear membrane synthesis that encapsulated the aggregates. Under proteostatic stress, nuclear aggregates localized adjacent to ER-derived aggregates. Our findings demonstrate that BiP is essential for organizing ER-derived aggregates in the nucleus, which further regulate nuclear proteostasis through spatial interactions with nuclear aggregates.