biostudies-literatureSontag EMU.S. Department of Health & Human Services | NIH | National Institute of General Medical SciencesNIA NIH HHSU.S. Department of Health & Human Services | NIH | National Institute on AgingNINDS NIH HHSNIGMS NIH HHS699-713https://www.ebi.ac.uk/biostudies/studies/S-EPMC12349969biostudies-literatureUnknown25(5)Effective protein quality control (PQC), essential for cellular health, relies on spatial sequestration of misfolded proteins into defined inclusions. Here we reveal the coordination of nuclear and cytoplasmic spatial PQC. Cytoplasmic misfolded proteins concentrate in a cytoplasmic juxtanuclear quality control compartment, while nuclear misfolded proteins sequester into an intranuclear quality control compartment (INQ). Particle tracking reveals that INQ and the juxtanuclear quality control compartment converge to face each other across the nuclear envelope at a site proximal to the nuclear-vacuolar junction marked by perinuclear ESCRT-II/III protein Chm7. Strikingly, convergence at nuclear-vacuolar junction contacts facilitates VPS4-dependent vacuolar clearance of misfolded cytoplasmic anNature cell biologyNuclear and cytoplasmic spatial protein quality control is coordinated by nuclear-vacuolar junctions and perinuclear ESCRT.PMC12349969F32 NS086253R01 GM056433P01 AG054407P41 GM103445Larabell CSontag EMMorales-Polanco FLe Gros MAMcDermott GChen JHGestaut DFrydman JDolan PTfalseNuclear and cytoplasmic spatial protein quality control is coordinated by nuclear-vacuolar junctions and perinuclear ESCRT.Effective protein quality control (PQC), essential for cellular health, relies on spatial sequestration of misfolded proteins into defined inclusions. Here we reveal the coordination of nuclear and cytoplasmic spatial PQC. Cytoplasmic misfolded proteins concentrate in a cytoplasmic juxtanuclear quality control compartment, while nuclear misfolded proteins sequester into an intranuclear quality control compartment (INQ). Particle tracking reveals that INQ and the juxtanuclear quality control compartment converge to face each other across the nuclear envelope at a site proximal to the nuclear-vacuolar junction marked by perinuclear ESCRT-II/III protein Chm7. Strikingly, convergence at nuclear-vacuolar junction contacts facilitates VPS4-dependent vacuolar clearance of misfolded cytoplasmic an2023-01-01T00:00:00Z2023 May2026-04-30T19:35:50.375Z2026-04-15T03:09:44.253ZS-EPMC123499693708116410.1038/s41556-023-01128-6