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 and nuclear proteins, the latter entailing extrusion of nuclear INQ into the vacuole. Finding that nuclear–vacuolar contact sites are cellular hubs of spatial PQC to facilitate vacuolar clearance of nuclear and cytoplasmic inclusions highlights the role of cellular architecture in proteostasis maintenance.

有效的蛋白质质量控​​制 (PQC) 对细胞健康至关重要，它依赖于错误折叠蛋白质在特定内含物中的空间隔离。在这里，我们揭示了核和细胞质空间 PQC 的协调。细胞质错误折叠蛋白集中在细胞质核旁质量控制区室中，而核错误折叠蛋白则隔离在核内质量控制区室 (INQ) 中。粒子追踪显示，INQ 和核旁质量控制区室在靠近核周 ESCRT-II/III 蛋白 Chm7 标记的核-液泡连接处的位置处会聚，穿过核膜彼此相对。引人注目的是，核-液泡连接处接触处的会聚促进了 VPS4 依赖性液泡清除错误折叠的细胞质和核蛋白，后者需要将核 INQ 挤出到液泡中。发现核-液泡接触位点是空间 PQC 的细胞中心，可促进核和细胞质内含物的液泡清除，这凸显了细胞结构在蛋白质稳态维持中的作用。