Spatial sequestration of misfolded proteins into membrane-less inclusions is a fundamental protein quality control (PQC) strategy. We combined super-resolution microscopy and soft-X-ray tomography to examine the relationship between nuclear and cytoplasmic spatial PQC. We find cytoplasmic misfolded proteins concentrate into a strictly cytoplasmic JUNQ compartment, while nuclear misfolded proteins sequester into a nuclear INQ compartment. JUNQ and INQ localize across each other on opposing sides of the nuclear envelope. Time resolved particle tracking reveals that JUNQ and INQ form independently, but converge to a site proximal to Nuclear-Vacuolar Junctions (NVJ) via a signal transmitted through nuclear pores. The convergence of JUNQ and INQ inclusions at nuclear-vacuolar contacts sites to enable their clearance reveals an unexpected degree of coordination between nuclear and cytoplasmic spatial PQC mediated by perinuclear ESCRT and the nuclear envelope. Using a combination of biochemical and microscopic techniques, my lab aims to dissect the role of these membrane-less PQC compartments in neurodegenerative diseases.

Talk by:
Emily Sontag
Marquette University

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