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Clearance of Nuclear and Cytosolic Aggregates at Nuclear‐Vacuolar Junctions
Author(s) -
Sontag Emily,
Chen JianHua,
McDermott Gerry,
Dolan Patrick,
Gestaut Dan,
LeGros Mark,
Larabell Carolyn,
Frydman Judith
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.02381
Subject(s) - cytoplasm , escrt , inner membrane , microbiology and biotechnology , vacuole , cytosol , nuclear transport , nuclear pore , chemistry , nuclear localization sequence , compartment (ship) , biophysics , nuclear protein , cell nucleus , nuclear lamina , endosome , biology , biochemistry , intracellular , gene , enzyme , oceanography , geology , transcription factor , mitochondrion
Clearing misfolded proteins is essential for cellular health. Spatial sequestration of misfolded proteins into membrane‐less inclusions is a fundamental protein quality control (PQC) strategy. We here 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 nuclear envelope‐localized ESCRT‐II/‐III protein Chm7 is required for convergence of JUNQ and INQ at NVJs. Disrupting NVJs or deleting ATPase Vsp4, required for membrane invagination into the vacuole, impair clearance of both INQ and JUNQ. Surprisingly, these deletions lead to egress of nuclear INQ into the cytoplasm, indicating a pathway to remove misfolded protein aggregates from the nucleus. 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.