TMX4-driven LINC complex disassembly and asymmetric autophagy of the nuclear envelope upon acute ER stress

The endoplasmic reticulum (ER) is an organelle of nucleated cells that produces proteins, lipids and oligosaccharides. ER volume and activity are increased upon induction of unfolded protein responses (UPR) and are reduced upon activation of ER-phagy programs. A specialized domain of the ER, the nuc...

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Bibliographic Details
Published in:Nature communications 2023-06, Vol.14 (1), p.3497-20, Article 3497
Main Authors: Kucińska, Marika K., Fedry, Juliette, Galli, Carmela, Morone, Diego, Raimondi, Andrea, Soldà, Tatiana, Förster, Friedrich, Molinari, Maurizio
Format: Article
Language:English
Subjects:
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Animals
Asymmetry
Autophagy
Dismantling
Endoplasmic Reticulum
Endoplasmic Reticulum Stress - genetics
Genomes
Humanities and Social Sciences
Lipid bilayers
Lipids
Mammals
multidisciplinary
Nuclear Envelope
Nuclear membranes
Oligosaccharides
Perturbation
Protein folding
Proteins
Reductases
Science
Science (multidisciplinary)
Unfolded Protein Response
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Summary:The endoplasmic reticulum (ER) is an organelle of nucleated cells that produces proteins, lipids and oligosaccharides. ER volume and activity are increased upon induction of unfolded protein responses (UPR) and are reduced upon activation of ER-phagy programs. A specialized domain of the ER, the nuclear envelope (NE), protects the cell genome with two juxtaposed lipid bilayers, the inner and outer nuclear membranes (INM and ONM) separated by the perinuclear space (PNS). Here we report that expansion of the mammalian ER upon homeostatic perturbations results in TMX4 reductase-driven disassembly of the LINC complexes connecting INM and ONM and in ONM swelling. The physiologic distance between ONM and INM is restored, upon resolution of the ER stress, by asymmetric autophagy of the NE, which involves the LC3 lipidation machinery, the autophagy receptor SEC62 and the direct capture of ONM-derived vesicles by degradative LAMP1/RAB7-positive endolysosomes in a catabolic pathway mechanistically defined as micro- ONM-phagy. Researchers reveal how the stress of the endoplasmic reticulum is transmitted to the nuclear envelope, which swells, and is brought back to physiologic shape by autophagic pathways.
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-023-39172-3