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

Marika K Kucińska, Juliette Fedry, Carmela Galli, Diego Morone, Andrea Raimondi, Tatiana Soldà, Friedrich Förster, Maurizio Molinari*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.

Original languageEnglish
Article number3497
Number of pages20
JournalNature Communications
Volume14
Issue number1
DOIs
Publication statusPublished - 13 Jun 2023

Bibliographical note

Publisher Copyright:
© 2023, The Author(s).

Funding

We thank the members of Molinari’s laboratory for the discussions and critical reading of the manuscript. We also thank Euro-BioImaging ( www.eurobioimaging.eu ) for providing access to imaging technologies and services via the Italian Node (ALEMBIC, Milan-Italy), Mihajlo Vanevic, Benjamin A. Barad, Miguel R. Leung and Gonzalo Obal for help with data processing and Andreas F. Sonnen for initial help with FIB milling. We are grateful to Stuart C. Howes and Menno Bergmeijer for cryo-EM support as well as to Mariska Gröllers-Mulderij for cell culture support. M.M. is supported by the ALPHA-1 Foundation Research Grant (ID: 681136), the Foundation for Research on Neurodegenerative Diseases, the Swiss National Science Foundation (SNF, 310030_184827/2), the Eurostar (E! 113321–CHAPERONE), Innosuisse (35449.1 IP-LS), and the Comel and Gelu Foundations. The work was also supported by the European Research Council under the European Union’s Horizon 2020 Program (ERC Consolidator Grant Agreement 724425-BENDER) and the Nederlandse Organisatie voor Wetenschappelijke Onderzoek (Vici 724.016.001 to F.F. and Veni 212.152 to J.F.).

FundersFunder number
Comel and Gelu Foundations
Foundation for Research on Neurodegenerative Diseases
Alpha-1 Foundation681136
EurostarsE! 113321, 35449.1 IP-LS
European Research Council724425-BENDER
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung310030_184827/2
Nederlandse Organisatie voor Wetenschappelijk Onderzoek212.152, 724.016.001
Horizon 2020

    Keywords

    • Animals
    • Nuclear Envelope
    • Endoplasmic Reticulum Stress/genetics
    • Autophagy
    • Unfolded Protein Response
    • Endoplasmic Reticulum
    • Mammals

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