TMX4-driven LINC complex disassembly and asymmetric autophagy of the nuclear envelope upon acute ER stress
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...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-06-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-39172-3 |
| _version_ | 1797801377672462336 |
|---|---|
| author | Marika K. Kucińska Juliette Fedry Carmela Galli Diego Morone Andrea Raimondi Tatiana Soldà Friedrich Förster Maurizio Molinari |
| author_facet | Marika K. Kucińska Juliette Fedry Carmela Galli Diego Morone Andrea Raimondi Tatiana Soldà Friedrich Förster Maurizio Molinari |
| author_sort | Marika K. Kucińska |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-13T04:49:33Z |
| format | Article |
| id | doaj.art-776f9f177eb6455eaad59ec9b6588efd |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-13T04:49:33Z |
| publishDate | 2023-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-776f9f177eb6455eaad59ec9b6588efd2023-06-18T11:18:01ZengNature PortfolioNature Communications2041-17232023-06-0114112010.1038/s41467-023-39172-3TMX4-driven LINC complex disassembly and asymmetric autophagy of the nuclear envelope upon acute ER stressMarika K. Kucińska0Juliette Fedry1Carmela Galli2Diego Morone3Andrea Raimondi4Tatiana Soldà5Friedrich Förster6Maurizio Molinari7Università della Svizzera italiana (USI), Faculty of Biomedical Sciences, Institute for Research in BiomedicineStructural Biochemistry, Bijvoet Center for Biomolecular Research, Utrecht UniversityUniversità della Svizzera italiana (USI), Faculty of Biomedical Sciences, Institute for Research in BiomedicineUniversità della Svizzera italiana (USI), Faculty of Biomedical Sciences, Institute for Research in BiomedicineUniversità della Svizzera italiana (USI), Faculty of Biomedical Sciences, Institute for Research in BiomedicineUniversità della Svizzera italiana (USI), Faculty of Biomedical Sciences, Institute for Research in BiomedicineStructural Biochemistry, Bijvoet Center for Biomolecular Research, Utrecht UniversityUniversità della Svizzera italiana (USI), Faculty of Biomedical Sciences, Institute for Research in BiomedicineAbstract 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.https://doi.org/10.1038/s41467-023-39172-3 |
| spellingShingle | Marika K. Kucińska Juliette Fedry Carmela Galli Diego Morone Andrea Raimondi Tatiana Soldà Friedrich Förster Maurizio Molinari TMX4-driven LINC complex disassembly and asymmetric autophagy of the nuclear envelope upon acute ER stress Nature Communications |
| title | TMX4-driven LINC complex disassembly and asymmetric autophagy of the nuclear envelope upon acute ER stress |
| title_full | TMX4-driven LINC complex disassembly and asymmetric autophagy of the nuclear envelope upon acute ER stress |
| title_fullStr | TMX4-driven LINC complex disassembly and asymmetric autophagy of the nuclear envelope upon acute ER stress |
| title_full_unstemmed | TMX4-driven LINC complex disassembly and asymmetric autophagy of the nuclear envelope upon acute ER stress |
| title_short | TMX4-driven LINC complex disassembly and asymmetric autophagy of the nuclear envelope upon acute ER stress |
| title_sort | tmx4 driven linc complex disassembly and asymmetric autophagy of the nuclear envelope upon acute er stress |
| url | https://doi.org/10.1038/s41467-023-39172-3 |
| work_keys_str_mv | AT marikakkucinska tmx4drivenlinccomplexdisassemblyandasymmetricautophagyofthenuclearenvelopeuponacuteerstress AT juliettefedry tmx4drivenlinccomplexdisassemblyandasymmetricautophagyofthenuclearenvelopeuponacuteerstress AT carmelagalli tmx4drivenlinccomplexdisassemblyandasymmetricautophagyofthenuclearenvelopeuponacuteerstress AT diegomorone tmx4drivenlinccomplexdisassemblyandasymmetricautophagyofthenuclearenvelopeuponacuteerstress AT andrearaimondi tmx4drivenlinccomplexdisassemblyandasymmetricautophagyofthenuclearenvelopeuponacuteerstress AT tatianasolda tmx4drivenlinccomplexdisassemblyandasymmetricautophagyofthenuclearenvelopeuponacuteerstress AT friedrichforster tmx4drivenlinccomplexdisassemblyandasymmetricautophagyofthenuclearenvelopeuponacuteerstress AT mauriziomolinari tmx4drivenlinccomplexdisassemblyandasymmetricautophagyofthenuclearenvelopeuponacuteerstress |