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dc.contributor.author | Orsi, Andrea | |
dc.contributor.author | van Anken, Eelco | |
dc.contributor.author | Vitale, Milena | |
dc.contributor.author | Zamai, Moreno | |
dc.contributor.author | Caiolfa, Valeria R | |
dc.contributor.author | Sitia, Roberto | |
dc.contributor.author | Bakunts, Anush | |
dc.date.accessioned | 2024-07-08T14:20:23Z | |
dc.date.available | 2024-07-08T14:20:23Z | |
dc.date.issued | 2024-09 | |
dc.identifier.citation | Life Sci Alliance. 2024 Jun 17;7(9):e202302562. | es_ES |
dc.identifier.uri | http://hdl.handle.net/20.500.12105/20212 | |
dc.description.abstract | The unfolded protein response can switch from a pro-survival to a maladaptive, pro-apoptotic mode. During ER stress, IRE1α sensors dimerize, become phosphorylated, and activate XBP1 splicing, increasing folding capacity in the ER protein factory. The steps that turn on the IRE1α endonuclease activity against endogenous mRNAs during maladaptive ER stress are still unknown. Here, we show that although necessary, IRE1α dimerization is not sufficient to trigger phosphorylation. Random and/or guided collisions among IRE1α dimers are needed to elicit cross-phosphorylation and endonuclease activities. Thus, reaching a critical concentration of IRE1α dimers in the ER membrane is a key event. Formation of stable IRE1α clusters is not necessary for RNase activity. However, clustering could modulate the potency of the response, promoting interactions between dimers and decreasing the accessibility of phosphorylated IRE1α to phosphatases. The stepwise activation of IRE1α molecules and their low concentration at the steady state prevent excessive responses, unleashing full-blown IRE1 activity only upon intense stress conditions. | es_ES |
dc.description.sponsorship | We thank David Ron for help with reagents, Tiziana Anelli for suggestions, and Giuliano Martino, Laura Tadè, Silvia Russo Krauss, Giuliano Martino, and Marco dalla Torre for help with experiments. We thank the ALEMBIC microscopy facility of San Raffaele Scientific Institute for technical support. This work was supported in part via grants from AIRC (IG 2019—ID. 23285) and MUR (PRIN 2017XA5J5N). TIRF-N&B microscopy was conducted at the Unit of Microscopy and Dynamic Imaging (CNIC). The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the MCIN, and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (grant CEX2020-001041-S funded by MICIN/AEI/10.13039/501100011033). | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | eLife Sciences Publications | es_ES |
dc.type.hasVersion | VoR | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | * |
dc.subject.mesh | Endoribonucleases | es_ES |
dc.subject.mesh | Protein Serine-Threonine Kinases | es_ES |
dc.subject.mesh | Endoplasmic Reticulum Stress | es_ES |
dc.subject.mesh | Phosphorylation | es_ES |
dc.subject.mesh | Humans | es_ES |
dc.subject.mesh | Protein Multimerization | es_ES |
dc.subject.mesh | Unfolded Protein Response | es_ES |
dc.subject.mesh | Endoplasmic Reticulum | es_ES |
dc.subject.mesh | Ribonucleases | es_ES |
dc.title | Congress of multiple dimers is needed for cross-phosphorylation of IRE1α and its RNase activity. | es_ES |
dc.type | journal article | es_ES |
dc.rights.license | Atribución 4.0 Internacional | * |
dc.identifier.pubmedID | 38886017 | es_ES |
dc.format.volume | 7 | es_ES |
dc.format.number | 9 | es_ES |
dc.identifier.doi | 10.26508/lsa.202302562 | es_ES |
dc.contributor.funder | Instituto de Salud Carlos III | es_ES |
dc.contributor.funder | Ministerio de Ciencia e Innovación (España) | es_ES |
dc.contributor.funder | Fundación ProCNIC | es_ES |
dc.contributor.funder | Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España) | es_ES |
dc.description.peerreviewed | Sí | es_ES |
dc.identifier.e-issn | 2575-1077 | es_ES |
dc.relation.publisherversion | 10.26508/lsa.202302562 | es_ES |
dc.identifier.journal | Life science alliance | es_ES |
dc.repisalud.orgCNIC | CNIC::Unidades técnicas::Microscopía | es_ES |
dc.repisalud.institucion | CNIC | es_ES |
dc.rights.accessRights | open access | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/MICIN/AEI/10.13039/501100011033/CEX2020-001041-S | es_ES |