Unstructured regions in IRE1α specify BiP-mediated destabilisation of the luminal domain dimer and repression of the UPR
Coupling of endoplasmic reticulum (ER) stress to dimerisation-dependent activation of the UPR transducer IRE1 is incompletely understood. Whilst the luminal co-chaperone ERdj4 promotes a complex between the Hsp70 BiP and IRE1’s stress-sensing luminal domain (IRE1LD) that favours the latter’s monomer...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2019-12-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/50793 |
| _version_ | 1811202772416069632 |
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| author | Niko Amin-Wetzel Lisa Neidhardt Yahui Yan Matthias P Mayer David Ron |
| author_facet | Niko Amin-Wetzel Lisa Neidhardt Yahui Yan Matthias P Mayer David Ron |
| author_sort | Niko Amin-Wetzel |
| collection | DOAJ |
| description | Coupling of endoplasmic reticulum (ER) stress to dimerisation-dependent activation of the UPR transducer IRE1 is incompletely understood. Whilst the luminal co-chaperone ERdj4 promotes a complex between the Hsp70 BiP and IRE1’s stress-sensing luminal domain (IRE1LD) that favours the latter’s monomeric inactive state and loss of ERdj4 de-represses IRE1, evidence linking these cellular and in vitro observations is presently lacking. We report that enforced loading of endogenous BiP onto endogenous IRE1α repressed UPR signalling in CHO cells and deletions in the IRE1α locus that de-repressed the UPR in cells, encode flexible regions of IRE1LD that mediated BiP-induced monomerisation in vitro. Changes in the hydrogen exchange mass spectrometry profile of IRE1LD induced by ERdj4 and BiP confirmed monomerisation and were consistent with active destabilisation of the IRE1LD dimer. Together, these observations support a competition model whereby waning ER stress passively partitions ERdj4 and BiP to IRE1LD to initiate active repression of UPR signalling. |
| first_indexed | 2024-04-12T02:44:18Z |
| format | Article |
| id | doaj.art-6243d75368fa4ac6bb92dcb63e2aed61 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T02:44:18Z |
| publishDate | 2019-12-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-6243d75368fa4ac6bb92dcb63e2aed612022-12-22T03:51:14ZengeLife Sciences Publications LtdeLife2050-084X2019-12-01810.7554/eLife.50793Unstructured regions in IRE1α specify BiP-mediated destabilisation of the luminal domain dimer and repression of the UPRNiko Amin-Wetzel0https://orcid.org/0000-0002-4640-3724Lisa Neidhardt1https://orcid.org/0000-0003-0256-5040Yahui Yan2https://orcid.org/0000-0001-6934-9874Matthias P Mayer3https://orcid.org/0000-0002-7859-3112David Ron4https://orcid.org/0000-0002-3014-5636Cambridge Institute for Medical Research (CIMR), University of Cambridge, Cambridge, United KingdomCambridge Institute for Medical Research (CIMR), University of Cambridge, Cambridge, United KingdomCambridge Institute for Medical Research (CIMR), University of Cambridge, Cambridge, United KingdomCenter for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance, Heidelberg, GermanyCambridge Institute for Medical Research (CIMR), University of Cambridge, Cambridge, United KingdomCoupling of endoplasmic reticulum (ER) stress to dimerisation-dependent activation of the UPR transducer IRE1 is incompletely understood. Whilst the luminal co-chaperone ERdj4 promotes a complex between the Hsp70 BiP and IRE1’s stress-sensing luminal domain (IRE1LD) that favours the latter’s monomeric inactive state and loss of ERdj4 de-represses IRE1, evidence linking these cellular and in vitro observations is presently lacking. We report that enforced loading of endogenous BiP onto endogenous IRE1α repressed UPR signalling in CHO cells and deletions in the IRE1α locus that de-repressed the UPR in cells, encode flexible regions of IRE1LD that mediated BiP-induced monomerisation in vitro. Changes in the hydrogen exchange mass spectrometry profile of IRE1LD induced by ERdj4 and BiP confirmed monomerisation and were consistent with active destabilisation of the IRE1LD dimer. Together, these observations support a competition model whereby waning ER stress passively partitions ERdj4 and BiP to IRE1LD to initiate active repression of UPR signalling.https://elifesciences.org/articles/50793IRE1BiP/Grp78endoplasmic reticulum (ER)unfolded protein response (UPR)ERdj4/DNAJB9Chinese Hamster Ovary (CHO) cells |
| spellingShingle | Niko Amin-Wetzel Lisa Neidhardt Yahui Yan Matthias P Mayer David Ron Unstructured regions in IRE1α specify BiP-mediated destabilisation of the luminal domain dimer and repression of the UPR eLife IRE1 BiP/Grp78 endoplasmic reticulum (ER) unfolded protein response (UPR) ERdj4/DNAJB9 Chinese Hamster Ovary (CHO) cells |
| title | Unstructured regions in IRE1α specify BiP-mediated destabilisation of the luminal domain dimer and repression of the UPR |
| title_full | Unstructured regions in IRE1α specify BiP-mediated destabilisation of the luminal domain dimer and repression of the UPR |
| title_fullStr | Unstructured regions in IRE1α specify BiP-mediated destabilisation of the luminal domain dimer and repression of the UPR |
| title_full_unstemmed | Unstructured regions in IRE1α specify BiP-mediated destabilisation of the luminal domain dimer and repression of the UPR |
| title_short | Unstructured regions in IRE1α specify BiP-mediated destabilisation of the luminal domain dimer and repression of the UPR |
| title_sort | unstructured regions in ire1α specify bip mediated destabilisation of the luminal domain dimer and repression of the upr |
| topic | IRE1 BiP/Grp78 endoplasmic reticulum (ER) unfolded protein response (UPR) ERdj4/DNAJB9 Chinese Hamster Ovary (CHO) cells |
| url | https://elifesciences.org/articles/50793 |
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