[{"day":"21","doi":"10.1371/journal.pbio.3001684","abstract":[{"text":"The ability to detect and respond to acute oxygen (O2) shortages is indispensable to aerobic life. The molecular mechanisms and circuits underlying this capacity are poorly understood. Here, we characterize the behavioral responses of feeding Caenorhabditis elegans to approximately 1% O2. Acute hypoxia triggers a bout of turning maneuvers followed by a persistent switch to rapid forward movement as animals seek to avoid and escape hypoxia. While the behavioral responses to 1% O2 closely resemble those evoked by 21% O2, they have distinct molecular and circuit underpinnings. Disrupting phosphodiesterases (PDEs), specific G proteins, or BBSome function inhibits escape from 1% O2 due to increased cGMP signaling. A primary source of cGMP is GCY-28, the ortholog of the atrial natriuretic peptide (ANP) receptor. cGMP activates the protein kinase G EGL-4 and enhances neuroendocrine secretion to inhibit acute responses to 1% O2. Triggering a rise in cGMP optogenetically in multiple neurons, including AIA interneurons, rapidly and reversibly inhibits escape from 1% O2. Ca2+ imaging reveals that a 7% to 1% O2 stimulus evokes a Ca2+ decrease in several neurons. Defects in mitochondrial complex I (MCI) and mitochondrial complex I (MCIII), which lead to persistently high reactive oxygen species (ROS), abrogate acute hypoxia responses. In particular, repressing the expression of isp-1, which encodes the iron sulfur protein of MCIII, inhibits escape from 1% O2 without affecting responses to 21% O2. Both genetic and pharmacological up-regulation of mitochondrial ROS increase cGMP levels, which contribute to the reduced hypoxia responses. Our results implicate ROS and precise regulation of intracellular cGMP in the modulation of acute responses to hypoxia by C. elegans.","lang":"eng"}],"citation":{"apa":"Zhao, L., Fenk, L. A., Nilsson, L., Amin-Wetzel, N. P., Ramirez, N., de Bono, M., &#38; Chen, C. (2022). ROS and cGMP signaling modulate persistent escape from hypoxia in Caenorhabditis elegans. <i>PLoS Biology</i>. Public Library of Science. <a href=\"https://doi.org/10.1371/journal.pbio.3001684\">https://doi.org/10.1371/journal.pbio.3001684</a>","ama":"Zhao L, Fenk LA, Nilsson L, et al. ROS and cGMP signaling modulate persistent escape from hypoxia in Caenorhabditis elegans. <i>PLoS Biology</i>. 2022;20(6). doi:<a href=\"https://doi.org/10.1371/journal.pbio.3001684\">10.1371/journal.pbio.3001684</a>","chicago":"Zhao, Lina, Lorenz A. Fenk, Lars Nilsson, Niko Paresh Amin-Wetzel, Nelson Ramirez, Mario de Bono, and Changchun Chen. “ROS and CGMP Signaling Modulate Persistent Escape from Hypoxia in Caenorhabditis Elegans.” <i>PLoS Biology</i>. Public Library of Science, 2022. <a href=\"https://doi.org/10.1371/journal.pbio.3001684\">https://doi.org/10.1371/journal.pbio.3001684</a>.","ieee":"L. Zhao <i>et al.</i>, “ROS and cGMP signaling modulate persistent escape from hypoxia in Caenorhabditis elegans,” <i>PLoS Biology</i>, vol. 20, no. 6. Public Library of Science, 2022.","short":"L. Zhao, L.A. Fenk, L. Nilsson, N.P. Amin-Wetzel, N. Ramirez, M. de Bono, C. Chen, PLoS Biology 20 (2022).","mla":"Zhao, Lina, et al. “ROS and CGMP Signaling Modulate Persistent Escape from Hypoxia in Caenorhabditis Elegans.” <i>PLoS Biology</i>, vol. 20, no. 6, e3001684, Public Library of Science, 2022, doi:<a href=\"https://doi.org/10.1371/journal.pbio.3001684\">10.1371/journal.pbio.3001684</a>.","ista":"Zhao L, Fenk LA, Nilsson L, Amin-Wetzel NP, Ramirez N, de Bono M, Chen C. 2022. ROS and cGMP signaling modulate persistent escape from hypoxia in Caenorhabditis elegans. PLoS Biology. 20(6), e3001684."},"year":"2022","date_updated":"2023-08-03T12:11:44Z","external_id":{"pmid":["35727855"],"isi":["000828679600001"]},"isi":1,"acknowledgement":" This work was funded by H2020 European Research Council (ERC Advanced grant, 269058 ACMO, https://erc.europa.eu/funding/advanced-grants) and Wellcome Trust UK (Wellcome Investigator Award, 209504/Z/17/Z, https://wellcome.org/grant-funding/people-and-projects/grants-awarded/molecular-mechanisms-neural-circuit-function-0) to M.d.B, and by H2020 European Research Council (ERC starting grant, 802653 OXYGEN SENSING, https://erc.europa.eu/funding/starting-grants) and Vetenskapsrådet (VR starting grant, 2018-02216, https://www.vr.se/english.html) to C.C. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","volume":20,"ddc":["570"],"department":[{"_id":"MaDe"}],"article_processing_charge":"No","date_created":"2022-07-24T22:01:42Z","publication_status":"published","intvolume":"        20","title":"ROS and cGMP signaling modulate persistent escape from hypoxia in Caenorhabditis elegans","scopus_import":"1","pmid":1,"_id":"11637","issue":"6","author":[{"full_name":"Zhao, Lina","last_name":"Zhao","first_name":"Lina"},{"last_name":"Fenk","first_name":"Lorenz A.","full_name":"Fenk, Lorenz A."},{"last_name":"Nilsson","first_name":"Lars","full_name":"Nilsson, Lars"},{"id":"E95D3014-9D8C-11E9-9C80-D2F8E5697425","last_name":"Amin-Wetzel","first_name":"Niko Paresh","full_name":"Amin-Wetzel, Niko Paresh"},{"id":"39831956-E4FE-11E9-85DE-0DC7E5697425","first_name":"Nelson","last_name":"Ramirez","full_name":"Ramirez, Nelson"},{"id":"4E3FF80E-F248-11E8-B48F-1D18A9856A87","full_name":"De Bono, Mario","orcid":"0000-0001-8347-0443","last_name":"De Bono","first_name":"Mario"},{"last_name":"Chen","first_name":"Changchun","full_name":"Chen, Changchun"}],"publisher":"Public Library of Science","article_type":"original","quality_controlled":"1","file_date_updated":"2022-07-25T07:38:49Z","publication_identifier":{"eissn":["1545-7885"]},"oa":1,"tmp":{"legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","short":"CC BY (4.0)","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)"},"type":"journal_article","date_published":"2022-06-21T00:00:00Z","file":[{"file_name":"2022_PLoSBiology_Zhao.pdf","content_type":"application/pdf","date_updated":"2022-07-25T07:38:49Z","checksum":"df4902f854ad76769d3203bfdc69f16c","file_size":3721585,"date_created":"2022-07-25T07:38:49Z","creator":"dernst","file_id":"11643","success":1,"relation":"main_file","access_level":"open_access"}],"user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","status":"public","project":[{"grant_number":"209504/A/17/Z","name":"Molecular mechanisms of neural circuit function","_id":"23870BE8-32DE-11EA-91FC-C7463DDC885E"}],"oa_version":"Published Version","article_number":"e3001684","month":"06","has_accepted_license":"1","publication":"PLoS Biology","language":[{"iso":"eng"}]},{"isi":1,"external_id":{"pmid":["31873072"],"isi":["000512303700001"]},"date_updated":"2023-09-06T14:58:02Z","year":"2019","citation":{"chicago":"Amin-Wetzel, Niko Paresh, Lisa Neidhardt, Yahui Yan, Matthias P. Mayer, and David Ron. “Unstructured Regions in IRE1α Specify BiP-Mediated Destabilisation of the Luminal Domain Dimer and Repression of the UPR.” <i>ELife</i>. eLife Sciences Publications, 2019. <a href=\"https://doi.org/10.7554/eLife.50793\">https://doi.org/10.7554/eLife.50793</a>.","ieee":"N. P. Amin-Wetzel, L. Neidhardt, Y. Yan, M. P. Mayer, and D. Ron, “Unstructured regions in IRE1α specify BiP-mediated destabilisation of the luminal domain dimer and repression of the UPR,” <i>eLife</i>, vol. 8. eLife Sciences Publications, 2019.","ama":"Amin-Wetzel NP, Neidhardt L, Yan Y, Mayer MP, Ron D. Unstructured regions in IRE1α specify BiP-mediated destabilisation of the luminal domain dimer and repression of the UPR. <i>eLife</i>. 2019;8. doi:<a href=\"https://doi.org/10.7554/eLife.50793\">10.7554/eLife.50793</a>","apa":"Amin-Wetzel, N. P., Neidhardt, L., Yan, Y., Mayer, M. P., &#38; Ron, D. (2019). Unstructured regions in IRE1α specify BiP-mediated destabilisation of the luminal domain dimer and repression of the UPR. <i>ELife</i>. eLife Sciences Publications. <a href=\"https://doi.org/10.7554/eLife.50793\">https://doi.org/10.7554/eLife.50793</a>","ista":"Amin-Wetzel NP, Neidhardt L, Yan Y, Mayer MP, Ron D. 2019. Unstructured regions in IRE1α specify BiP-mediated destabilisation of the luminal domain dimer and repression of the UPR. eLife. 8, e50793.","short":"N.P. Amin-Wetzel, L. Neidhardt, Y. Yan, M.P. Mayer, D. Ron, ELife 8 (2019).","mla":"Amin-Wetzel, Niko Paresh, et al. “Unstructured Regions in IRE1α Specify BiP-Mediated Destabilisation of the Luminal Domain Dimer and Repression of the UPR.” <i>ELife</i>, vol. 8, e50793, eLife Sciences Publications, 2019, doi:<a href=\"https://doi.org/10.7554/eLife.50793\">10.7554/eLife.50793</a>."},"abstract":[{"lang":"eng","text":"Coupling of endoplasmic reticulum 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."}],"doi":"10.7554/eLife.50793","day":"24","ddc":["570"],"acknowledgement":"We thank the CIMR flow cytometry core facility team (Reiner Schulte, Chiara Cossetti and Gabriela Grondys-Kotarba) for assistance with FACS, the Huntington lab for access to the Octet machine, Steffen Preissler for advice on data interpretation, Roman Kityk and Nicole Luebbehusen for help and advice with HX-MS experiments.","volume":8,"author":[{"id":"E95D3014-9D8C-11E9-9C80-D2F8E5697425","first_name":"Niko Paresh","last_name":"Amin-Wetzel","full_name":"Amin-Wetzel, Niko Paresh"},{"full_name":"Neidhardt, Lisa","last_name":"Neidhardt","first_name":"Lisa"},{"first_name":"Yahui","last_name":"Yan","full_name":"Yan, Yahui"},{"full_name":"Mayer, Matthias P.","last_name":"Mayer","first_name":"Matthias P."},{"full_name":"Ron, David","last_name":"Ron","first_name":"David"}],"_id":"7340","pmid":1,"scopus_import":"1","title":"Unstructured regions in IRE1α specify BiP-mediated destabilisation of the luminal domain dimer and repression of the UPR","intvolume":"         8","publication_status":"published","date_created":"2020-01-19T23:00:39Z","department":[{"_id":"MaDe"}],"article_processing_charge":"No","file_date_updated":"2020-11-19T11:37:41Z","quality_controlled":"1","article_type":"original","publisher":"eLife Sciences Publications","date_published":"2019-12-24T00:00:00Z","type":"journal_article","tmp":{"legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","short":"CC BY (4.0)","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)"},"oa":1,"publication_identifier":{"eissn":["2050084X"]},"user_id":"c635000d-4b10-11ee-a964-aac5a93f6ac1","status":"public","file":[{"relation":"main_file","success":1,"access_level":"open_access","creator":"dernst","file_id":"8777","file_size":4817384,"checksum":"29fcbcd8c1fc7f11a596ed7f14ea1c82","date_created":"2020-11-19T11:37:41Z","content_type":"application/pdf","file_name":"2019_eLife_AminWetzel.pdf","date_updated":"2020-11-19T11:37:41Z"}],"publication":"eLife","has_accepted_license":"1","month":"12","article_number":"e50793","oa_version":"Published Version","language":[{"iso":"eng"}]}]