---
_id: '11637'
abstract:
- lang: eng
  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.
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.'
article_number: e3001684
article_processing_charge: No
article_type: original
author:
- first_name: Lina
  full_name: Zhao, Lina
  last_name: Zhao
- first_name: Lorenz A.
  full_name: Fenk, Lorenz A.
  last_name: Fenk
- first_name: Lars
  full_name: Nilsson, Lars
  last_name: Nilsson
- first_name: Niko Paresh
  full_name: Amin-Wetzel, Niko Paresh
  id: E95D3014-9D8C-11E9-9C80-D2F8E5697425
  last_name: Amin-Wetzel
- first_name: Nelson
  full_name: Ramirez, Nelson
  id: 39831956-E4FE-11E9-85DE-0DC7E5697425
  last_name: Ramirez
- first_name: Mario
  full_name: De Bono, Mario
  id: 4E3FF80E-F248-11E8-B48F-1D18A9856A87
  last_name: De Bono
  orcid: 0000-0001-8347-0443
- first_name: Changchun
  full_name: Chen, Changchun
  last_name: Chen
citation:
  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>
  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>
  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.
  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.
  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>.
  short: L. Zhao, L.A. Fenk, L. Nilsson, N.P. Amin-Wetzel, N. Ramirez, M. de Bono,
    C. Chen, PLoS Biology 20 (2022).
date_created: 2022-07-24T22:01:42Z
date_published: 2022-06-21T00:00:00Z
date_updated: 2023-08-03T12:11:44Z
day: '21'
ddc:
- '570'
department:
- _id: MaDe
doi: 10.1371/journal.pbio.3001684
external_id:
  isi:
  - '000828679600001'
  pmid:
  - '35727855'
file:
- access_level: open_access
  checksum: df4902f854ad76769d3203bfdc69f16c
  content_type: application/pdf
  creator: dernst
  date_created: 2022-07-25T07:38:49Z
  date_updated: 2022-07-25T07:38:49Z
  file_id: '11643'
  file_name: 2022_PLoSBiology_Zhao.pdf
  file_size: 3721585
  relation: main_file
  success: 1
file_date_updated: 2022-07-25T07:38:49Z
has_accepted_license: '1'
intvolume: '        20'
isi: 1
issue: '6'
language:
- iso: eng
license: https://creativecommons.org/licenses/by/4.0/
month: '06'
oa: 1
oa_version: Published Version
pmid: 1
project:
- _id: 23870BE8-32DE-11EA-91FC-C7463DDC885E
  grant_number: 209504/A/17/Z
  name: Molecular mechanisms of neural circuit function
publication: PLoS Biology
publication_identifier:
  eissn:
  - 1545-7885
publication_status: published
publisher: Public Library of Science
quality_controlled: '1'
scopus_import: '1'
status: public
title: ROS and cGMP signaling modulate persistent escape from hypoxia in Caenorhabditis
  elegans
tmp:
  image: /images/cc_by.png
  legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
  name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
  short: CC BY (4.0)
type: journal_article
user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8
volume: 20
year: '2022'
...
---
_id: '7340'
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.
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.
article_number: e50793
article_processing_charge: No
article_type: original
author:
- first_name: Niko Paresh
  full_name: Amin-Wetzel, Niko Paresh
  id: E95D3014-9D8C-11E9-9C80-D2F8E5697425
  last_name: Amin-Wetzel
- first_name: Lisa
  full_name: Neidhardt, Lisa
  last_name: Neidhardt
- first_name: Yahui
  full_name: Yan, Yahui
  last_name: Yan
- first_name: Matthias P.
  full_name: Mayer, Matthias P.
  last_name: Mayer
- first_name: David
  full_name: Ron, David
  last_name: Ron
citation:
  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>
  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.
  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.
  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>.
  short: N.P. Amin-Wetzel, L. Neidhardt, Y. Yan, M.P. Mayer, D. Ron, ELife 8 (2019).
date_created: 2020-01-19T23:00:39Z
date_published: 2019-12-24T00:00:00Z
date_updated: 2023-09-06T14:58:02Z
day: '24'
ddc:
- '570'
department:
- _id: MaDe
doi: 10.7554/eLife.50793
external_id:
  isi:
  - '000512303700001'
  pmid:
  - '31873072'
file:
- access_level: open_access
  checksum: 29fcbcd8c1fc7f11a596ed7f14ea1c82
  content_type: application/pdf
  creator: dernst
  date_created: 2020-11-19T11:37:41Z
  date_updated: 2020-11-19T11:37:41Z
  file_id: '8777'
  file_name: 2019_eLife_AminWetzel.pdf
  file_size: 4817384
  relation: main_file
  success: 1
file_date_updated: 2020-11-19T11:37:41Z
has_accepted_license: '1'
intvolume: '         8'
isi: 1
language:
- iso: eng
month: '12'
oa: 1
oa_version: Published Version
pmid: 1
publication: eLife
publication_identifier:
  eissn:
  - 2050084X
publication_status: published
publisher: eLife Sciences Publications
quality_controlled: '1'
scopus_import: '1'
status: public
title: Unstructured regions in IRE1α specify BiP-mediated destabilisation of the luminal
  domain dimer and repression of the UPR
tmp:
  image: /images/cc_by.png
  legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
  name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
  short: CC BY (4.0)
type: journal_article
user_id: c635000d-4b10-11ee-a964-aac5a93f6ac1
volume: 8
year: '2019'
...