---
OA_place: publisher
OA_type: gold
_id: '18073'
abstract:
- lang: eng
  text: Conserved signaling cascades monitor protein-folding homeostasis to ensure
    proper cellular function. One of the evolutionary conserved key players is IRE1,
    which maintains endoplasmic reticulum (ER) homeostasis through the unfolded protein
    response (UPR). Upon accumulation of misfolded proteins in the ER, IRE1 forms
    clusters on the ER membrane to initiate UPR signaling. What regulates IRE1 cluster
    formation is not fully understood. Here, we show that the ER lumenal domain (LD)
    of human IRE1α forms biomolecular condensates in vitro. IRE1α LD condensates were
    stabilized both by binding to unfolded polypeptides as well as by tethering to
    model membranes, suggesting their role in assembling IRE1α into signaling-competent
    stable clusters. Molecular dynamics simulations indicated that weak multivalent
    interactions drive IRE1α LD clustering. Mutagenesis experiments identified disordered
    regions in IRE1α LD to control its clustering in vitro and in cells. Importantly,
    dysregulated clustering of IRE1α mutants led to defects in IRE1α signaling. Our
    results revealed that disordered regions in IRE1α LD control its clustering and
    suggest their role as a common strategy in regulating protein assembly on membranes.
acknowledgement: We thank late Thomas Peterbauer at the Max Perutz Labs Biooptics
  Light Microscopy Facility for his help and support. We are grateful to Kitti Csalyi
  and Thomas Sauer at Max Perutz Labs Biooptics FACS facility for their help. We thank
  Grzegorz Scibisz and Sertan Atilla for their support with the expression and purification
  of mCherry-IRE1α LD-10His. We are grateful to Aleksandra S Anisimova with her help
  in the generation of stable cell lines and the statistical analyses of the data.
  We thank Venja Vieweger for her help with the characterization of the WLLI and D123P
  IRE1 mutants in cells. We are thankful to Monika Kubickova for the help with the
  AUC experiments. We acknowledge CF BIC of CIISB, Instruct-CZ Centre, supported by
  MEYS CR (LM2023042)) and European Regional Development Fund-Project, UP CIISB“ (No.
  CZ.02.1.01/0.0/0.0/18_046/0015974). We thank the members of the Karagöz lab for
  the critical reading and editing of the manuscript. We are thankful to our colleagues
  Diego Acosta-Alvear, Vladislav Belyy, Jirka Peschek, Yasin Dagdas, Javier Martinez,
  Sascha Martens and Alwin Köhler for their invaluable input on the manuscript. We
  are grateful to Life Science Editors, especially Katrina Woolcock for her useful
  edits and comments on the manuscript. We acknowledge funding from Austrian Science
  Fund (FWF-SFB F79 and FWF-W 1261) to GEK. PK acknowledges the support of the Max
  Perutz PhD fellowship. GAV is funded by Stand-Alone grants (P30231-B, P30415-B,
  P36572), Special Research Grant (SFB grant F79), and Doctoral School grant (DK grant
  W1261) from the Austrian Science Fund (FWF). ES and RC acknowledge support and funding
  by the Frankfurt Institute of Advanced Studies, the LOEWE Center for Multiscale
  Modelling in Life Sciences of the state of Hesse, the Collaborative Research Center
  1507 “Membrane-associated Protein Assemblies, Machineries, and Supercomplexes” (Project
  ID 450648163), and the International Max Planck Research School on Cellular Biophysics
  (to RC), the Center for Scientific Computing of the Goethe University and the Jülich
  Supercomputing Centre for computational resources and support.
article_processing_charge: Yes
article_type: original
author:
- first_name: Paulina
  full_name: Kettel, Paulina
  last_name: Kettel
- first_name: Laura
  full_name: Marosits, Laura
  last_name: Marosits
- first_name: Elena
  full_name: Spinetti, Elena
  last_name: Spinetti
- first_name: Michael
  full_name: Rechberger, Michael
  last_name: Rechberger
- first_name: Caterina
  full_name: Giannini, Caterina
  id: e3fdddd5-f6e0-11ea-865d-ca99ee6367f4
  last_name: Giannini
- first_name: Philipp
  full_name: Radler, Philipp
  id: 40136C2A-F248-11E8-B48F-1D18A9856A87
  last_name: Radler
  orcid: '0000-0001-9198-2182 '
- first_name: Isabell
  full_name: Niedermoser, Isabell
  last_name: Niedermoser
- first_name: Irmgard
  full_name: Fischer, Irmgard
  last_name: Fischer
- first_name: Gijs A.
  full_name: Versteeg, Gijs A.
  last_name: Versteeg
- first_name: Martin
  full_name: Loose, Martin
  id: 462D4284-F248-11E8-B48F-1D18A9856A87
  last_name: Loose
  orcid: 0000-0001-7309-9724
- first_name: Roberto
  full_name: Covino, Roberto
  last_name: Covino
- first_name: G. Elif
  full_name: Karagöz, G. Elif
  last_name: Karagöz
citation:
  ama: Kettel P, Marosits L, Spinetti E, et al. Disordered regions in the IRE1α ER
    lumenal domain mediate its stress-induced clustering. <i>EMBO Journal</i>. 2024;43(20):4668-4698.
    doi:<a href="https://doi.org/10.1038/s44318-024-00207-0">10.1038/s44318-024-00207-0</a>
  apa: Kettel, P., Marosits, L., Spinetti, E., Rechberger, M., Giannini, C., Radler,
    P., … Karagöz, G. E. (2024). Disordered regions in the IRE1α ER lumenal domain
    mediate its stress-induced clustering. <i>EMBO Journal</i>. Embo Press. <a href="https://doi.org/10.1038/s44318-024-00207-0">https://doi.org/10.1038/s44318-024-00207-0</a>
  chicago: Kettel, Paulina, Laura Marosits, Elena Spinetti, Michael Rechberger, Caterina
    Giannini, Philipp Radler, Isabell Niedermoser, et al. “Disordered Regions in the
    IRE1α ER Lumenal Domain Mediate Its Stress-Induced Clustering.” <i>EMBO Journal</i>.
    Embo Press, 2024. <a href="https://doi.org/10.1038/s44318-024-00207-0">https://doi.org/10.1038/s44318-024-00207-0</a>.
  ieee: P. Kettel <i>et al.</i>, “Disordered regions in the IRE1α ER lumenal domain
    mediate its stress-induced clustering,” <i>EMBO Journal</i>, vol. 43, no. 20.
    Embo Press, pp. 4668–4698, 2024.
  ista: Kettel P, Marosits L, Spinetti E, Rechberger M, Giannini C, Radler P, Niedermoser
    I, Fischer I, Versteeg GA, Loose M, Covino R, Karagöz GE. 2024. Disordered regions
    in the IRE1α ER lumenal domain mediate its stress-induced clustering. EMBO Journal.
    43(20), 4668–4698.
  mla: Kettel, Paulina, et al. “Disordered Regions in the IRE1α ER Lumenal Domain
    Mediate Its Stress-Induced Clustering.” <i>EMBO Journal</i>, vol. 43, no. 20,
    Embo Press, 2024, pp. 4668–98, doi:<a href="https://doi.org/10.1038/s44318-024-00207-0">10.1038/s44318-024-00207-0</a>.
  short: P. Kettel, L. Marosits, E. Spinetti, M. Rechberger, C. Giannini, P. Radler,
    I. Niedermoser, I. Fischer, G.A. Versteeg, M. Loose, R. Covino, G.E. Karagöz,
    EMBO Journal 43 (2024) 4668–4698.
date_created: 2024-09-15T22:01:42Z
date_published: 2024-10-15T00:00:00Z
date_updated: 2025-09-08T09:22:11Z
day: '15'
ddc:
- '570'
department:
- _id: MaLo
- _id: JiFr
doi: 10.1038/s44318-024-00207-0
external_id:
  isi:
  - '001306286100002'
  pmid:
  - '39232130'
file:
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fulldoi: https://doi.org/10.1038/s44318-024-00207-0
has_accepted_license: '1'
intvolume: '        43'
isi: 1
issue: '20'
language:
- iso: eng
license: https://creativecommons.org/licenses/by/4.0/
month: '10'
oa: 1
oa_version: Published Version
page: 4668-4698
pmid: 1
publication: EMBO Journal
publication_identifier:
  eissn:
  - 1460-2075
  issn:
  - 0261-4189
publication_status: published
publisher: Embo Press
quality_controlled: '1'
scopus_import: '1'
status: public
title: Disordered regions in the IRE1α ER lumenal domain mediate its stress-induced
  clustering
tmp:
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  name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
  short: CC BY (4.0)
type: journal_article
user_id: 317138e5-6ab7-11ef-aa6d-ffef3953e345
volume: 43
year: '2024'
...