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The stress-sensing domain of activated IRE1α forms helical filaments in narrow ER membrane tubes

Tran, Ngoc-Han and Carter, Stephen D. and De Maziere, Ann and Ashkenazi, Avi and Klumperman, Judith and Walter, Peter and Jensen, Grant J. (2021) The stress-sensing domain of activated IRE1α forms helical filaments in narrow ER membrane tubes. Science, 374 (6563). pp. 52-57. ISSN 0036-8075. doi:10.1126/science.abh2474.

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The signaling network of the unfolded protein response (UPR) adjusts the protein-folding capacity of the endoplasmic reticulum (ER) according to need. The most conserved UPR sensor, IRE1α, spans the ER membrane and activates through oligomerization. IRE1α oligomers accumulate in dynamic foci. We determined the in situ structure of IRE1α foci by cryogenic correlated light and electron microscopy combined with electron cryo-tomography and complementary immuno–electron microscopy in mammalian cell lines. IRE1α foci localized to a network of narrow anastomosing ER tubes (diameter, ~28 nm) with complex branching. The lumen of the tubes contained protein filaments, which were likely composed of arrays of IRE1α lumenal domain dimers that were arranged in two intertwined, left-handed helices. This specialized ER subdomain may play a role in modulating IRE1α signaling.

Item Type:Article
Related URLs:
URLURL TypeDescription Paper ItemCode
Tran, Ngoc-Han0000-0003-0638-2583
Carter, Stephen D.0000-0002-4237-4276
De Maziere, Ann0000-0001-8070-5104
Ashkenazi, Avi0000-0002-6890-4589
Klumperman, Judith0000-0003-4835-6228
Walter, Peter0000-0002-6849-708X
Jensen, Grant J.0000-0003-1556-4864
Additional Information:© 2021 American Association for the Advancement of Science. Received 24 February 2021; accepted 11 August 2021. We thank E. Karagoz, S. Niekamp, V. Belyy, M. Elvekrog, D. Acosta-Alvear, R. Fetter, and S. van Dijk for their advice and technical assistance and G. Huber, R. Ernst, A. Frost, and J. Nunnari for insightful discussions. This work was supported in part by NWO NEMI (grant 184.034.014 to J.K.) and the NIH (grants P50 AI150464 and R35 GM122588 to G.J.J. and R01-GM032384 to P.W.). N.-H.T. is supported by the NSF GRFP. P.W. is an Investigator of the Howard Hughes Medical Institute. Author contributions: Methodology: N.-H.T., S.D.C., A.D.M.; Formal analysis: N.-H.T., S.D.C., A.D.M. Visualization: N.-H.T., S.D.C.; Writing – original draft & editing: N.-H.T., S.D.C.; Conceptualization: A.A., J.K., P.W., G.J.J.; Resources: A.A., J.K., P.W., G.J.J.; Supervision: A.A., J.K., P.W., G.J.J.; Funding acquisition: A.A., J.K., P.W., G.J.J.; Writing – review & editing: P.W., G.J.J. Competing interests: A.D.M. received a salary from Genentech, Inc. The authors declare no other competing interests. Data and materials availability: The codes used for analyses are available through Zenodo (38). The subtomogram-averaged maps can be accessed at EMDB (EMD-23058). Raw and processed data, cell lines, and reagents are available upon request.
Funding AgencyGrant Number
Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO)184.034.014
NIHP50 AI150464
NIHR35 GM122588
NSF Graduate Research FellowshipUNSPECIFIED
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Issue or Number:6563
Record Number:CaltechAUTHORS:20210225-141123693
Persistent URL:
Official Citation:The stress-sensing domain of activated IRE1α forms helical filaments in narrow ER membrane tubes. Ngoc-Han Tran, Stephen D. Carter, Ann De Mazière, Avi Ashkenazi, Judith Klumperman, Peter Walter, Grant J. Jensen. Science, 374 (6563); DOI: 10.1126/science.abh2474
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:108215
Deposited By: Tony Diaz
Deposited On:26 Feb 2021 00:29
Last Modified:04 Oct 2021 20:38

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