A nonenzymatic dependency on inositol-requiring enzyme 1 controls cancer cell cycle progression and tumor growth

Iratxe Zuazo-Gaztelu; David Lawrence; Ioanna Oikonomidi; Scot Marsters; Ximo Pechuan-Jorge; Catarina J. Gaspar; David Kan; Ehud Segal; Kevin Clark; Maureen Beresini; Marie Gabrielle Braun; Joachim Rudolph; Zora Modrusan; Meena Choi; Wendy Sandoval; Mike Reichelt; David C. DeWitt; Pekka Kujala; Suzanne van Dijk; Judith Klumperman; Avi Ashkenazi

doi:10.1371/journal.pbio.3003086

A nonenzymatic dependency on inositol-requiring enzyme 1 controls cancer cell cycle progression and tumor growth

Iratxe Zuazo-Gaztelu, David Lawrence, Ioanna Oikonomidi, Scot Marsters, Ximo Pechuan-Jorge, Catarina J. Gaspar, David Kan, Ehud Segal, Kevin Clark, Maureen Beresini, Marie Gabrielle Braun, Joachim Rudolph, Zora Modrusan, Meena Choi, Wendy Sandoval, Mike Reichelt, David C. DeWitt, Pekka Kujala, Suzanne van Dijk, Judith KlumpermanAvi Ashkenazi^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

2 Downloads (Pure)

Abstract

Endoplasmic-reticulum resident inositol-requiring enzyme 1α (IRE1) supports protein homeostasis via its cytoplasmic kinase-RNase module. Known cancer dependency on IRE1 entails its enzymatic activation of the transcription factor XBP1s and regulated RNA decay. We discovered that some cancer cells surprisingly require IRE1 but not its enzymatic activity. IRE1 knockdown but not enzymatic IRE1 inhibition or XBP1 disruption attenuated cell cycle progression and tumor growth. IRE1 silencing led to activation of TP53 and CDKN1A/p21 in conjunction with increased DNA damage and chromosome instability, while decreasing heterochromatin as well as DNA and histone H3K9me3 methylation. Immunoelectron microscopy detected endogenous IRE1 at the nuclear envelope. Thus, cancer cells co-opt IRE1 either enzymatically or nonenzymatically, which has significant implications for IRE1’s biological role and therapeutic targeting.

Original language	English
Article number	e3003086
Journal	PLoS Biology
Volume	23
Issue number	4
DOIs	https://doi.org/10.1371/journal.pbio.3003086
Publication status	Published - Apr 2025

Access to Document

10.1371/journal.pbio.3003086Licence: CC BY

journal.pbio.3003086Final published version, 2.96 MBLicence: CC BY

Cite this

Zuazo-Gaztelu, I., Lawrence, D., Oikonomidi, I., Marsters, S., Pechuan-Jorge, X., Gaspar, C. J., Kan, D., Segal, E., Clark, K., Beresini, M., Braun, M. G., Rudolph, J., Modrusan, Z., Choi, M., Sandoval, W., Reichelt, M., DeWitt, D. C., Kujala, P., van Dijk, S., ... Ashkenazi, A. (2025). A nonenzymatic dependency on inositol-requiring enzyme 1 controls cancer cell cycle progression and tumor growth. PLoS Biology, 23(4), Article e3003086. https://doi.org/10.1371/journal.pbio.3003086

@article{6600eceaf7934d08952172f9c5c3cb46,

title = "A nonenzymatic dependency on inositol-requiring enzyme 1 controls cancer cell cycle progression and tumor growth",

abstract = "Endoplasmic-reticulum resident inositol-requiring enzyme 1α (IRE1) supports protein homeostasis via its cytoplasmic kinase-RNase module. Known cancer dependency on IRE1 entails its enzymatic activation of the transcription factor XBP1s and regulated RNA decay. We discovered that some cancer cells surprisingly require IRE1 but not its enzymatic activity. IRE1 knockdown but not enzymatic IRE1 inhibition or XBP1 disruption attenuated cell cycle progression and tumor growth. IRE1 silencing led to activation of TP53 and CDKN1A/p21 in conjunction with increased DNA damage and chromosome instability, while decreasing heterochromatin as well as DNA and histone H3K9me3 methylation. Immunoelectron microscopy detected endogenous IRE1 at the nuclear envelope. Thus, cancer cells co-opt IRE1 either enzymatically or nonenzymatically, which has significant implications for IRE1{\textquoteright}s biological role and therapeutic targeting.",

author = "Iratxe Zuazo-Gaztelu and David Lawrence and Ioanna Oikonomidi and Scot Marsters and Ximo Pechuan-Jorge and Gaspar, {Catarina J.} and David Kan and Ehud Segal and Kevin Clark and Maureen Beresini and Braun, {Marie Gabrielle} and Joachim Rudolph and Zora Modrusan and Meena Choi and Wendy Sandoval and Mike Reichelt and DeWitt, {David C.} and Pekka Kujala and {van Dijk}, Suzanne and Judith Klumperman and Avi Ashkenazi",

note = "Publisher Copyright: {\textcopyright} 2025 Zuazo-Gaztelu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",

year = "2025",

month = apr,

doi = "10.1371/journal.pbio.3003086",

language = "English",

volume = "23",

journal = "PLoS Biology",

issn = "1544-9173",

publisher = "Public Library of Science",

number = "4",

}

Zuazo-Gaztelu, I, Lawrence, D, Oikonomidi, I, Marsters, S, Pechuan-Jorge, X, Gaspar, CJ, Kan, D, Segal, E, Clark, K, Beresini, M, Braun, MG, Rudolph, J, Modrusan, Z, Choi, M, Sandoval, W, Reichelt, M, DeWitt, DC, Kujala, P, van Dijk, S, Klumperman, J & Ashkenazi, A 2025, 'A nonenzymatic dependency on inositol-requiring enzyme 1 controls cancer cell cycle progression and tumor growth', PLoS Biology, vol. 23, no. 4, e3003086. https://doi.org/10.1371/journal.pbio.3003086

TY - JOUR

T1 - A nonenzymatic dependency on inositol-requiring enzyme 1 controls cancer cell cycle progression and tumor growth

AU - Zuazo-Gaztelu, Iratxe

AU - Lawrence, David

AU - Oikonomidi, Ioanna

AU - Marsters, Scot

AU - Pechuan-Jorge, Ximo

AU - Gaspar, Catarina J.

AU - Kan, David

AU - Segal, Ehud

AU - Clark, Kevin

AU - Beresini, Maureen

AU - Braun, Marie Gabrielle

AU - Rudolph, Joachim

AU - Modrusan, Zora

AU - Choi, Meena

AU - Sandoval, Wendy

AU - Reichelt, Mike

AU - DeWitt, David C.

AU - Kujala, Pekka

AU - van Dijk, Suzanne

AU - Klumperman, Judith

AU - Ashkenazi, Avi

N1 - Publisher Copyright: © 2025 Zuazo-Gaztelu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

PY - 2025/4

Y1 - 2025/4

N2 - Endoplasmic-reticulum resident inositol-requiring enzyme 1α (IRE1) supports protein homeostasis via its cytoplasmic kinase-RNase module. Known cancer dependency on IRE1 entails its enzymatic activation of the transcription factor XBP1s and regulated RNA decay. We discovered that some cancer cells surprisingly require IRE1 but not its enzymatic activity. IRE1 knockdown but not enzymatic IRE1 inhibition or XBP1 disruption attenuated cell cycle progression and tumor growth. IRE1 silencing led to activation of TP53 and CDKN1A/p21 in conjunction with increased DNA damage and chromosome instability, while decreasing heterochromatin as well as DNA and histone H3K9me3 methylation. Immunoelectron microscopy detected endogenous IRE1 at the nuclear envelope. Thus, cancer cells co-opt IRE1 either enzymatically or nonenzymatically, which has significant implications for IRE1’s biological role and therapeutic targeting.

AB - Endoplasmic-reticulum resident inositol-requiring enzyme 1α (IRE1) supports protein homeostasis via its cytoplasmic kinase-RNase module. Known cancer dependency on IRE1 entails its enzymatic activation of the transcription factor XBP1s and regulated RNA decay. We discovered that some cancer cells surprisingly require IRE1 but not its enzymatic activity. IRE1 knockdown but not enzymatic IRE1 inhibition or XBP1 disruption attenuated cell cycle progression and tumor growth. IRE1 silencing led to activation of TP53 and CDKN1A/p21 in conjunction with increased DNA damage and chromosome instability, while decreasing heterochromatin as well as DNA and histone H3K9me3 methylation. Immunoelectron microscopy detected endogenous IRE1 at the nuclear envelope. Thus, cancer cells co-opt IRE1 either enzymatically or nonenzymatically, which has significant implications for IRE1’s biological role and therapeutic targeting.

UR - http://www.scopus.com/inward/record.url?scp=105002392591&partnerID=8YFLogxK

U2 - 10.1371/journal.pbio.3003086

DO - 10.1371/journal.pbio.3003086

M3 - Article

AN - SCOPUS:105002392591

SN - 1544-9173

VL - 23

JO - PLoS Biology

JF - PLoS Biology

IS - 4

M1 - e3003086

ER -

A nonenzymatic dependency on inositol-requiring enzyme 1 controls cancer cell cycle progression and tumor growth

Abstract

Access to Document

Other files and links

Fingerprint

Cite this