Spatial proteomics identifies a CRTC-dependent viral signaling pathway that stimulates production of interleukin-11

Benjamin J Ravenhill; Marisa Oliveira; George Wood; Ying Di; Joanne Kite; Xinyue Wang; Colin T R Davies; Yongxu Lu; Robin Antrobus; Gill Elliott; Nerea Irigoyen; David J Hughes; Paul A Lyons; Betty Chung; Georg H H Borner; Michael P Weekes

doi:10.1016/j.celrep.2025.115263

Spatial proteomics identifies a CRTC-dependent viral signaling pathway that stimulates production of interleukin-11

Benjamin J Ravenhill, Marisa Oliveira, George Wood, Ying Di, Joanne Kite, Xinyue Wang, Colin T R Davies, Yongxu Lu, Robin Antrobus, Gill Elliott, Nerea Irigoyen, David J Hughes, Paul A Lyons, Betty Chung, Georg H H Borner, Michael P Weekes^*

^*Corresponding author for this work

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

Abstract

Appropriate cellular recognition of viruses is essential for the generation of an effective innate and adaptive immune response. Viral sensors and their downstream signaling components thus provide a crucial first line of host defense. Many of them exhibit subcellular relocalization upon activation, resulting in the expression of interferon and antiviral genes. To comprehensively identify signaling factors, we analyzed protein relocalization on a global scale during viral infection. cAMP-responsive element-binding protein (CREB)-regulated transcription coactivators 2 and 3 (CRTC2/3) exhibited early cytoplasmic-to-nuclear translocation upon infection with multiple viruses in diverse cell types. This movement was dependent on mitochondrial antiviral signaling protein (MAVS), cyclo-oxygenase proteins, and protein kinase A. A key effect of CRTC2/3 translocation is transcription of the fibro-inflammatory cytokine interleukin (IL)-11. This may be important clinically in viral infections associated with fibrosis, including SARS-CoV-2. Nuclear translocation of CRTC2/3 is, therefore, identified as an important pathway in the context of viral infection.

Original language	English
Article number	115263
Number of pages	21
Journal	Cell Reports
Volume	44
Issue number	2
Early online date	7 Feb 2025
DOIs	https://doi.org/10.1016/j.celrep.2025.115263
Publication status	Published - 25 Feb 2025

Keywords

Proteomics
Systems virology
Virus signaling
Sendai virus
CRTC
Interleukin-11

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Copyright © 2025 The Authors. This is an open access article distributed under the terms of the Creative Commons CC-BY license (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Ravenhill, B. J., Oliveira, M., Wood, G., Di, Y., Kite, J., Wang, X., Davies, C. T. R., Lu, Y., Antrobus, R., Elliott, G., Irigoyen, N., Hughes, D. J., Lyons, P. A., Chung, B., Borner, G. H. H., & Weekes, M. P. (2025). Spatial proteomics identifies a CRTC-dependent viral signaling pathway that stimulates production of interleukin-11. Cell Reports, 44(2), Article 115263. https://doi.org/10.1016/j.celrep.2025.115263

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title = "Spatial proteomics identifies a CRTC-dependent viral signaling pathway that stimulates production of interleukin-11",

abstract = "Appropriate cellular recognition of viruses is essential for the generation of an effective innate and adaptive immune response. Viral sensors and their downstream signaling components thus provide a crucial first line of host defense. Many of them exhibit subcellular relocalization upon activation, resulting in the expression of interferon and antiviral genes. To comprehensively identify signaling factors, we analyzed protein relocalization on a global scale during viral infection. cAMP-responsive element-binding protein (CREB)-regulated transcription coactivators 2 and 3 (CRTC2/3) exhibited early cytoplasmic-to-nuclear translocation upon infection with multiple viruses in diverse cell types. This movement was dependent on mitochondrial antiviral signaling protein (MAVS), cyclo-oxygenase proteins, and protein kinase A. A key effect of CRTC2/3 translocation is transcription of the fibro-inflammatory cytokine interleukin (IL)-11. This may be important clinically in viral infections associated with fibrosis, including SARS-CoV-2. Nuclear translocation of CRTC2/3 is, therefore, identified as an important pathway in the context of viral infection.",

keywords = "Proteomics, Systems virology, Virus signaling, Sendai virus, CRTC, Interleukin-11",

author = "Ravenhill, {Benjamin J} and Marisa Oliveira and George Wood and Ying Di and Joanne Kite and Xinyue Wang and Davies, {Colin T R} and Yongxu Lu and Robin Antrobus and Gill Elliott and Nerea Irigoyen and Hughes, {David J} and Lyons, {Paul A} and Betty Chung and Borner, {Georg H H} and Weekes, {Michael P}",

note = "Funding: This work was supported by a Medical Research Council project grant (MR/W025647/1) to M.P.W., an Addenbrooke{\textquoteright}s Charitable Trust grant (900408) to M.P.W., an Evelyn Trust fellowship (project reference 18/27) to B.J.R., an Evelyn Trust grant (20/75) to P.A.L., a Medical Research Council fellowship and BBSRC project grants to B.C. (MR/R021821/1, BB/X001261/1, BB/V017780/1, and BB/V006096/1), and the NIHR Cambridge Biomedical Research Centre (NIHR203312). G.H.H.B. was supported by the Max Planck Society for the Advancement of Science.",

year = "2025",

month = feb,

day = "25",

doi = "10.1016/j.celrep.2025.115263",

language = "English",

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Ravenhill, BJ, Oliveira, M, Wood, G, Di, Y, Kite, J, Wang, X, Davies, CTR, Lu, Y, Antrobus, R, Elliott, G, Irigoyen, N, Hughes, DJ, Lyons, PA, Chung, B, Borner, GHH & Weekes, MP 2025, 'Spatial proteomics identifies a CRTC-dependent viral signaling pathway that stimulates production of interleukin-11', Cell Reports, vol. 44, no. 2, 115263. https://doi.org/10.1016/j.celrep.2025.115263

TY - JOUR

T1 - Spatial proteomics identifies a CRTC-dependent viral signaling pathway that stimulates production of interleukin-11

AU - Ravenhill, Benjamin J

AU - Oliveira, Marisa

AU - Wood, George

AU - Di, Ying

AU - Kite, Joanne

AU - Wang, Xinyue

AU - Davies, Colin T R

AU - Lu, Yongxu

AU - Antrobus, Robin

AU - Elliott, Gill

AU - Irigoyen, Nerea

AU - Hughes, David J

AU - Lyons, Paul A

AU - Chung, Betty

AU - Borner, Georg H H

AU - Weekes, Michael P

N1 - Funding: This work was supported by a Medical Research Council project grant (MR/W025647/1) to M.P.W., an Addenbrooke’s Charitable Trust grant (900408) to M.P.W., an Evelyn Trust fellowship (project reference 18/27) to B.J.R., an Evelyn Trust grant (20/75) to P.A.L., a Medical Research Council fellowship and BBSRC project grants to B.C. (MR/R021821/1, BB/X001261/1, BB/V017780/1, and BB/V006096/1), and the NIHR Cambridge Biomedical Research Centre (NIHR203312). G.H.H.B. was supported by the Max Planck Society for the Advancement of Science.

PY - 2025/2/25

Y1 - 2025/2/25

N2 - Appropriate cellular recognition of viruses is essential for the generation of an effective innate and adaptive immune response. Viral sensors and their downstream signaling components thus provide a crucial first line of host defense. Many of them exhibit subcellular relocalization upon activation, resulting in the expression of interferon and antiviral genes. To comprehensively identify signaling factors, we analyzed protein relocalization on a global scale during viral infection. cAMP-responsive element-binding protein (CREB)-regulated transcription coactivators 2 and 3 (CRTC2/3) exhibited early cytoplasmic-to-nuclear translocation upon infection with multiple viruses in diverse cell types. This movement was dependent on mitochondrial antiviral signaling protein (MAVS), cyclo-oxygenase proteins, and protein kinase A. A key effect of CRTC2/3 translocation is transcription of the fibro-inflammatory cytokine interleukin (IL)-11. This may be important clinically in viral infections associated with fibrosis, including SARS-CoV-2. Nuclear translocation of CRTC2/3 is, therefore, identified as an important pathway in the context of viral infection.

AB - Appropriate cellular recognition of viruses is essential for the generation of an effective innate and adaptive immune response. Viral sensors and their downstream signaling components thus provide a crucial first line of host defense. Many of them exhibit subcellular relocalization upon activation, resulting in the expression of interferon and antiviral genes. To comprehensively identify signaling factors, we analyzed protein relocalization on a global scale during viral infection. cAMP-responsive element-binding protein (CREB)-regulated transcription coactivators 2 and 3 (CRTC2/3) exhibited early cytoplasmic-to-nuclear translocation upon infection with multiple viruses in diverse cell types. This movement was dependent on mitochondrial antiviral signaling protein (MAVS), cyclo-oxygenase proteins, and protein kinase A. A key effect of CRTC2/3 translocation is transcription of the fibro-inflammatory cytokine interleukin (IL)-11. This may be important clinically in viral infections associated with fibrosis, including SARS-CoV-2. Nuclear translocation of CRTC2/3 is, therefore, identified as an important pathway in the context of viral infection.

KW - Proteomics

KW - Systems virology

KW - Virus signaling

KW - Sendai virus

KW - CRTC

KW - Interleukin-11

U2 - 10.1016/j.celrep.2025.115263

DO - 10.1016/j.celrep.2025.115263

M3 - Article

C2 - 39921859

SN - 2211-1247

VL - 44

JO - Cell Reports

JF - Cell Reports

IS - 2

M1 - 115263

ER -

Spatial proteomics identifies a CRTC-dependent viral signaling pathway that stimulates production of interleukin-11

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Keywords

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