miR-4734 conditionally suppresses ER stress-associated proinflammatory responses

Dan Michael; Ester Feldmesser; Chagay Gonen; Noa Furth; Alexander Maman; Ori Heyman; Amir Argoetti; Adin Tofield; Amichai Baichman-Kass; Aviyah Ben-Dov; Dan Benbenisti; Nadav Hen; Ron Rotkopf; Federica Ganci; Giovanni Blandino; Igor Ulitsky; Moshe Oren

doi:10.1002/1873-3468.14548

miR-4734 conditionally suppresses ER stress-associated proinflammatory responses

Dan Michael^*, Ester Feldmesser, Chagay Gonen, Noa Furth, Alexander Maman, Ori Heyman, Amir Argoetti, Adin Tofield, Amichai Baichman-Kass, Aviyah Ben-Dov, Dan Benbenisti, Nadav Hen, Ron Rotkopf, Federica Ganci, Giovanni Blandino, Igor Ulitsky, Moshe Oren^*

^*Corresponding author for this work

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

1 Citation (Scopus)

Abstract

Prolonged metabolic stress can lead to severe pathologies. In metabolically challenged primary fibroblasts, we assigned a novel role for the poorly characterized miR-4734 in restricting ATF4 and IRE1-mediated upregulation of a set of proinflammatory cytokines and endoplasmic reticulum stress-associated genes. Conversely, inhibition of this miRNA augmented the expression of those genes. Mechanistically, miR-4734 was found to restrict the expression of the transcriptional activator NF-kappa-B inhibitor zeta (NFKBIZ), which is required for optimal expression of the proinflammatory genes and whose mRNA is targeted directly by miR-4734. Concordantly, overexpression of NFKBIZ compromised the effects of miR-4734, underscoring the importance of this direct targeting. As the effects of miR-4734 were evident under stress but not under basal conditions, it may possess therapeutic utility towards alleviating stress-induced pathologies.

Original language	English
Pages (from-to)	1233-1245
Number of pages	13
Journal	FEBS Letters
Volume	597
Issue number	9
DOIs	https://doi.org/10.1002/1873-3468.14548
Publication status	Published - May 2023

Bibliographical note

Funding Information:
The authors thank and Gilgi Friedlander for analysis of the mRNA expression array data. This work was supported in part by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, a grant from Anat and Amnon Shashua, and the Moross Integrated Cancer Center. MO is incumbent of the Andre Lwoff chair in molecular biology.

Author contributions -DM involved in research design and experimental planning; DM, AA, CG, NF, FG, AM, OH, AT, AB-K, AB-D, NH and DB performed the experiments; EF and RR performed the statistical analysis; MO and DM involved in supervision and data analysis; IU provided the experimental advice; DM and MO involved in manuscript writing; NF, IU and GB involved in manuscript editing.

All Science Journal Classification (ASJC) codes

Biophysics
Structural Biology
Biochemistry
Molecular Biology
Genetics
Cell Biology

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Michael, D., Feldmesser, E., Gonen, C., Furth, N., Maman, A., Heyman, O., Argoetti, A., Tofield, A., Baichman-Kass, A., Ben-Dov, A., Benbenisti, D., Hen, N., Rotkopf, R., Ganci, F., Blandino, G., Ulitsky, I., & Oren, M. (2023). miR-4734 conditionally suppresses ER stress-associated proinflammatory responses. FEBS Letters, 597(9), 1233-1245. https://doi.org/10.1002/1873-3468.14548

@article{616a75defff949248c282b9d75600fbc,

title = "miR-4734 conditionally suppresses ER stress-associated proinflammatory responses",

abstract = "Prolonged metabolic stress can lead to severe pathologies. In metabolically challenged primary fibroblasts, we assigned a novel role for the poorly characterized miR-4734 in restricting ATF4 and IRE1-mediated upregulation of a set of proinflammatory cytokines and endoplasmic reticulum stress-associated genes. Conversely, inhibition of this miRNA augmented the expression of those genes. Mechanistically, miR-4734 was found to restrict the expression of the transcriptional activator NF-kappa-B inhibitor zeta (NFKBIZ), which is required for optimal expression of the proinflammatory genes and whose mRNA is targeted directly by miR-4734. Concordantly, overexpression of NFKBIZ compromised the effects of miR-4734, underscoring the importance of this direct targeting. As the effects of miR-4734 were evident under stress but not under basal conditions, it may possess therapeutic utility towards alleviating stress-induced pathologies.",

author = "Dan Michael and Ester Feldmesser and Chagay Gonen and Noa Furth and Alexander Maman and Ori Heyman and Amir Argoetti and Adin Tofield and Amichai Baichman-Kass and Aviyah Ben-Dov and Dan Benbenisti and Nadav Hen and Ron Rotkopf and Federica Ganci and Giovanni Blandino and Igor Ulitsky and Moshe Oren",

note = "Funding Information: The authors thank and Gilgi Friedlander for analysis of the mRNA expression array data. This work was supported in part by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, a grant from Anat and Amnon Shashua, and the Moross Integrated Cancer Center. MO is incumbent of the Andre Lwoff chair in molecular biology. Author contributions -DM involved in research design and experimental planning; DM, AA, CG, NF, FG, AM, OH, AT, AB-K, AB-D, NH and DB performed the experiments; EF and RR performed the statistical analysis; MO and DM involved in supervision and data analysis; IU provided the experimental advice; DM and MO involved in manuscript writing; NF, IU and GB involved in manuscript editing.",

year = "2023",

month = may,

doi = "10.1002/1873-3468.14548",

language = "English",

volume = "597",

pages = "1233--1245",

journal = "FEBS Letters",

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Michael, D , Feldmesser, E, Gonen, C, Furth, N , Maman, A, Heyman, O, Argoetti, A, Tofield, A, Baichman-Kass, A, Ben-Dov, A, Benbenisti, D, Hen, N, Rotkopf, R, Ganci, F, Blandino, G, Ulitsky, I & Oren, M 2023, 'miR-4734 conditionally suppresses ER stress-associated proinflammatory responses', FEBS Letters, vol. 597, no. 9, pp. 1233-1245. https://doi.org/10.1002/1873-3468.14548

TY - JOUR

T1 - miR-4734 conditionally suppresses ER stress-associated proinflammatory responses

AU - Michael, Dan

AU - Feldmesser, Ester

AU - Gonen, Chagay

AU - Furth, Noa

AU - Maman, Alexander

AU - Heyman, Ori

AU - Argoetti, Amir

AU - Tofield, Adin

AU - Baichman-Kass, Amichai

AU - Ben-Dov, Aviyah

AU - Benbenisti, Dan

AU - Hen, Nadav

AU - Rotkopf, Ron

AU - Ganci, Federica

AU - Blandino, Giovanni

AU - Ulitsky, Igor

AU - Oren, Moshe

N1 - Funding Information: The authors thank and Gilgi Friedlander for analysis of the mRNA expression array data. This work was supported in part by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, a grant from Anat and Amnon Shashua, and the Moross Integrated Cancer Center. MO is incumbent of the Andre Lwoff chair in molecular biology. Author contributions -DM involved in research design and experimental planning; DM, AA, CG, NF, FG, AM, OH, AT, AB-K, AB-D, NH and DB performed the experiments; EF and RR performed the statistical analysis; MO and DM involved in supervision and data analysis; IU provided the experimental advice; DM and MO involved in manuscript writing; NF, IU and GB involved in manuscript editing.

PY - 2023/5

Y1 - 2023/5

N2 - Prolonged metabolic stress can lead to severe pathologies. In metabolically challenged primary fibroblasts, we assigned a novel role for the poorly characterized miR-4734 in restricting ATF4 and IRE1-mediated upregulation of a set of proinflammatory cytokines and endoplasmic reticulum stress-associated genes. Conversely, inhibition of this miRNA augmented the expression of those genes. Mechanistically, miR-4734 was found to restrict the expression of the transcriptional activator NF-kappa-B inhibitor zeta (NFKBIZ), which is required for optimal expression of the proinflammatory genes and whose mRNA is targeted directly by miR-4734. Concordantly, overexpression of NFKBIZ compromised the effects of miR-4734, underscoring the importance of this direct targeting. As the effects of miR-4734 were evident under stress but not under basal conditions, it may possess therapeutic utility towards alleviating stress-induced pathologies.

AB - Prolonged metabolic stress can lead to severe pathologies. In metabolically challenged primary fibroblasts, we assigned a novel role for the poorly characterized miR-4734 in restricting ATF4 and IRE1-mediated upregulation of a set of proinflammatory cytokines and endoplasmic reticulum stress-associated genes. Conversely, inhibition of this miRNA augmented the expression of those genes. Mechanistically, miR-4734 was found to restrict the expression of the transcriptional activator NF-kappa-B inhibitor zeta (NFKBIZ), which is required for optimal expression of the proinflammatory genes and whose mRNA is targeted directly by miR-4734. Concordantly, overexpression of NFKBIZ compromised the effects of miR-4734, underscoring the importance of this direct targeting. As the effects of miR-4734 were evident under stress but not under basal conditions, it may possess therapeutic utility towards alleviating stress-induced pathologies.

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U2 - 10.1002/1873-3468.14548

DO - 10.1002/1873-3468.14548

M3 - Article

C2 - 36445168

AN - SCOPUS:85144093686

SN - 0014-5793

VL - 597

SP - 1233

EP - 1245

JO - FEBS Letters

JF - FEBS Letters

IS - 9

ER -

miR-4734 conditionally suppresses ER stress-associated proinflammatory responses

Abstract

Bibliographical note

All Science Journal Classification (ASJC) codes

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