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. 2023 May;597(9):1233-1245.
doi: 10.1002/1873-3468.14548. Epub 2022 Dec 11.

miR-4734 conditionally suppresses ER stress-associated proinflammatory responses

Dan Michael  1   2 , Ester Feldmesser  3 , Chagay Gonen  1 , Noa Furth  4 , Alexander Maman  5 , Ori Heyman  4 , Amir Argoetti  6 , Adin Tofield  7 , Amichai Baichman-Kass  8 , Aviyah Ben-Dov  9 , Dan Benbenisti  9 , Nadav Hen  9 , Ron Rotkopf  3 , Federica Ganci  10 , Giovanni Blandino  10 , Igor Ulitsky  4 , Moshe Oren  1
Affiliations
Free article

miR-4734 conditionally suppresses ER stress-associated proinflammatory responses

Dan Michael et al. FEBS Lett. 2023 May.
Free article

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.

Keywords: ATF4; ER stress; IRE1a; NFKBIZ; inflammation; miR-4734.

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