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Research article - Peer-reviewed, 2022

ZC3H11A loss of function enhances NF-κB signaling through defective IκBα protein expression

Darweesh, Mahmoud; Younis, Shady; Hajikhezri, Zamaneh; Ali, Arwa; Jin, Chuan; Punga, Tanel; Gupta, Soham; Essand, Magnus; Andersson, Leif; Akusjaervi, Goran

Abstract

ZC3H11A is a cellular protein associated with the transcription export (TREX) complex that is induced during heat-shock. Several nuclear-replicating viruses exploit the mRNA export mechanism of ZC3H11A protein for their efficient replication. Here we show that ZC3H11A protein plays a role in regulation of NF-kappa B signal transduction. Depletion of ZC3H11A resulted in enhanced NF-kappa B mediated signaling, with upregulation of numerous innate immune related mRNAs, including IL-6 and a large group of interferon-stimulated genes. IL-6 upregulation in the absence of the ZC3H11A protein correlated with an increased NF-kappa B transcription factor binding to the IL-6 promoter and decreased IL-6 mRNA decay. The enhanced NF-kappa B signaling pathway in ZC3H11A deficient cells correlated with a defect in I kappa B alpha inhibitory mRNA and protein accumulation. Upon ZC3H11A depletion The I kappa B alpha mRNA was retained in the cell nucleus resulting in failure to maintain normal levels of the cytoplasmic I kappa B alpha mRNA and protein that is essential for its inhibitory feedback loop on NF-kappa B activity. These findings indicate towards a previously unknown mechanism of ZC3H11A in regulating the NF-kappa B pathway at the level of IkB alpha mRNA export.

Keywords

ZC3H11A; NF-kB, IkBa; IL6; adenovirus

Published in

Frontiers in Immunology
2022, volume: 13, article number: 1002823
Publisher: FRONTIERS MEDIA SA

Authors' information

Darweesh, Mahmoud
Uppsala University
Younis, Shady
Uppsala University
Younis, Shady
Stanford University
Hajikhezri, Zamaneh
Uppsala University
Ali, Arwa
Uppsala University
Jin, Chuan
Uppsala University
Punga, Tanel
Uppsala University
Gupta, Soham
Karolinska Institutet
Essand, Magnus
Uppsala University
Andersson, Leif
Uppsala University
Andersson, Leif
Swedish University of Agricultural Sciences, Department of Animal Breeding and Genetics
Andersson, Leif
Texas A&M University
Akusjaervi, Goran
Uppsala University

UKÄ Subject classification

Cell Biology

Publication Identifiers

DOI: https://doi.org/10.3389/fimmu.2022.1002823

URI (permanent link to this page)

https://res.slu.se/id/publ/120396