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The noncoding RNA nc886 regulates PKR signaling and cytokine production in human cells

Golec, Ewelina LU ; Lind, Liza; Qayyum, Munazza; Blom, Anna M. LU and King, Ben C. LU (2019) In Journal of Immunology 202(1). p.131-141
Abstract

Protein kinase RNA-activated (PKR) is a cytoplasmic receptor for dsRNA, and as such is involved in detection of viral infection. On binding dsRNA, PKR dimerizes, autophosphorylates, and then phosphorylates its substrate, eukaryotic translation initiation factor 2 subunit a (eIF2α), causing inhibition of mRNA translation and shutdown of viral protein production. However, active PKR has also been found to be involved in the NF-κB signaling pathway by inducing phosphorylation of IkBa. PKR is regulated by the noncoding RNA nc886, which has altered expression in cancer. We have found that expression of nc886 is highly upregulated during activation of human CD4+ T cells. As has been described in other cell types, nc886 bound to PKR... (More)

Protein kinase RNA-activated (PKR) is a cytoplasmic receptor for dsRNA, and as such is involved in detection of viral infection. On binding dsRNA, PKR dimerizes, autophosphorylates, and then phosphorylates its substrate, eukaryotic translation initiation factor 2 subunit a (eIF2α), causing inhibition of mRNA translation and shutdown of viral protein production. However, active PKR has also been found to be involved in the NF-κB signaling pathway by inducing phosphorylation of IkBa. PKR is regulated by the noncoding RNA nc886, which has altered expression in cancer. We have found that expression of nc886 is highly upregulated during activation of human CD4+ T cells. As has been described in other cell types, nc886 bound to PKR in human T cell lysates, preventing PKR phosphorylation by polyinosinic:polycytidylic acid or HIV trans-activation response element RNA in lysates of T cell lines or primary human CD4+ T cells. Using clonal human T cell lines, we found that nc886 expression was strictly required for IFN-γ and IL-2 expression and secretion after T cell activation but did not affect proliferation or activation-induced cell death. In stimulated human PBMCs, nc886 expression strongly correlated with IFN-γ expression. Although nc886 inhibited PKR activation by dsRNA, it was required for PKR phosphorylation during T cell stimulation, with subsequent NF-κB signaling and CREB phosphorylation. nc886 also regulated PKR phosphorylation during human monocyte-derived macrophage activation. We have therefore identified nc886 as a noncoding RNA marker of T cell activation and regulator of PKR-dependent signaling.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Immunology
volume
202
issue
1
pages
11 pages
publisher
American Association of Immunologists
external identifiers
  • scopus:85059231263
ISSN
0022-1767
DOI
10.4049/jimmunol.1701234
language
English
LU publication?
yes
id
36fa45fd-1142-4a9b-aa1a-d0e5ab084dc4
date added to LUP
2019-01-11 09:01:11
date last changed
2019-01-11 09:01:11
@article{36fa45fd-1142-4a9b-aa1a-d0e5ab084dc4,
  abstract     = {<p>Protein kinase RNA-activated (PKR) is a cytoplasmic receptor for dsRNA, and as such is involved in detection of viral infection. On binding dsRNA, PKR dimerizes, autophosphorylates, and then phosphorylates its substrate, eukaryotic translation initiation factor 2 subunit a (eIF2α), causing inhibition of mRNA translation and shutdown of viral protein production. However, active PKR has also been found to be involved in the NF-κB signaling pathway by inducing phosphorylation of IkBa. PKR is regulated by the noncoding RNA nc886, which has altered expression in cancer. We have found that expression of nc886 is highly upregulated during activation of human CD4<sup>+</sup> T cells. As has been described in other cell types, nc886 bound to PKR in human T cell lysates, preventing PKR phosphorylation by polyinosinic:polycytidylic acid or HIV trans-activation response element RNA in lysates of T cell lines or primary human CD4<sup>+</sup> T cells. Using clonal human T cell lines, we found that nc886 expression was strictly required for IFN-γ and IL-2 expression and secretion after T cell activation but did not affect proliferation or activation-induced cell death. In stimulated human PBMCs, nc886 expression strongly correlated with IFN-γ expression. Although nc886 inhibited PKR activation by dsRNA, it was required for PKR phosphorylation during T cell stimulation, with subsequent NF-κB signaling and CREB phosphorylation. nc886 also regulated PKR phosphorylation during human monocyte-derived macrophage activation. We have therefore identified nc886 as a noncoding RNA marker of T cell activation and regulator of PKR-dependent signaling.</p>},
  author       = {Golec, Ewelina and Lind, Liza and Qayyum, Munazza and Blom, Anna M. and King, Ben C.},
  issn         = {0022-1767},
  language     = {eng},
  number       = {1},
  pages        = {131--141},
  publisher    = {American Association of Immunologists},
  series       = {Journal of Immunology},
  title        = {The noncoding RNA nc886 regulates PKR signaling and cytokine production in human cells},
  url          = {http://dx.doi.org/10.4049/jimmunol.1701234},
  volume       = {202},
  year         = {2019},
}