PKR is activated by cellular dsRNAs during mitosis and acts as a mitotic regulator

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dsRNA-dependent protein kinase R (PKR) is a ubiquitously expressed enzyme well known for its roles in immune response. Upon binding to viral dsRNA, PKR undergoes autophosphorylation, and the phosphorylated PKR (pPKR) regulates translation and multiple signaling pathways in infected cells. Here, we found that PKR is activated in uninfected cells, specifically during mitosis, by binding to dsRNAs formed by inverted Alu repeats (IRAlus). While PKR and IRAlu-containing RNAs are segregated in the cytosol and nucleus of interphase cells, respectively, they interact during mitosis when nuclear structure is disrupted. Once phosphorylated, PKR suppresses global translation by phosphorylating the alpha subunit of eukaryotic initiation factor 2 (eIF2 alpha). In addition, pPKR acts as an upstream kinase for c-Jun N-terminal kinase and regulates the levels of multiple mitotic factors such as CYCLINS A and B and POLO-LIKE KINASE 1 and phosphorylation of HISTONE H3. Disruption of PKR activation via RNAi or expression of a transdominant-negative mutant leads to misregulation of the mitotic factors, delay in mitotic progression, and defects in cytokinesis. Our study unveils a novel function of PKR and endogenous dsRNAs as signaling molecules during the mitosis of uninfected cells.
Publisher
COLD SPRING HARBOR LAB PRESS
Issue Date
2014-06
Language
English
Article Type
Article
Citation

GENES & DEVELOPMENT, v.28, no.12, pp.1310 - 1322

ISSN
0890-9369
DOI
10.1101/gad.242644.114
URI
http://hdl.handle.net/10203/211810
Appears in Collection
CBE-Journal Papers(저널논문)MSE-Journal Papers(저널논문)
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