Abstract
Subcellular localization of RNA-binding proteins is a key determinant of their ability to control RNA metabolism and cellular stress response. Using an RNAi-based kinome-wide screen, we identified hexokinase 2 (HK2) as a regulator of the cytoplasmic accumulation of hnRNP A1 in response to hypertonic stress and human rhinovirus infection (HRV). We show that inhibition of HK2 expression or pharmacological inhibition of HK2 activity blocks the cytoplasmic accumulation of heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1), restores expression of B-cell lymphoma-extra large (Bcl-xL), and protects cells against hypertonic stress-induced apoptosis. Reduction of HK2 protein levels by knockdown results in decreased HRV replication, a delay in HRV-induced cell death, and a reduced number of infected cells, all of which can be rescued by forced expression of a cytoplasm-restricted hnRNP A1. Our data elucidate a novel role for HK2 in cellular stress response and viral infection that could be exploited for therapeutic intervention.
Highlights
Heterogeneous nuclear ribonucleoprotein A1 is a highly conserved RNA-binding proteins (RBPs) that plays diverse roles in RNA metabolism, including telomere repair, alternative mRNA splicing, mRNA export, stress granule formation, miRNA processing, and selective mRNA translation.[5]
HnRNP A1 normally shuttles between the nucleus and the cytoplasm, with the bulk of the protein displaying nuclear localization.[7]
Several reports implicated a role for p38 mitogen-activated protein kinase (MAPK) signaling pathway in the control of hnRNP A1 localization in response to hypertonic stress, the systematic interrogation of signaling pathways has never been conducted
Summary
Heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) is a highly conserved RBP that plays diverse roles in RNA metabolism, including telomere repair, alternative mRNA splicing, mRNA export, stress granule formation, miRNA processing, and selective mRNA translation.[5]. We further characterized one such kinase, hexokinase 2 (HK2), and showed that inhibition of HK2 expression or activity blocks the cytoplasmic accumulation of hnRNP A1, restores expression of Bcl-xL, and protects cells against hypertonic stress-induced apoptosis. Transient transfection of cells with the cytoplasm-restricted hnRNP A1, but not the nucleus-restricted variant of hnRNP A1, restores HRV infection in cells with reduced levels of HK2. These data elucidate a novel role for HK2 in rhinovirus infection that could be exploited for antiviral intervention
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