Courteau L, Crasto J, Hassanzadeh G, Baird S D, Hodgins J, Liwak-Muir U, Fung G, Luo H, Stojdl D F, Screaton R A, Holcik M
1] Molecular Biomedicine Program, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, Ontario K1H 8L1, Canada [2] Department of Biochemistry, Microbiology and Immunology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario K1H 8M5, Canada.
Molecular Biomedicine Program, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, Ontario K1H 8L1, Canada.
Cell Death Dis. 2015 Aug 6;6(8):e1837. doi: 10.1038/cddis.2015.209.
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.
RNA结合蛋白的亚细胞定位是其控制RNA代谢和细胞应激反应能力的关键决定因素。通过基于RNA干扰的全激酶组筛选，我们鉴定出己糖激酶2（HK2）是响应高渗应激和人鼻病毒感染（HRV）时hnRNP A1细胞质积累的调节因子。我们表明，抑制HK2表达或对HK2活性进行药理学抑制可阻断异质性核糖核蛋白A1（hnRNP A1）的细胞质积累，恢复B细胞淋巴瘤-特大（Bcl-xL）的表达，并保护细胞免受高渗应激诱导的凋亡。通过敲低降低HK2蛋白水平会导致HRV复制减少、HRV诱导的细胞死亡延迟以及感染细胞数量减少，所有这些都可以通过强制表达细胞质受限的hnRNP A1来挽救。我们的数据阐明了HK2在细胞应激反应和病毒感染中的新作用，这可能被用于治疗干预。
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