RNA传感器蛋白催化酶PKR研究新进展
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摘要
PKR(Protein Kinase Double-Stranded RNA-Dependent)是丝氨酸-苏氨酸催化酶,细胞浆中重要的RNA传感器(RNA sensor),能自身磷酸化,也可使真核细胞初始化因子2亚单位(subunit of eukaryotic initiation factor 2,e IF-2α)磷酸化。PKR结合病毒dsRNA通过激活PKR/e IF-2α信号通路,抑制病毒基因的翻译,降低病毒蛋白合成,有效减少病毒复制。PKR还可通过激活IκB(inhibitor of NF-κB)/转导核因子(NF-κB,nuclear factorκB)信号通路抑制病毒的转录。PKR与肿瘤的发生具有相关性,能作为治疗癌症的靶点。本文主要综述PKR的分子生物学性质、PKR分子的活化、PKR对IFN转录和转录后的调节、PKR的信号转导、PKR对非病毒病原体感染的调节、PKR对肿瘤细胞的调节等方面的最新进展。
PKR( Protein Kinase Double-Stranded RNA-Dependent) is a serine / threonine catalytic enzyme,an important RNA sensor in cell plasm,that could auto-phosphorylate,also could phosphorylate α-subunit of eukaryotic cells initialization factor 2α( e IF2α). PKR binding viral dsRNA inhibits translation of viral gene through stimulating signal path to decrease viral protein synthesis,and effectively to reduce viral replication. In addition,PKR could also inhibit viral transcription through stimulating IκB( inhibitor of NF-κB) / NF-κB( nuclear factor κB) signal pathway.PKR has reciprocity with genesis of tumor and can be used as a target of cancer therapy. In this paper,we mainly review recent progress on the molecular biology character,the activation,the regulating to IFN 's transcription and translation,the signaling pathway,the protection against non-viral pathogen infection and the modulating tumor cells of PKR,and preview the perspectives of PKR studying.
PKR( Protein Kinase Double-Stranded RNA-Dependent) is a serine / threonine catalytic enzyme,an important RNA sensor in cell plasm,that could auto-phosphorylate,also could phosphorylate α-subunit of eukaryotic cells initialization factor 2α( e IF2α). PKR binding viral dsRNA inhibits translation of viral gene through stimulating signal path to decrease viral protein synthesis,and effectively to reduce viral replication. In addition,PKR could also inhibit viral transcription through stimulating IκB( inhibitor of NF-κB) / NF-κB( nuclear factor κB) signal pathway.PKR has reciprocity with genesis of tumor and can be used as a target of cancer therapy. In this paper,we mainly review recent progress on the molecular biology character,the activation,the regulating to IFN 's transcription and translation,the signaling pathway,the protection against non-viral pathogen infection and the modulating tumor cells of PKR,and preview the perspectives of PKR studying.
引文
[1]Hull CM,Bevilacqua PC.Mechanistic Analysis of Activation of the Innate Immune Sensor PKR by Bacterial RNA[J].J Mol Biol,2015,427(22):3501-3515.
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[6]Munir M,Berg M.The multiple faces of proteinkinase R in antiviral defense[J].Virulence,2013,4(1):85-89.
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[8]wasaki A,Pillai PS.Innate immunity to influenza virus infection[J].Nat Rev Immunol,2014,14(5):315-328.
[9]Yoo JS,Takahasi K,Ng CS,et al.DHX36 enhances RIG-I signaling by facilitating PKR-mediated antiviral stress granule formation[J].PLo S Pathog,2014,10(3):e1004012.
[10]Li Y,Xie J,Wu S,et al.Protein kinase regulated by dsRNA downregulates the interferon production in dengue virus-and dsRNA-stimulated human lung epithelial cells[J].PLo S One,2013,8(1):e55108.
[11]Zhang S,Sun Y,Chen H,et al.Activation of the PKR/e IF2αsignaling cascade inhibits replication of Newcastle disease virus[J].Virol J,2014,11:62.
[12]Cheung BK,Lee DC,Li JC,et al.A role for double-stranded RNA-activated protein kinase PKR in Mycobacterium-induced cytokine expression[J].J Immunol,2005,175(11):7218-7225.
[13]He Y,Franchi L,Nú珘nez G.The protein kinase PKR is critical for LPS-induced i NOS production but dispensable for inflammasome activation in macrophages[J].Eur J Immunol,2013,43(5):1147-1152.
[14]Yim HC,Williams BR.Protein kinase R and the inflammasome[J].J Interferon Cytokine Res,2014,34(6):447-454.
[15]Pereira RM,Teixeira KL,Barreto-de-Souza V,et al.Novel role for the double-stranded RNA-activated protein kinase PKR:modulation of macrophage infection by the protozoan parasite Leishmania[J].FASEB J,2010,24(2):617-626.
[16]Cheng X,Bennett RL,Liu X,et al.PKR negatively regulates leukemia progression in association with PP2A activation,Bcl-2inhibition and increased apoptosis[J].Blood Cancer J,2013,3:e144.
[17]Sanghvi VR,Steel LF.The cellular TAR RNA binding protein,TRBP,promotes HIV-1 replication primarily by inhibiting the activation of double-stranded RNA-dependent kinase PKR[J].J Virol,2011,85(23):12614-12621.
[18]Guo C,Hao C,Shao R,et al.RNA-dependent protein kinase(PKR)depletes nutrients,inducing phosphorylation of AMPactivated kinase in lung cancer[J].Oncotarget,2015,6(13):11114-11124.
[19]Roh MS,Kwak JY,Kim SJ,et al.Expression of double-stranded RNA-activated protein kinase in small-size peripheral adenocarcinoma of the lung[J].Pathol Int,2005,55(11):688-693.
[20]Kwon HC1,Moon CH,Kim SH,et al.Expression of doublestranded RNA-activated protein kinase(PKR)and its prognostic significance in lymph node negative rectal cancer[J].Jpn J Clin Oncol,2005,35(9):545-550.
[21]Agios to Present Clinical and Preclinical Data from PKR Activators AG-348 and AG-519 at the 21st Congress of the European Hematology Association[EB/OL].http://globenewswire.com/news-release/2016/05/19/841550/0/en,2016-06-09/2016-06-12.
[2]García MA,Gil J,Ventoso I,et al.Impact of protein kinase PKR in cell biology:from antiviral to antiproliferative action[J].Microbiol Mol Biol Rev,2006,70(4):1032-1060.
[3]Jha HC,Banerjee S,Robertson ES.The Role of Gammaherpesviruses in Cancer Pathogenesis[J].Pathogens,2016,5(1).pathogens5010018.
[4]Vivarini Ade C,Pereira Rde M,Teixeira KL,et al.Human cutaneous leishmaniasis:interferon-dependent expression of double-stranded RNA-dependent protein kinase(PKR)via TLR2[J].FASEB J,2011,25(12):4162-4173.
[5]Ogolla PS,Portillo JA,White CL,et al.The protein kinase double-stranded RNA-dependent(PKR)enhances protection against disease cause by a non-viral pathogen[J].PLo S Pathog,2013,9(8):e1003557.
[6]Munir M,Berg M.The multiple faces of proteinkinase R in antiviral defense[J].Virulence,2013,4(1):85-89.
[7]Wu KK,Koo J,Jiang X,et al.Improved control of tuberculosis and activation of macrophages in mice lacking protein kinase R[J].PLo S One,2012,7:e30512.
[8]wasaki A,Pillai PS.Innate immunity to influenza virus infection[J].Nat Rev Immunol,2014,14(5):315-328.
[9]Yoo JS,Takahasi K,Ng CS,et al.DHX36 enhances RIG-I signaling by facilitating PKR-mediated antiviral stress granule formation[J].PLo S Pathog,2014,10(3):e1004012.
[10]Li Y,Xie J,Wu S,et al.Protein kinase regulated by dsRNA downregulates the interferon production in dengue virus-and dsRNA-stimulated human lung epithelial cells[J].PLo S One,2013,8(1):e55108.
[11]Zhang S,Sun Y,Chen H,et al.Activation of the PKR/e IF2αsignaling cascade inhibits replication of Newcastle disease virus[J].Virol J,2014,11:62.
[12]Cheung BK,Lee DC,Li JC,et al.A role for double-stranded RNA-activated protein kinase PKR in Mycobacterium-induced cytokine expression[J].J Immunol,2005,175(11):7218-7225.
[13]He Y,Franchi L,Nú珘nez G.The protein kinase PKR is critical for LPS-induced i NOS production but dispensable for inflammasome activation in macrophages[J].Eur J Immunol,2013,43(5):1147-1152.
[14]Yim HC,Williams BR.Protein kinase R and the inflammasome[J].J Interferon Cytokine Res,2014,34(6):447-454.
[15]Pereira RM,Teixeira KL,Barreto-de-Souza V,et al.Novel role for the double-stranded RNA-activated protein kinase PKR:modulation of macrophage infection by the protozoan parasite Leishmania[J].FASEB J,2010,24(2):617-626.
[16]Cheng X,Bennett RL,Liu X,et al.PKR negatively regulates leukemia progression in association with PP2A activation,Bcl-2inhibition and increased apoptosis[J].Blood Cancer J,2013,3:e144.
[17]Sanghvi VR,Steel LF.The cellular TAR RNA binding protein,TRBP,promotes HIV-1 replication primarily by inhibiting the activation of double-stranded RNA-dependent kinase PKR[J].J Virol,2011,85(23):12614-12621.
[18]Guo C,Hao C,Shao R,et al.RNA-dependent protein kinase(PKR)depletes nutrients,inducing phosphorylation of AMPactivated kinase in lung cancer[J].Oncotarget,2015,6(13):11114-11124.
[19]Roh MS,Kwak JY,Kim SJ,et al.Expression of double-stranded RNA-activated protein kinase in small-size peripheral adenocarcinoma of the lung[J].Pathol Int,2005,55(11):688-693.
[20]Kwon HC1,Moon CH,Kim SH,et al.Expression of doublestranded RNA-activated protein kinase(PKR)and its prognostic significance in lymph node negative rectal cancer[J].Jpn J Clin Oncol,2005,35(9):545-550.
[21]Agios to Present Clinical and Preclinical Data from PKR Activators AG-348 and AG-519 at the 21st Congress of the European Hematology Association[EB/OL].http://globenewswire.com/news-release/2016/05/19/841550/0/en,2016-06-09/2016-06-12.
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