核糖核酸酶5在宿主防御中的作用及机制
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摘要
抗菌肽是机体天然免疫的重要组成部分。核糖核酸酶5 (ribonuclease5,RNASE5;又名angiogenin)属于核糖核酸酶A超家族,是一个分泌型小分子蛋白质,广泛分布于机体需要抵御外界病原微生物的组织中。RNASE5对病毒、细菌以及真菌都存在抑制效应,具有广谱抗菌特点,但其表达和活性受到宿主生理状态和外界环境多层次的调控。RNASE5存在多样的抗微生物作用机制,其带正电荷的理化特性破坏微生物细胞壁,而其核糖核酸酶活性则是杀伤真菌所必须的。除了直接作用于微生物外,RNASE5还可作为重要因子调节宿主免疫功能,参与多种病理过程。本文综述了RANSE5的结构、生物活性与功能、作用特点与机制,并讨论了在其研究中存在的问题,以期为今后的研究提供新思路和新方向。
Antimicrobial peptides are key components of the innate immune system. Ribonuclease 5( RNASE5,also named as angiogenin),the fifth member of the ribonuclease A superfamily,is a secreted small protein and widely distributed in the tissues that resist pathogenic microorganisms. As a multifunctional antimicrobial peptide,RNASE5 exhibits broad-spectrum antimicrobial activity,including growth inhibition of viruses,bacteria and fungi. However,its expression and activity are regulated by the physiological states of host and the external environment at multiple levels. Mechanistically,RNASE5 mainly plays its antimicrobial role through its positively charged physicochemical properties and ribonuclease activity. Besides killing microorganisms directly,RNASE5 also regulates host defense and immune functions in a variety of pathological processes. Here,we systematically review the structure and biological activity of RNASE5 in host defense,as well as discuss the existing problems and future directions for further research.
Antimicrobial peptides are key components of the innate immune system. Ribonuclease 5( RNASE5,also named as angiogenin),the fifth member of the ribonuclease A superfamily,is a secreted small protein and widely distributed in the tissues that resist pathogenic microorganisms. As a multifunctional antimicrobial peptide,RNASE5 exhibits broad-spectrum antimicrobial activity,including growth inhibition of viruses,bacteria and fungi. However,its expression and activity are regulated by the physiological states of host and the external environment at multiple levels. Mechanistically,RNASE5 mainly plays its antimicrobial role through its positively charged physicochemical properties and ribonuclease activity. Besides killing microorganisms directly,RNASE5 also regulates host defense and immune functions in a variety of pathological processes. Here,we systematically review the structure and biological activity of RNASE5 in host defense,as well as discuss the existing problems and future directions for further research.
引文
[1]Sender R,Fuchs S,Milo R.Are we really vastly outnumbered?revisiting the ratio of bacterial to host cells in humans[J].Cell,2016,164(3):337-340
[2]Gallo RL,Hooper LV.Epithelial antimicrobial defence of the skin and intestine[J].Nat Rev Immunol,2012,12(7):503-516
[3]Mukherjee S,Hooper LV.Antimicrobial defense of the intestine[J].Immunity,2015,42(1):28-39
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[5]Wang G.Human antimicrobial peptides and proteins[J].Pharmaceuticals(Basel),2014,7(5):545-594
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[10]Koczera P,Martin L,Marx G,et al.The Ribonuclease ASuperfamily in Humans:Canonical RNases as the Buttress of Innate Immunity[J].Int J Mol Sci,2016,17(8):pii:E1278
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[20]Ionova II,Komolova GS,Shalygina AM,et al.Angiogenin content in human milk in the early period of lactation[J].Vopr Pitan,2001,70(1):7-9
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[23]Kim WS,Wee SW,Lee SH,et al.Angiogenin for the Diagnosis and Grading of Dry Eye Syndrome[J].Korean J Ophthalmol,2016,30(3):163-171
[24]Eissa S,Swellam M,Labib RA,et al.A panel of angiogenic factors for early bladder cancer detection:enzyme immunoassay and Western blot[J].J Urol,2009,181(3):1353-1360
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[26]Fagerberg L,Hallstrom BM,Oksvold P,et al.Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics[J].Mol Cell Proteomics,2014,13(2):397-406
[27]Hooper LV,Stappenbeck TS,Hong CV,et al.Angiogenins:a new class of microbicidal proteins involved in innate immunity[J].Nat Immunol,2003,4(3):269-273
[28]Walker CR,Hautefort I,Dalton JE,et al.Intestinal intraepithelial lymphocyte-enterocyte crosstalk regulates production of bactericidal angiogenin 4 by Paneth cells upon microbial challenge[J].PLoS One,2013,8(12):e84553
[29]Bedoya VI,Boasso A,Hardy AW,et al.Ribonucleases in HIVtype 1 inhibition:effect of recombinant RNases on infection of primary T cells and immune activation-induced RNase gene and protein expression[J].AIDS Res Hum Retroviruses,2006,22(9):897-907
[30]Avdeeva SV,Chernukha MU,Shaginyan IA,et al.Human angiogenin lacks specific antimicrobial activity[J].Curr Microbiol,2006,53(6):477-478
[31]Bahar AA,Ren D.Antimicrobial peptides[J].Pharmaceuticals(Basel),2013,6(12):1543-1575
[32]Harris F,Dennison SR,Phoenix DA.Anionic antimicrobial peptides from eukaryotic organisms[J].Curr Protein Pept Sci,2009,10(6):585-606
[33]Bohling A,Hagge SO,Roes S,et al.Lipid-specific membrane activity of human beta-defensin-3[J].Biochemistry,2006,45(17):5663-5670
[34]Lehotzky RE,Partch CL,Mukherjee S,et al.Molecular basis for peptidoglycan recognition by a bactericidal lectin[J].Proc Natl Acad Sci U S A,2010,107(17):7722-7727
[35]Oren Z,Lerman JC,Gudmundsson GH,et al.Structure and organization of the human antimicrobial peptide LL-37 in phospholipid membranes:relevance to the molecular basis for its non-cell-selective activity[J].Biochem J,1999,341(Pt 3):501-513
[36]Miller KW,Evans RJ,Eisenberg SP,et al.Secretory leukocyte protease inhibitor binding to mRNA and DNA as a possible cause of toxicity to Escherichia coli[J].J Bacteriol,1989,171(4):2166-2172
[37]den Hertog AL,van Marle J,van Veen HA,et al.Candidacidal effects of two antimicrobial peptides:histatin 5 causes small membrane defects,but LL-37 causes massive disruption of the cell membrane[J].Biochem J,2005,388(Pt 2):689-695
[38]Levy M,Thaiss CA,Zeevi D,et al.Microbiota-Modulated Metabolites Shape the Intestinal Microenvironment by Regulating NLRP6 Inflammasome Signaling[J].Cell,2015,163(6):1428-1443
[39]Kulka M,Fukuishi N,Metcalfe DD.Human mast cells synthesize and release angiogenin,a member of the ribonuclease A(RNase A)superfamily[J].J Leukocyte Biol,2009,86(5):1217-1226
[40]Pizzo E,Sarcinelli C,Sheng J,et al.Ribonuclease/angiogenin inhibitor 1 regulates stress-induced subcellular localization of angiogenin to control growth and survival[J].J Cell Sci,2013,126(Pt 18):4308-4319
[41]Haigis MC,Kurten EL,Raines RT.Ribonuclease inhibitor as an intracellular sentry[J].Nucleic Acids Res,2003,31(3):1024-1032
[42]Thomas SP,Hoang TT,Ressler VT,et al.Human angiogenin is a potent cytotoxin in the absence of ribonuclease inhibitor[J].RNA,2018,24(8):1018-1027
[43]Bals R,Wang X,Wu Z,et al.Human beta-defensin 2 is a saltsensitive peptide antibiotic expressed in human lung[J].J Clin Invest,1998,102(5):874-880
[44]Murata M,Wakabayashi H,Yamauchi K,et al.Identification of milk proteins enhancing the antimicrobial activity of lactoferrin and lactoferricin[J].J Dairy Sci,2013,96(8):4891-4898
[45]Mangoni ML,Mc Dermott AM,Zasloff M.Antimicrobial peptides and wound healing:biological and therapeutic considerations[J].Exp Dermatol,2016,25(3):167-173
[46]Hancock RE,Sahl HG.Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies[J].Nat Biotechnol,2006,24(12):1551-1557
[47]Tschesche H,Kopp C,Horl WH,et al.Inhibition of degranulation of polymorphonuclear leukocytes by angiogenin and its tryptic fragment[J].J Biol Chem,1994,269(48):30274-30280
[48]Schmaldienst S,Oberpichler A,Tschesche H,et al.Angiogenin:a novel inhibitor of neutrophil lactoferrin release during extracorporeal circulation[J].Kidney Blood Press Res,2003,26(2):107-112
[49]Lee SH,Kim KW,Joo K,et al.Angiogenin ameliorates corneal opacity and neovascularization via regulating immune response in corneal fibroblasts[J].BMC Ophthalmol,2016,16:57.doi:10.1186/s12886-016-0235-z
[50]Koutroubakis IE,Xidakis C,Karmiris K,et al.Serum angiogenin in inflammatory bowel disease[J].Dig Dis Sci,2004,49(11-12):1758-1762
[51]Kanwar JR,Kanwar RK,Stathopoulos S,et al.Comparative activities of milk components in reversing chronic colitis[J].JDairy Sci,2016,99(4):2488-2501
[52]Spear GT,Kendrick SR,Chen HY,et al.Multiplex immunoassay of lower genital tract mucosal fluid from women attending an urban STD clinic shows broadly increased IL1βand lactoferrin[J].PLoS One,2011,6(5):e19560
[2]Gallo RL,Hooper LV.Epithelial antimicrobial defence of the skin and intestine[J].Nat Rev Immunol,2012,12(7):503-516
[3]Mukherjee S,Hooper LV.Antimicrobial defense of the intestine[J].Immunity,2015,42(1):28-39
[4]Mukherjee S,Vaishnava S,Hooper LV.Multi-layered regulation of intestinal antimicrobial defense[J].Cell Mol Life Sci,2008,65(19):3019-3027
[5]Wang G.Human antimicrobial peptides and proteins[J].Pharmaceuticals(Basel),2014,7(5):545-594
[6]Fett JW,Strydom DJ,Lobb RR,et al.Isolation and characterization of angiogenin,an angiogenic protein from human carcinoma cells[J].Biochemistry,1985,24(20):5480-5486
[7]Gao X,Xu Z.Mechanisms of action of angiogenin[J].Acta Biochim Biophys Sin(Shanghai),2008,40(7):619-624
[8]Sheng J,Xu Z.Three decades of research on angiogenin:a review and perspective[J].Acta Biochim Biophys Sin(Shanghai),2016,48(5):399-410
[9]Pizzo E,Merlino A,Turano M,et al.A new RNase sheds light on the RNase/angiogenin subfamily from zebrafish[J].Biochem J,2011,433(2):345-355
[10]Koczera P,Martin L,Marx G,et al.The Ribonuclease ASuperfamily in Humans:Canonical RNases as the Buttress of Innate Immunity[J].Int J Mol Sci,2016,17(8):pii:E1278
[11]Cho S,Beintema JJ,Zhang J.The ribonuclease A superfamily of mammals and birds:identifying new members and tracing evolutionary histories[J].Genomics,2005,85(2):208-220
[12]Rosenberg HF,Dyer KD.Human ribonuclease 4(RNase 4):coding sequence,chromosomal localization and identification of two distinct transcripts in human somatic tissues[J].Nucleic Acids Res,1995,23(21):4290-4295
[13]Dyer KD,Rosenberg HF.The mouse RNase 4 and RNase 5/ang1 locus utilizes dual promoters for tissue-specific expression[J].Nucleic Acids Res,2005,33(3):1077-1086
[14]Sheng J,Luo C,Jiang Y,et al.Transcription of angiogenin and ribonuclease 4 is regulated by RNA polymerase III elements and a CCCTC binding factor(CTCF)-dependent intragenic chromatin loop[J].J Biol Chem,2014,289(18):12520-12534
[15]Hoang TT,Raines RT.Molecular basis for the autonomous promotion of cell proliferation by angiogenin[J].Nucleic Acids Res,2017,45(2):818-831
[16]Harper JW,Vallee BL.A covalent angiogenin/ribonuclease hybrid with a fourth disulfide bond generated by regional mutagenesis[J].Biochemistry,1989,28(4):1875-1884
[17]Lee FS,Vallee BL.Characterization of ribonucleolytic activity of angiogenin towards tRNA[J].Biochem Biophys Res Commun,1989,161(1):121-126
[18]Leland PA,Staniszewski KE,Park C,et al.The ribonucleolytic activity of angiogenin[J].Biochemistry,2002,41(4):1343-1350
[19]Abtin A,Eckhart L,Mildner M,et al.Degradation by stratum corneum proteases prevents endogenous RNase inhibitor from blocking antimicrobial activities of RNase 5 and RNase 7[J].JInvest Dermatol,2009,129(9):2193-2201
[20]Ionova II,Komolova GS,Shalygina AM,et al.Angiogenin content in human milk in the early period of lactation[J].Vopr Pitan,2001,70(1):7-9
[21]Harris P,Johannessen KM,Smolenski G,et al.Characterisation of the anti-microbial activity of bovine milk ribonuclease 4 and ribonuclease 5(angiogenin)[J].Int Dairy J,2010,20(6):400-407
[22]Komolova GS,Fedorova TV.[Milk angiogenin(Review)][J].Prikl Biokhim Mikrobiol,2002,38(3):229-236
[23]Kim WS,Wee SW,Lee SH,et al.Angiogenin for the Diagnosis and Grading of Dry Eye Syndrome[J].Korean J Ophthalmol,2016,30(3):163-171
[24]Eissa S,Swellam M,Labib RA,et al.A panel of angiogenic factors for early bladder cancer detection:enzyme immunoassay and Western blot[J].J Urol,2009,181(3):1353-1360
[25]Yu D,Cai Y,Zhou W,et al.The Potential of Angiogenin as a Serum Biomarker for Diseases:Systematic Review and MetaAnalysis[J].Dis Markers,2018,2018:1984718
[26]Fagerberg L,Hallstrom BM,Oksvold P,et al.Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics[J].Mol Cell Proteomics,2014,13(2):397-406
[27]Hooper LV,Stappenbeck TS,Hong CV,et al.Angiogenins:a new class of microbicidal proteins involved in innate immunity[J].Nat Immunol,2003,4(3):269-273
[28]Walker CR,Hautefort I,Dalton JE,et al.Intestinal intraepithelial lymphocyte-enterocyte crosstalk regulates production of bactericidal angiogenin 4 by Paneth cells upon microbial challenge[J].PLoS One,2013,8(12):e84553
[29]Bedoya VI,Boasso A,Hardy AW,et al.Ribonucleases in HIVtype 1 inhibition:effect of recombinant RNases on infection of primary T cells and immune activation-induced RNase gene and protein expression[J].AIDS Res Hum Retroviruses,2006,22(9):897-907
[30]Avdeeva SV,Chernukha MU,Shaginyan IA,et al.Human angiogenin lacks specific antimicrobial activity[J].Curr Microbiol,2006,53(6):477-478
[31]Bahar AA,Ren D.Antimicrobial peptides[J].Pharmaceuticals(Basel),2013,6(12):1543-1575
[32]Harris F,Dennison SR,Phoenix DA.Anionic antimicrobial peptides from eukaryotic organisms[J].Curr Protein Pept Sci,2009,10(6):585-606
[33]Bohling A,Hagge SO,Roes S,et al.Lipid-specific membrane activity of human beta-defensin-3[J].Biochemistry,2006,45(17):5663-5670
[34]Lehotzky RE,Partch CL,Mukherjee S,et al.Molecular basis for peptidoglycan recognition by a bactericidal lectin[J].Proc Natl Acad Sci U S A,2010,107(17):7722-7727
[35]Oren Z,Lerman JC,Gudmundsson GH,et al.Structure and organization of the human antimicrobial peptide LL-37 in phospholipid membranes:relevance to the molecular basis for its non-cell-selective activity[J].Biochem J,1999,341(Pt 3):501-513
[36]Miller KW,Evans RJ,Eisenberg SP,et al.Secretory leukocyte protease inhibitor binding to mRNA and DNA as a possible cause of toxicity to Escherichia coli[J].J Bacteriol,1989,171(4):2166-2172
[37]den Hertog AL,van Marle J,van Veen HA,et al.Candidacidal effects of two antimicrobial peptides:histatin 5 causes small membrane defects,but LL-37 causes massive disruption of the cell membrane[J].Biochem J,2005,388(Pt 2):689-695
[38]Levy M,Thaiss CA,Zeevi D,et al.Microbiota-Modulated Metabolites Shape the Intestinal Microenvironment by Regulating NLRP6 Inflammasome Signaling[J].Cell,2015,163(6):1428-1443
[39]Kulka M,Fukuishi N,Metcalfe DD.Human mast cells synthesize and release angiogenin,a member of the ribonuclease A(RNase A)superfamily[J].J Leukocyte Biol,2009,86(5):1217-1226
[40]Pizzo E,Sarcinelli C,Sheng J,et al.Ribonuclease/angiogenin inhibitor 1 regulates stress-induced subcellular localization of angiogenin to control growth and survival[J].J Cell Sci,2013,126(Pt 18):4308-4319
[41]Haigis MC,Kurten EL,Raines RT.Ribonuclease inhibitor as an intracellular sentry[J].Nucleic Acids Res,2003,31(3):1024-1032
[42]Thomas SP,Hoang TT,Ressler VT,et al.Human angiogenin is a potent cytotoxin in the absence of ribonuclease inhibitor[J].RNA,2018,24(8):1018-1027
[43]Bals R,Wang X,Wu Z,et al.Human beta-defensin 2 is a saltsensitive peptide antibiotic expressed in human lung[J].J Clin Invest,1998,102(5):874-880
[44]Murata M,Wakabayashi H,Yamauchi K,et al.Identification of milk proteins enhancing the antimicrobial activity of lactoferrin and lactoferricin[J].J Dairy Sci,2013,96(8):4891-4898
[45]Mangoni ML,Mc Dermott AM,Zasloff M.Antimicrobial peptides and wound healing:biological and therapeutic considerations[J].Exp Dermatol,2016,25(3):167-173
[46]Hancock RE,Sahl HG.Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies[J].Nat Biotechnol,2006,24(12):1551-1557
[47]Tschesche H,Kopp C,Horl WH,et al.Inhibition of degranulation of polymorphonuclear leukocytes by angiogenin and its tryptic fragment[J].J Biol Chem,1994,269(48):30274-30280
[48]Schmaldienst S,Oberpichler A,Tschesche H,et al.Angiogenin:a novel inhibitor of neutrophil lactoferrin release during extracorporeal circulation[J].Kidney Blood Press Res,2003,26(2):107-112
[49]Lee SH,Kim KW,Joo K,et al.Angiogenin ameliorates corneal opacity and neovascularization via regulating immune response in corneal fibroblasts[J].BMC Ophthalmol,2016,16:57.doi:10.1186/s12886-016-0235-z
[50]Koutroubakis IE,Xidakis C,Karmiris K,et al.Serum angiogenin in inflammatory bowel disease[J].Dig Dis Sci,2004,49(11-12):1758-1762
[51]Kanwar JR,Kanwar RK,Stathopoulos S,et al.Comparative activities of milk components in reversing chronic colitis[J].JDairy Sci,2016,99(4):2488-2501
[52]Spear GT,Kendrick SR,Chen HY,et al.Multiplex immunoassay of lower genital tract mucosal fluid from women attending an urban STD clinic shows broadly increased IL1βand lactoferrin[J].PLoS One,2011,6(5):e19560