六磷酸肌醇激酶(IP6Ks)的生物学功能及其在疾病中的作用
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摘要
可溶性和脂质状态的磷酸肌醇在真核细胞中广泛存在,它们在细胞的发育和生物学功能中起到重要作用。其中,六磷酸肌醇激酶(inositol hexaphosphate kinases,IP6Ks)是焦磷酸肌醇合成的限速酶,它可以在肌醇环第一位、第三位或第五位已有的磷酸基团上再加一个磷酸基团合成焦磷酸肌醇,例如5-焦磷酸–五磷酸肌醇(5-pyrophosphate inositol pentaphosphate,IP_7、PP-IP_5)和1,3-二焦磷酸肌醇–四磷酸(bis-diphosphoinositol tetrakisphosphate,IP_8、[PP]_2-IP_4)。IP6Ks通过以上过程在DNA修复、染色体重组、细胞死亡、凝血作用、造血调控、免疫调控、癌症进展等方面发挥作用,因而受到越来越多的重视。该文基于近期IP6Ks的相关研究进展,就IP6Ks在细胞功能调控以及疾病治疗中的作用作一综述。
Both soluble and lipid states of inositol phosphates exist extensively in eukaryotic cells and play important roles in cell development and biological processes. Among them, inositol hexaphosphate kinases(IP6Ks), the key rate-limiting enzymes in the synthesis of inositol pyrophosphates, can biologically add a phosphate group in the first/third/fifth site of inositol ring to synthesize inositol pyrophosphate, such as 5-pyrophosphate inositol pentaphosphate(IP_7, PP-IP_5) and bis-diphosphoinositol tetrakisphosphate(IP_8, [PP]_2-IP_4). As to function, IP6Ks can pose effect on DNA repairing, chromosome recombination, cell death, coagulation, hematopoietic regulation, immunoregulation, cancer progression, etc. Therefore, more and more attention have been taken into the diverse roles of IP6Ks. Based on the previous experimental studies, the functions of IP6Ks in cellular processes are reviewed in this paper.
Both soluble and lipid states of inositol phosphates exist extensively in eukaryotic cells and play important roles in cell development and biological processes. Among them, inositol hexaphosphate kinases(IP6Ks), the key rate-limiting enzymes in the synthesis of inositol pyrophosphates, can biologically add a phosphate group in the first/third/fifth site of inositol ring to synthesize inositol pyrophosphate, such as 5-pyrophosphate inositol pentaphosphate(IP_7, PP-IP_5) and bis-diphosphoinositol tetrakisphosphate(IP_8, [PP]_2-IP_4). As to function, IP6Ks can pose effect on DNA repairing, chromosome recombination, cell death, coagulation, hematopoietic regulation, immunoregulation, cancer progression, etc. Therefore, more and more attention have been taken into the diverse roles of IP6Ks. Based on the previous experimental studies, the functions of IP6Ks in cellular processes are reviewed in this paper.
引文
1 Saiardi A,Nagata E,Luo HR,Snowman AM,Snyder SH.Identification and characterization of a novel inositol hexakisphosphate kinase.J Biol Chem 2001;276(42):39179-85.
2 Wang H,De Rose EF,London RE,Shears SB.Ip6k structure and the molecular determinants of catalytic specificity in an inositol phosphate kinase family.Nat Commun 2014;5:4178.
3 Bhandari R,Juluri KR,Resnick AC,Snyder SH.Gene deletion of inositol hexakisphosphate kinase-1 reveals inositol pyrophosphate regulation of insulin secretion,growth,and spermiogenesis.Proc Natl Acad Sci USA 2008;105(7):2349-53.
4 Fu C,Xu J,Li RJ,Crawford JA,Khan AB,Snyder SH,et al.Inositol hexakisphosphate kinase-3 regulates the morphology and synapse formation of cerebellar purkinje cells via spectrin/adducin.J Neurosci 2015;35(31):11056-67.
5 Jadav RS,Chanduri MV,Sengupta S,Bhandari R.Inositol pyrophosphate synthesis by inositol hexakisphosphate kinase 1is required for homologous recombination repair.J Biol Chem2013;288(5):3312-21.
6 Burton A,Azevedo C,Andreassi C,Riccio A,Saiardi A.Inositol pyrophosphates regulate JMJD2C-dependent histone demethylation.Proc Natl Acad Sci USA 2013;110(47):18970-5.
7 Scrima A,Fischer ES,Lingaraju GM,Bohm K,Cavadini S,Thoma NH.Detecting UV-lesions in the genome:the modular CRL4 ubiquitin ligase does it best.FEBS Lett 2011;585(18):2818-25.
8 Rao F,Xu J,Khan AB,Gadalla MM,Chakraborty A,Snyder SH,et al.Inositol hexakisphosphate kinase-1 mediates assembly/disassembly of the CRL4-signalosome complex to regulate DNArepair and cell death.Proc Natl Acad Sci USA 2014;111(45):16005-10.
9 Luo HR,Huang YE,Chen JC,Saiardi A,Devreotes P,Snyder SH.Inositol pyrophosphates mediate chemotaxis in Dictyostelium via pleckstrin homology domain-PtdIns(3,4,5)P3interactions.Cell 2003;114(5):559-72.
10 Chakraborty A,Koldobskiy MA,Bello NT,Maxwell M,Potter JJ,Snyder SH,et al.Inositol pyrophosphates inhibit Akt signaling,thereby regulating insulin sensitivity and weight gain.Cell 2010;143(6):897-910.
11 Bhandari R,Juluri KR,Resnick AC,Snyder SH.Gene deletion of inositol hexakisphosphate kinase 1 reveals inositol pyrophosphate regulation of insulin secretion,growth,and spermiogenesis.Proc Natl Acad Sci USA 2008;105(7):2349-53.
12 Prasad A,Jia Y,Chakraborty A,Li Y,Snyder SH,Luo HR,et al.Inositol hexakisphosphate kinase 1 regulates neutrophil function in innate immunity by inhibiting phosphatidylinositol-(3,4,5)-trisphosphate signaling.Nat Immunol 2011;12(8):752-60.
13 Morrissey JH,Choi SH,Smith SA.Polyphosphate:an ancient molecule that links platelets,coagulation,and inflammation.Blood 2012;119(25):5972-9.
14 Müller F,Mutch NJ,Schenk WA,Smith SA,Morrissey JH,RennéT,et al.Platelet polyphosphates are proinflammatory and procoagulant mediators in vivo.Cell 2009;139(6):1143-56.
15 Smith SA,Morrissey JH.Polyphosphate enhances fibrin clot structure.Blood 2008;112(7):2810-6.
16 Semeraro F,Ammollo CT,Morrissey JH,Dale GL,Friese P,Esmon CT,et al.Extracellular histones promote thrombin generation through platelet-dependent mechanisms:involvement of platelet TLR2 and TLR4.Blood 2011;118(7):1952-61.
17 Ghosh S,Shukla D,Suman K,Lakshmi BJ,Manorama R,Bhandari R,et al.Inositol hexakisphosphate kinase 1 maintains hemostasis in mice by regulating platelet polyphosphate levels.Blood 2013;122(8):1478-86.
18 Hill R,Lee PW.The DNA-dependent protein kinase(DNA-PK):More than just a case of making ends meet.Cell Cycle 2010;9(17):3460-9.
19 Vousden KH,Prives C.Blinded by the light:the growing complexity of p53.Cell 2009;137(3):413-31.
20 Rao F,Cha J,Xu J,Xu R,Vandiver MS,Snyder SH,et al.Inositol pyrophosphates mediate the DNA-PK/ATM-p53 cell death pathway by regulating CK2 phosphorylation of Tti1/Tel2.Mol Cell 2014;54(1):119-32.
21 Hill R,Madureira PA,Waisman DM,Lee PW.DNA-PKCSbinding to p53 on the p21WAF1/CIP1 promoter blocks transcription resulting in cell death.Oncotarget 2011;2(12):1094-108.
22 Rao F,Xu J,Fu C,Cha JY,Barrow JC,Snyder SH,et al.Inositol pyrophosphates promote tumor growth and metastasis by antagonizing liver kinase B1.Proc Natl Acad Sci USA 2015;112(6):1773-8.
23 Goodwin JM,Svensson RU,Lou HJ,Winslow MM,Turk BE,Shaw RJ.An AMPK-independent signaling pathway downstream of the LKB1 tumor suppressor controls Snail1 and metastatic potential.Mol Cell 2014;55(3):436-50.
24 Boregowda SV,Ghoshal S,Booker CN,Krishnappa V,Chakraborty A,Phinney DG.IP6K1 reduces mesenchymal stem/stromal cell fitness and potentiates high fat diet-induced skeletal involution.Stem Cells 2017;35(8):1973-83.
25 Markel TA,Wang Y,Herrmann JL,Crisostomo PR,Lahm T,Meldrum DR,et al.VEGF is critical for stem cell-mediated cardioprotection and a crucial paracrine factor for defining the age threshold in adult and neonatal stem cell function.Am JPhysiol Heart Circ Physiol 2008;295(10):H2308-14.
26 Manning BD,Cantley LC.AKT/PKB signaling:navigating downstream.Cell 2007;129(7):1261-74.
27 Zhang Z,Liang D,Gao X,Zhao C,Liu B,Cao F,et al.Selective inhibition of inositol hexakisphosphate kinases(IP6Ks)enhances mesenchymal stem cell engraftment and improves therapeutic efficacy for myocardial infarction.Basic Res Cardiol 2014;109(4):417.
28 Xu Y,Li H,Bajrami B,Kwak H,Cao S,Luo HR,et al.Cigarette smoke(CS)and nicotine delay neutrophil spontaneous death via suppressing production of diphosphoinositol pentakisphosphate.Proc Natl Acad Sci USA 2013;110(19):7726-31.
2 Wang H,De Rose EF,London RE,Shears SB.Ip6k structure and the molecular determinants of catalytic specificity in an inositol phosphate kinase family.Nat Commun 2014;5:4178.
3 Bhandari R,Juluri KR,Resnick AC,Snyder SH.Gene deletion of inositol hexakisphosphate kinase-1 reveals inositol pyrophosphate regulation of insulin secretion,growth,and spermiogenesis.Proc Natl Acad Sci USA 2008;105(7):2349-53.
4 Fu C,Xu J,Li RJ,Crawford JA,Khan AB,Snyder SH,et al.Inositol hexakisphosphate kinase-3 regulates the morphology and synapse formation of cerebellar purkinje cells via spectrin/adducin.J Neurosci 2015;35(31):11056-67.
5 Jadav RS,Chanduri MV,Sengupta S,Bhandari R.Inositol pyrophosphate synthesis by inositol hexakisphosphate kinase 1is required for homologous recombination repair.J Biol Chem2013;288(5):3312-21.
6 Burton A,Azevedo C,Andreassi C,Riccio A,Saiardi A.Inositol pyrophosphates regulate JMJD2C-dependent histone demethylation.Proc Natl Acad Sci USA 2013;110(47):18970-5.
7 Scrima A,Fischer ES,Lingaraju GM,Bohm K,Cavadini S,Thoma NH.Detecting UV-lesions in the genome:the modular CRL4 ubiquitin ligase does it best.FEBS Lett 2011;585(18):2818-25.
8 Rao F,Xu J,Khan AB,Gadalla MM,Chakraborty A,Snyder SH,et al.Inositol hexakisphosphate kinase-1 mediates assembly/disassembly of the CRL4-signalosome complex to regulate DNArepair and cell death.Proc Natl Acad Sci USA 2014;111(45):16005-10.
9 Luo HR,Huang YE,Chen JC,Saiardi A,Devreotes P,Snyder SH.Inositol pyrophosphates mediate chemotaxis in Dictyostelium via pleckstrin homology domain-PtdIns(3,4,5)P3interactions.Cell 2003;114(5):559-72.
10 Chakraborty A,Koldobskiy MA,Bello NT,Maxwell M,Potter JJ,Snyder SH,et al.Inositol pyrophosphates inhibit Akt signaling,thereby regulating insulin sensitivity and weight gain.Cell 2010;143(6):897-910.
11 Bhandari R,Juluri KR,Resnick AC,Snyder SH.Gene deletion of inositol hexakisphosphate kinase 1 reveals inositol pyrophosphate regulation of insulin secretion,growth,and spermiogenesis.Proc Natl Acad Sci USA 2008;105(7):2349-53.
12 Prasad A,Jia Y,Chakraborty A,Li Y,Snyder SH,Luo HR,et al.Inositol hexakisphosphate kinase 1 regulates neutrophil function in innate immunity by inhibiting phosphatidylinositol-(3,4,5)-trisphosphate signaling.Nat Immunol 2011;12(8):752-60.
13 Morrissey JH,Choi SH,Smith SA.Polyphosphate:an ancient molecule that links platelets,coagulation,and inflammation.Blood 2012;119(25):5972-9.
14 Müller F,Mutch NJ,Schenk WA,Smith SA,Morrissey JH,RennéT,et al.Platelet polyphosphates are proinflammatory and procoagulant mediators in vivo.Cell 2009;139(6):1143-56.
15 Smith SA,Morrissey JH.Polyphosphate enhances fibrin clot structure.Blood 2008;112(7):2810-6.
16 Semeraro F,Ammollo CT,Morrissey JH,Dale GL,Friese P,Esmon CT,et al.Extracellular histones promote thrombin generation through platelet-dependent mechanisms:involvement of platelet TLR2 and TLR4.Blood 2011;118(7):1952-61.
17 Ghosh S,Shukla D,Suman K,Lakshmi BJ,Manorama R,Bhandari R,et al.Inositol hexakisphosphate kinase 1 maintains hemostasis in mice by regulating platelet polyphosphate levels.Blood 2013;122(8):1478-86.
18 Hill R,Lee PW.The DNA-dependent protein kinase(DNA-PK):More than just a case of making ends meet.Cell Cycle 2010;9(17):3460-9.
19 Vousden KH,Prives C.Blinded by the light:the growing complexity of p53.Cell 2009;137(3):413-31.
20 Rao F,Cha J,Xu J,Xu R,Vandiver MS,Snyder SH,et al.Inositol pyrophosphates mediate the DNA-PK/ATM-p53 cell death pathway by regulating CK2 phosphorylation of Tti1/Tel2.Mol Cell 2014;54(1):119-32.
21 Hill R,Madureira PA,Waisman DM,Lee PW.DNA-PKCSbinding to p53 on the p21WAF1/CIP1 promoter blocks transcription resulting in cell death.Oncotarget 2011;2(12):1094-108.
22 Rao F,Xu J,Fu C,Cha JY,Barrow JC,Snyder SH,et al.Inositol pyrophosphates promote tumor growth and metastasis by antagonizing liver kinase B1.Proc Natl Acad Sci USA 2015;112(6):1773-8.
23 Goodwin JM,Svensson RU,Lou HJ,Winslow MM,Turk BE,Shaw RJ.An AMPK-independent signaling pathway downstream of the LKB1 tumor suppressor controls Snail1 and metastatic potential.Mol Cell 2014;55(3):436-50.
24 Boregowda SV,Ghoshal S,Booker CN,Krishnappa V,Chakraborty A,Phinney DG.IP6K1 reduces mesenchymal stem/stromal cell fitness and potentiates high fat diet-induced skeletal involution.Stem Cells 2017;35(8):1973-83.
25 Markel TA,Wang Y,Herrmann JL,Crisostomo PR,Lahm T,Meldrum DR,et al.VEGF is critical for stem cell-mediated cardioprotection and a crucial paracrine factor for defining the age threshold in adult and neonatal stem cell function.Am JPhysiol Heart Circ Physiol 2008;295(10):H2308-14.
26 Manning BD,Cantley LC.AKT/PKB signaling:navigating downstream.Cell 2007;129(7):1261-74.
27 Zhang Z,Liang D,Gao X,Zhao C,Liu B,Cao F,et al.Selective inhibition of inositol hexakisphosphate kinases(IP6Ks)enhances mesenchymal stem cell engraftment and improves therapeutic efficacy for myocardial infarction.Basic Res Cardiol 2014;109(4):417.
28 Xu Y,Li H,Bajrami B,Kwak H,Cao S,Luo HR,et al.Cigarette smoke(CS)and nicotine delay neutrophil spontaneous death via suppressing production of diphosphoinositol pentakisphosphate.Proc Natl Acad Sci USA 2013;110(19):7726-31.