#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Regulation of Toll-like Receptor Signaling by the SF3a mRNA Splicing Complex


Within minutes after we are exposed to pathogens, our bodies react with a rapid response known as the “innate immune response.” This arm of the immune response regulates the process of inflammation, in which various immune cells are recruited to sites of infection and are activated to produce a host of antimicrobial compounds. This response is critical to fight infection. However, this response, if it is activated too strongly or if it becomes chronic, can do damage and can contribute to numerous very common diseases ranging from atherosclerosis to asthma to cancer. Thus it is essential that this response be tightly regulated, turned on when we have an infection, and turned off when not needed. We are investigating a mechanism that helps turn off this response, to ensure that inflammation is limited to prevent inflammatory disease. This mechanism involves the production of alternate forms of RNAs and proteins that control inflammation. We have discovered that a protein known as SF3a1 can regulate the expression of these alternate inhibitory RNA forms and are investigating how to use this knowledge to better control inflammation.


Vyšlo v časopise: Regulation of Toll-like Receptor Signaling by the SF3a mRNA Splicing Complex. PLoS Genet 11(2): e32767. doi:10.1371/journal.pgen.1004932
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004932

Souhrn

Within minutes after we are exposed to pathogens, our bodies react with a rapid response known as the “innate immune response.” This arm of the immune response regulates the process of inflammation, in which various immune cells are recruited to sites of infection and are activated to produce a host of antimicrobial compounds. This response is critical to fight infection. However, this response, if it is activated too strongly or if it becomes chronic, can do damage and can contribute to numerous very common diseases ranging from atherosclerosis to asthma to cancer. Thus it is essential that this response be tightly regulated, turned on when we have an infection, and turned off when not needed. We are investigating a mechanism that helps turn off this response, to ensure that inflammation is limited to prevent inflammatory disease. This mechanism involves the production of alternate forms of RNAs and proteins that control inflammation. We have discovered that a protein known as SF3a1 can regulate the expression of these alternate inhibitory RNA forms and are investigating how to use this knowledge to better control inflammation.


Zdroje

1. Chaudhuri N, Dower SK, Whyte MK, Sabroe I (2005) Toll-like receptors and chronic lung disease. Clin Sci (Lond) 109: 125–133. doi: 10.1042/CS20050044 16033327

2. Cook DN, Pisetsky DS, Schwartz DA (2004) Toll-like receptors in the pathogenesis of human disease. Nat Immunol 5: 975–979. doi: 10.1038/ni1116 15454920

3. Grivennikov SI, Greten FR, Karin M (2010) Immunity, inflammation, and cancer. Cell 140: 883–899. doi: 10.1016/j.cell.2010.01.025 20303878

4. Takeda K, Akira S (2005) Toll-like receptors in innate immunity. Int Immunol 17: 1–14. doi: 10.1093/intimm/dxh186 15585605

5. Kawai T, Akira S (2010) The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 11: 373–384. doi: 10.1038/ni.1863 20404851

6. Takeuchi O, Akira S (2010) Pattern recognition receptors and inflammation. Cell 140: 805–820. doi: 10.1016/j.cell.2010.01.022 20303872

7. Ostuni R, Zanoni I, Granucci F (2010) Deciphering the complexity of Toll-like receptor signaling. Cell Mol Life Sci 67: 4109–4134. doi: 10.1007/s00018-010-0464-x 20680392

8. Alam MM, O’Neill LA (2011) MicroRNAs and the resolution phase of inflammation in macrophages. Eur J Immunol 41: 2482–2485. doi: 10.1002/eji.201141740 21952801

9. Kondo T, Kawai T, Akira S (2012) Dissecting negative regulation of Toll-like receptor signaling. Trends Immunol 33: 449–458. doi: 10.1016/j.it.2012.05.002 22721918

10. Lang T, Mansell A (2007) The negative regulation of Toll-like receptor and associated pathways. Immunol Cell Biol 85: 425–434. doi: 10.1038/sj.icb.7100094 17621314

11. Liew FY, Xu D, Brint EK, O’Neill LA (2005) Negative regulation of toll-like receptor-mediated immune responses. Nature Reviews Immunology 5: 446–458. doi: 10.1038/nri1630 15928677

12. Murray PJ, Smale ST (2012) Restraint of inflammatory signaling by interdependent strata of negative regulatory pathways. Nat Immunol 13: 916–924. doi: 10.1038/ni.2391 22990889

13. Sun SC (2008) Deubiquitylation and regulation of the immune response. Nat Rev Immunol 8: 501–511. doi: 10.1038/nri2337 18535581

14. Wang J, Hu Y, Deng WW, Sun B (2009) Negative regulation of Toll-like receptor signaling pathway. Microbes Infect 11: 321–327. doi: 10.1016/j.micinf.2008.12.011 19146978

15. Burns K, Janssens S, Brissoni B, Olivos N, Beyaert R, et al. (2003) Inhibition of interleukin 1 receptor/Toll-like receptor signaling through the alternatively spliced, short form of MyD88 is due to its failure to recruit IRAK-4. Journal of Experimental Medicine 197: 263–268. doi: 10.1084/jem.20021790 12538665

16. Gray P, Michelsen KS, Sirois CM, Lowe E, Shimada K, et al. (2010) Identification of a novel human MD-2 splice variant that negatively regulates Lipopolysaccharide-induced TLR4 signaling. J Immunol 184: 6359–6366. doi: 10.4049/jimmunol.0903543 20435923

17. Hardy MP, O’Neill LA (2004) The murine IRAK2 gene encodes four alternatively spliced isoforms, two of which are inhibitory. J Biol Chem 279: 27699–27708. doi: 10.1074/jbc.M403068200 15082713

18. Iwami KI, Matsuguchi T, Masuda A, Kikuchi T, Musikacharoen T, et al. (2000) Cutting edge: naturally occurring soluble form of mouse Toll-like receptor 4 inhibits lipopolysaccharide signaling. J Immunol 165: 6682–6686. 11120784

19. Janssens S, Burns K, Tschopp J, Beyaert R (2002) Regulation of interleukin-1- and lipopolysaccharide-induced NF-kappaB activation by alternative splicing of MyD88. Curr Biol 12: 467–471. doi: 10.1016/S0960-9822(02)00712-1 11909531

20. Janssens S, Burns K, Vercammen E, Tschopp J, Beyaert R (2003) MyD88S, a splice variant of MyD88, differentially modulates NF-kappaB- and AP-1-dependent gene expression. FEBS Lett 548: 103–107. doi: 10.1016/S0014-5793(03)00747-6 12885415

21. Leeman JR, Gilmore TD (2008) Alternative splicing in the NF-kappaB signaling pathway. Gene 423: 97–107. doi: 10.1016/j.gene.2008.07.015 18718859

22. Lynch KW (2004) Consequences of regulated pre-mRNA splicing in the immune system. Nat Rev Immunol 4: 931–940. doi: 10.1038/nri1497 15573128

23. Ohta S, Bahrun U, Tanaka M, Kimoto M (2004) Identification of a novel isoform of MD-2 that downregulates lipopolysaccharide signaling. Biochem Biophys Res Commun 323: 1103–1108. doi: 10.1016/j.bbrc.2004.08.203 15381113

24. Rao N, Nguyen S, Ngo K, Fung-Leung WP (2005) A novel splice variant of interleukin-1 receptor (IL-1R)-associated kinase 1 plays a negative regulatory role in Toll/IL-1R-induced inflammatory signaling. Mol Cell Biol 25: 6521–6532. doi: 10.1128/MCB.25.15.6521-6532.2005 16024789

25. Wells CA, Chalk AM, Forrest A, Taylor D, Waddell N, et al. (2006) Alternate transcription of the Toll-like receptor signaling cascade. Genome Biol 7: R10. doi: 10.1186/gb-2006-7-2-r10 16507160

26. De Arras L, Alper S (2013) The Sf3a mRNA splicing complex mediates a MyD88-dependent negative feedback loop that limits the innate immune response. PLOS Genetics: 9(10):e1003855. doi: 10.1371/journal.pgen.1003855 24204290

27. De Arras L, Seng A, Lackford B, Keikhaee M, Bowerman B, et al. (2013) An evolutionarily conserved innate immunity protein interaction network. J Biol Chem 288: 1967–1978. doi: 10.1074/jbc.M112.407205 23209288

28. Das BK, Xia L, Palandjian L, Gozani O, Chyung Y, et al. (1999) Characterization of a protein complex containing spliceosomal proteins SAPs 49, 130, 145, and 155. Mol Cell Biol 19: 6796–6802. 10490618

29. Hodges PE, Beggs JD (1994) RNA splicing. U2 fulfils a commitment. Curr Biol 4: 264–267. doi: 10.1016/S0960-9822(00)00061-0 7922333

30. Kramer A (1996) The structure and function of proteins involved in mammalian pre-mRNA splicing. Annu Rev Biochem 65: 367–409. doi: 10.1146/annurev.bi.65.070196.002055 8811184

31. Kramer A, Ferfoglia F, Huang CJ, Mulhaupt F, Nesic D, et al. (2005) Structure-function analysis of the U2 snRNP-associated splicing factor SF3a. Biochem Soc Trans 33: 439–442. doi: 10.1042/BST0330439 15916536

32. Kramer A, Gruter P, Groning K, Kastner B (1999) Combined biochemical and electron microscopic analyses reveal the architecture of the mammalian U2 snRNP. J Cell Biol 145: 1355–1368. doi: 10.1083/jcb.145.7.1355 10385517

33. Kramer A, Utans U (1991) Three protein factors (SF1, SF3 and U2AF) function in pre-splicing complex formation in addition to snRNPs. EMBO J 10: 1503–1509. 1827409

34. Will CL, Schneider C, Reed R, Luhrmann R (1999) Identification of both shared and distinct proteins in the major and minor spliceosomes. Science 284: 2003–2005. doi: 10.1126/science.284.5422.2003 10373121

35. An M, Henion PD (2012) The zebrafish sf3b1b460 mutant reveals differential requirements for the sf3b1 pre-mRNA processing gene during neural crest development. Int J Dev Biol 56: 223–237. doi: 10.1387/ijdb.113383ma 22562198

36. Corrionero A, Minana B, Valcarcel J (2011) Reduced fidelity of branch point recognition and alternative splicing induced by the anti-tumor drug spliceostatin A. Genes Dev 25: 445–459. doi: 10.1101/gad.2014311 21363963

37. Fan L, Lagisetti C, Edwards CC, Webb TR, Potter PM (2011) Sudemycins, novel small molecule analogues of FR901464, induce alternative gene splicing. ACS Chem Biol 6: 582–589. doi: 10.1021/cb100356k 21344922

38. Visconte V, Rogers HJ, Singh J, Barnard J, Bupathi M, et al. (2012) SF3B1 haploinsufficiency leads to formation of ring sideroblasts in myelodysplastic syndromes. Blood 120: 3173–3186. doi: 10.1182/blood-2012-05-430876 22826563

39. Bartels C, Klatt C, Luhrmann R, Fabrizio P (2002) The ribosomal translocase homologue Snu114p is involved in unwinding U4/U6 RNA during activation of the spliceosome. EMBO Rep 3: 875–880. doi: 10.1093/embo-reports/kvf172 12189173

40. Bartels C, Urlaub H, Luhrmann R, Fabrizio P (2003) Mutagenesis suggests several roles of Snu114p in pre-mRNA splicing. J Biol Chem 278: 28324–28334. doi: 10.1074/jbc.M303043200 12736260

41. Brenner TJ, Guthrie C (2006) Assembly of Snu114 into U5 snRNP requires Prp8 and a functional GTPase domain. RNA 12: 862–871. doi: 10.1261/rna.2319806 16540695

42. Fabrizio P, Laggerbauer B, Lauber J, Lane WS, Luhrmann R (1997) An evolutionarily conserved U5 snRNP-specific protein is a GTP-binding factor closely related to the ribosomal translocase EF-2. EMBO J 16: 4092–4106. doi: 10.1093/emboj/16.13.4092 9233818

43. Small EC, Leggett SR, Winans AA, Staley JP (2006) The EF-G-like GTPase Snu114p regulates spliceosome dynamics mediated by Brr2p, a DExD/H box ATPase. Mol Cell 23: 389–399. doi: 10.1016/j.molcel.2006.05.043 16885028

44. Sperling J, Azubel M, Sperling R (2008) Structure and function of the Pre-mRNA splicing machine. Structure 16: 1605–1615. doi: 10.1016/j.str.2008.08.011 19000813

45. Wahl MC, Will CL, Luhrmann R (2009) The spliceosome: design principles of a dynamic RNP machine. Cell 136: 701–718. doi: 10.1016/j.cell.2009.02.009 19239890

46. De Arras L, Laws R, Leach S, Pontis K, Freedman J, et al. (2014) Comparative genomics RNAi screen identifies Eftud2 as a novel regulator of innate immunity. Genetics 197: 485–496. doi: 10.1534/genetics.113.160499 24361939

47. Katz Y, Wang ET, Airoldi EM, Burge CB (2010) Analysis and design of RNA sequencing experiments for identifying isoform regulation. Nat Methods 7: 1009–1015. doi: 10.1038/nmeth.1528 21057496

48. Anders S, Huber W (2010) Differential expression analysis for sequence count data. Genome Biol 11: R106. doi: 10.1186/gb-2010-11-10-r106 20979621

49. Anders S, Reyes A, Huber W (2012) Detecting differential usage of exons from RNA-seq data. Genome Res 22: 2008–2017. doi: 10.1101/gr.133744.111 22722343

50. Trapnell C, Williams BA, Pertea G, Mortazavi A, Kwan G, et al. (2010) Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat Biotechnol 28: 511–515. doi: 10.1038/nbt.1621 20436464

51. Trapnell C, Hendrickson DG, Sauvageau M, Goff L, Rinn JL, et al. (2013) Differential analysis of gene regulation at transcript resolution with RNA-seq. Nat Biotechnol 31: 46–53. doi: 10.1038/nbt.2450 23222703

52. Chang JT, Nevins JR (2006) GATHER: a systems approach to interpreting genomic signatures. Bioinformatics 22: 2926–2933. doi: 10.1093/bioinformatics/btl483 17000751

53. Huang da W, Sherman BT, Lempicki RA (2009) Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 4: 44–57. doi: 10.1038/nprot.2008.211 19131956

54. Jiao X, Sherman BT, Huang da W, Stephens R, Baseler MW, et al. (2012) DAVID-WS: a stateful web service to facilitate gene/protein list analysis. Bioinformatics 28: 1805–1806. doi: 10.1093/bioinformatics/bts251 22543366

55. Horowitz DS (2012) The mechanism of the second step of pre-mRNA splicing. Wiley Interdiscip Rev RNA 3: 331–350. doi: 10.1002/wrna.112 22012849

56. Berglund JA, Chua K, Abovich N, Reed R, Rosbash M (1997) The splicing factor BBP interacts specifically with the pre-mRNA branchpoint sequence UACUAAC. Cell 89: 781–787. doi: 10.1016/S0092-8674(00)80261-5 9182766

57. Liu Z, Luyten I, Bottomley MJ, Messias AC, Houngninou-Molango S, et al. (2001) Structural basis for recognition of the intron branch site RNA by splicing factor 1. Science 294: 1098–1102. doi: 10.1126/science.1064719 11691992

58. Rymond BC (2010) The branchpoint binding protein: in and out of the spliceosome cycle. Adv Exp Med Biol 693: 123–141. 21189690

59. Ruskin B, Zamore PD, Green MR (1988) A factor, U2AF, is required for U2 snRNP binding and splicing complex assembly. Cell 52: 207–219. doi: 10.1016/0092-8674(88)90509-0 2963698

60. Zamore PD, Green MR (1989) Identification, purification, and biochemical characterization of U2 small nuclear ribonucleoprotein auxiliary factor. Proc Natl Acad Sci U S A 86: 9243–9247. doi: 10.1073/pnas.86.23.9243 2531895

61. Zamore PD, Green MR (1991) Biochemical characterization of U2 snRNP auxiliary factor: an essential pre-mRNA splicing factor with a novel intranuclear distribution. EMBO J 10: 207–214. 1824937

62. Zorio DA, Blumenthal T (1999) Both subunits of U2AF recognize the 3’ splice site in Caenorhabditis elegans. Nature 402: 835–838. doi: 10.1038/45597 10617207

63. Brosi R, Groning K, Behrens SE, Luhrmann R, Kramer A (1993) Interaction of mammalian splicing factor SF3a with U2 snRNP and relation of its 60-kD subunit to yeast PRP9. Science 262: 102–105. doi: 10.1126/science.8211112 8211112

64. Brosi R, Hauri HP, Kramer A (1993) Separation of splicing factor SF3 into two components and purification of SF3a activity. J Biol Chem 268: 17640–17646. 8349644

65. Kramer A (1988) Presplicing complex formation requires two proteins and U2 snRNP. Genes Dev 2: 1155–1167. doi: 10.1101/gad.2.9.1155 3192077

66. Resch A, Xing Y, Alekseyenko A, Modrek B, Lee C (2004) Evidence for a subpopulation of conserved alternative splicing events under selection pressure for protein reading frame preservation. Nucleic Acids Res 32: 1261–1269. doi: 10.1093/nar/gkh284 14982953

67. Sorek R, Shemesh R, Cohen Y, Basechess O, Ast G, et al. (2004) A non-EST-based method for exon-skipping prediction. Genome Res 14: 1617–1623. doi: 10.1101/gr.2572604 15289480

68. Barbosa-Morais NL, Irimia M, Pan Q, Xiong HY, Gueroussov S, et al. (2012) The evolutionary landscape of alternative splicing in vertebrate species. Science 338: 1587–1593. doi: 10.1126/science.1230612 23258890

69. Wang Y, Chen T, Han C, He D, Liu H, et al. (2007) Lysosome-associated small Rab GTPase Rab7b negatively regulates TLR4 signaling in macrophages by promoting lysosomal degradation of TLR4. Blood 110: 962–971. doi: 10.1182/blood-2007-01-066027 17395780

70. Miyake K (2006) Roles for accessory molecules in microbial recognition by Toll-like receptors. J Endotoxin Res 12: 195–204. doi: 10.1179/096805106X118807 16953972

71. Jansen WT, Bolm M, Balling R, Chhatwal GS, Schnabel R (2002) Hydrogen peroxide-mediated killing of Caenorhabditis elegans by Streptococcus pyogenes. Infect Immun 70: 5202–5207. doi: 10.1128/IAI.70.9.5202-5207.2002 12183571

72. Kollewe C, Mackensen AC, Neumann D, Knop J, Cao P, et al. (2004) Sequential autophosphorylation steps in the interleukin-1 receptor-associated kinase-1 regulate its availability as an adapter in interleukin-1 signaling. J Biol Chem 279: 5227–5236. doi: 10.1074/jbc.M309251200 14625308

73. Windheim M, Stafford M, Peggie M, Cohen P (2008) Interleukin-1 (IL-1) induces the Lys63-linked polyubiquitination of IL-1 receptor-associated kinase 1 to facilitate NEMO binding and the activation of IkappaBalpha kinase. Mol Cell Biol 28: 1783–1791. doi: 10.1128/MCB.02380-06 18180283

74. Yamin TT, Miller DK (1997) The interleukin-1 receptor-associated kinase is degraded by proteasomes following its phosphorylation. J Biol Chem 272: 21540–21547. doi: 10.1074/jbc.272.34.21540 9261174

75. Israel A (2010) The IKK complex, a central regulator of NF-kappaB activation. Cold Spring Harb Perspect Biol 2: a000158. doi: 10.1101/cshperspect.a000158 20300203

76. Solt LA, May MJ (2008) The IkappaB kinase complex: master regulator of NF-kappaB signaling. Immunol Res 42: 3–18. doi: 10.1007/s12026-008-8025-1 18626576

77. Koop A, Lepenies I, Braum O, Davarnia P, Scherer G, et al. (2011) Novel splice variants of human IKKepsilon negatively regulate IKKepsilon-induced IRF3 and NF-kB activation. Eur J Immunol 41: 224–234. doi: 10.1002/eji.201040814 21182093

78. Nilsen TW, Graveley BR (2010) Expansion of the eukaryotic proteome by alternative splicing. Nature 463: 457–463. doi: 10.1038/nature08909 20110989

79. Pan Q, Bakowski MA, Morris Q, Zhang W, Frey BJ, et al. (2005) Alternative splicing of conserved exons is frequently species-specific in human and mouse. Trends Genet 21: 73–77. doi: 10.1016/j.tig.2004.12.004 15661351

80. Wang ET, Sandberg R, Luo S, Khrebtukova I, Zhang L, et al. (2008) Alternative isoform regulation in human tissue transcriptomes. Nature 456: 470–476. doi: 10.1038/nature07509 18978772

81. Cooper TA, Wan L, Dreyfuss G (2009) RNA and disease. Cell 136: 777–793. doi: 10.1016/j.cell.2009.02.011 19239895

82. Padgett RA (2012) New connections between splicing and human disease. Trends Genet 28: 147–154. doi: 10.1016/j.tig.2012.01.001 22397991

83. Wang GS, Cooper TA (2007) Splicing in disease: disruption of the splicing code and the decoding machinery. Nat Rev Genet 8: 749–761. doi: 10.1038/nrg2164 17726481

84. Sterne-Weiler T, Howard J, Mort M, Cooper DN, Sanford JR (2011) Loss of exon identity is a common mechanism of human inherited disease. Genome Res 21: 1563–1571. doi: 10.1101/gr.118638.110 21750108

85. Bernier FP, Caluseriu O, Ng S, Schwartzentruber J, Buckingham KJ, et al. (2012) Haploinsufficiency of SF3B4, a component of the pre-mRNA spliceosomal complex, causes Nager syndrome. Am J Hum Genet 90: 925–933. doi: 10.1016/j.ajhg.2012.04.004 22541558

86. Czeschik JC, Voigt C, Alanay Y, Albrecht B, Avci S, et al. (2013) Clinical and mutation data in 12 patients with the clinical diagnosis of Nager syndrome. Hum Genet 132: 885–898. doi: 10.1007/s00439-013-1295-2 23568615

87. Gordon CT, Petit F, Oufadem M, Decaestecker C, Jourdain AS, et al. (2012) EFTUD2 haploinsufficiency leads to syndromic oesophageal atresia. J Med Genet 49: 737–746. doi: 10.1136/jmedgenet-2012-101173 23188108

88. Lefebvre S, Burglen L, Reboullet S, Clermont O, Burlet P, et al. (1995) Identification and characterization of a spinal muscular atrophy-determining gene. Cell 80: 155–165. doi: 10.1016/0092-8674(95)90460-3 7813012

89. Lines MA, Huang L, Schwartzentruber J, Douglas SL, Lynch DC, et al. (2012) Haploinsufficiency of a spliceosomal GTPase encoded by EFTUD2 causes mandibulofacial dysostosis with microcephaly. Am J Hum Genet 90: 369–377. doi: 10.1016/j.ajhg.2011.12.023 22305528

90. Luquetti DV, Hing AV, Rieder MJ, Nickerson DA, Turner EH, et al. (2013) “Mandibulofacial dysostosis with microcephaly” caused by EFTUD2 mutations: expanding the phenotype. Am J Med Genet A 161A: 108–113. doi: 10.1002/ajmg.a.35696 23239648

91. Mordes D, Luo X, Kar A, Kuo D, Xu L, et al. (2006) Pre-mRNA splicing and retinitis pigmentosa. Mol Vis 12: 1259–1271. 17110909

92. Neuenkirchen N, Chari A, Fischer U (2008) Deciphering the assembly pathway of Sm-class U snRNPs. FEBS Lett 582: 1997–2003. doi: 10.1016/j.febslet.2008.03.009 18348870

93. Petit F, Escande F, Jourdain A, Porchet N, Amiel J, et al. (2014) Nager syndrome: confirmation of SF3B4 haploinsufficiency as the major cause. Clin Genet. 86: 245–251. doi: 10.1111/cge.12259 24003905

94. Voigt C, Megarbane A, Neveling K, Czeschik JC, Albrecht B, et al. (2013) Oto-facial syndrome and esophageal atresia, intellectual disability and zygomatic anomalies—expanding the phenotypes associated with EFTUD2 mutations. Orphanet J Rare Dis 8: 110. doi: 10.1186/1750-1172-8-110 23879989

95. Damm F, Kosmider O, Gelsi-Boyer V, Renneville A, Carbuccia N, et al. (2012) Mutations affecting mRNA splicing define distinct clinical phenotypes and correlate with patient outcome in myelodysplastic syndromes. Blood 119: 3211–3218. doi: 10.1182/blood-2011-12-400994 22343920

96. Damm F, Thol F, Kosmider O, Kade S, Loffeld P, et al. (2012) SF3B1 mutations in myelodysplastic syndromes: clinical associations and prognostic implications. Leukemia 26: 1137–1140. doi: 10.1038/leu.2011.321 22064355

97. Ellis MJ, Ding L, Shen D, Luo J, Suman VJ, et al. (2012) Whole-genome analysis informs breast cancer response to aromatase inhibition. Nature 486: 353–360. doi: 10.1038/nature11143 22722193

98. Makishima H, Visconte V, Sakaguchi H, Jankowska AM, Abu Kar S, et al. (2012) Mutations in the spliceosome machinery, a novel and ubiquitous pathway in leukemogenesis. Blood 119: 3203–3210. doi: 10.1182/blood-2011-12-399774 22323480

99. Malcovati L, Papaemmanuil E, Bowen DT, Boultwood J, Della Porta MG, et al. (2011) Clinical significance of SF3B1 mutations in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms. Blood 118: 6239–6246. doi: 10.1182/blood-2011-09-377275 21998214

100. Papaemmanuil E, Cazzola M, Boultwood J, Malcovati L, Vyas P, et al. (2011) Somatic SF3B1 mutation in myelodysplasia with ring sideroblasts. N Engl J Med 365: 1384–1395. doi: 10.1056/NEJMoa1103283 21995386

101. Patnaik MM, Lasho TL, Hodnefield JM, Knudson RA, Ketterling RP, et al. (2012) SF3B1 mutations are prevalent in myelodysplastic syndromes with ring sideroblasts but do not hold independent prognostic value. Blood 119: 569–572. doi: 10.1182/blood-2011-09-377994 22096241

102. Quesada V, Conde L, Villamor N, Ordonez GR, Jares P, et al. (2012) Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia. Nat Genet 44: 47–52. doi: 10.1038/ng.1032 22158541

103. Rossi D, Bruscaggin A, Spina V, Rasi S, Khiabanian H, et al. (2011) Mutations of the SF3B1 splicing factor in chronic lymphocytic leukemia: association with progression and fludarabine-refractoriness. Blood 118: 6904–6908. doi: 10.1182/blood-2011-08-373159 22039264

104. Visconte V, Makishima H, Jankowska A, Szpurka H, Traina F, et al. (2012) SF3B1, a splicing factor is frequently mutated in refractory anemia with ring sideroblasts. Leukemia 26: 542–545. doi: 10.1038/leu.2011.232 21886174

105. Wang L, Lawrence MS, Wan Y, Stojanov P, Sougnez C, et al. (2011) SF3B1 and other novel cancer genes in chronic lymphocytic leukemia. N Engl J Med 365: 2497–2506. doi: 10.1056/NEJMoa1109016 22150006

106. Yoshida K, Sanada M, Shiraishi Y, Nowak D, Nagata Y, et al. (2011) Frequent pathway mutations of splicing machinery in myelodysplasia. Nature 478: 64–69. doi: 10.1038/nature10496 21909114

107. Adib-Conquy M, Adrie C, Fitting C, Gattolliat O, Beyaert R, et al. (2006) Up-regulation of MyD88s and SIGIRR, molecules inhibiting Toll-like receptor signaling, in monocytes from septic patients. Crit Care Med 34: 2377–2385. doi: 10.1097/01.CCM.0000233875.93866.88 16850005

108. Jaresova I, Rozkova D, Spisek R, Janda A, Brazova J, et al. (2007) Kinetics of Toll-like receptor-4 splice variants expression in lipopolysaccharide-stimulated antigen presenting cells of healthy donors and patients with cystic fibrosis. Microbes Infect 9: 1359–1367. doi: 10.1016/j.micinf.2007.06.009 17890129

109. Li JP, Chen Y, Ng CH, Fung ML, Xu A, et al. (2014) Differential expression of Toll-like receptor 4 in healthy and diseased human gingiva. J Periodontal Res. epub ahead of print (March 12, 2014).

110. Mendoza-Barbera E, Corral-Rodriguez MA, Soares-Schanoski A, Velarde M, Macieira S, et al. (2009) Contribution of globular death domains and unstructured linkers to MyD88.IRAK-4 heterodimer formation: an explanation for the antagonistic activity of MyD88s. Biochem Biophys Res Commun 380: 183–187. doi: 10.1016/j.bbrc.2009.01.069 19167362

111. Miao HL, Qiu ZD, Hao FL, Bi YH, Li MY, et al. (2010) Significance of MD-2 and MD-2B expression in rat liver during acute cholangitis. World J Hepatol 2: 233–238. doi: 10.4254/wjh.v2.i6.233 21161002

112. Zunt SL, Burton LV, Goldblatt LI, Dobbins EE, Srinivasan M (2009) Soluble forms of Toll-like receptor 4 are present in human saliva and modulate tumour necrosis factor-alpha secretion by macrophage-like cells. Clin Exp Immunol 156: 285–293. doi: 10.1111/j.1365-2249.2009.03854.x 19292767

113. Bechara E, Valcarcel J (2013) Competition by the masses. Mol Cell 51: 279–280. doi: 10.1016/j.molcel.2013.07.018 23932711

114. Munding EM, Shiue L, Katzman S, Donohue JP, Ares M Jr. (2013) Competition between pre-mRNAs for the splicing machinery drives global regulation of splicing. Mol Cell 51: 338–348. doi: 10.1016/j.molcel.2013.06.012 23891561

115. Clark TA, Sugnet CW, Ares M Jr. (2002) Genomewide analysis of mRNA processing in yeast using splicing-specific microarrays. Science 296: 907–910. doi: 10.1126/science.1069415 11988574

116. Jia Y, Mu JC, Ackerman SL (2012) Mutation of a U2 snRNA gene causes global disruption of alternative splicing and neurodegeneration. Cell 148: 296–308. doi: 10.1016/j.cell.2011.11.057 22265417

117. Kershaw CJ, Barrass JD, Beggs JD, O’Keefe RT (2009) Mutations in the U5 snRNA result in altered splicing of subsets of pre-mRNAs and reduced stability of Prp8. RNA 15: 1292–1304. doi: 10.1261/rna.1347409 19447917

118. McGlincy NJ, Smith CW (2008) Alternative splicing resulting in nonsense-mediated mRNA decay: what is the meaning of nonsense? Trends Biochem Sci 33: 385–393. doi: 10.1016/j.tibs.2008.06.001 18621535

119. Park JW, Parisky K, Celotto AM, Reenan RA, Graveley BR (2004) Identification of alternative splicing regulators by RNA interference in Drosophila. Proc Natl Acad Sci U S A 101: 15974–15979. doi: 10.1073/pnas.0407004101 15492211

120. Pleiss JA, Whitworth GB, Bergkessel M, Guthrie C (2007) Transcript specificity in yeast pre-mRNA splicing revealed by mutations in core spliceosomal components. PLoS Biol 5: e90. doi: 10.1371/journal.pbio.0050090 17388687

121. Rosel TD, Hung LH, Medenbach J, Donde K, Starke S, et al. (2011) RNA-Seq analysis in mutant zebrafish reveals role of U1C protein in alternative splicing regulation. EMBO J 30: 1965–1976. doi: 10.1038/emboj.2011.106 21468032

122. Saltzman AL, Pan Q, Blencowe BJ (2011) Regulation of alternative splicing by the core spliceosomal machinery. Genes Dev 25: 373–384. doi: 10.1101/gad.2004811 21325135

123. Sapra AK, Arava Y, Khandelia P, Vijayraghavan U (2004) Genome-wide analysis of pre-mRNA splicing: intron features govern the requirement for the second-step factor, Prp17 in Saccharomyces cerevisiae and Schizosaccharomyces pombe. J Biol Chem 279: 52437–52446. doi: 10.1074/jbc.M408815200 15452114

124. Sridharan V, Heimiller J, Singh R (2011) Genomic mRNA profiling reveals compensatory mechanisms for the requirement of the essential splicing factor U2AF. Mol Cell Biol 31: 652–661. doi: 10.1128/MCB.01000-10 21149581

125. Zhou X, Wu W, Li H, Cheng Y, Wei N, et al. (2014) Transcriptome analysis of alternative splicing events regulated by SRSF10 reveals position-dependent splicing modulation. Nucleic Acids Res 42: 4019–4030. doi: 10.1093/nar/gkt1387 24442672

126. Sakabe NJ, de Souza SJ (2007) Sequence features responsible for intron retention in human. BMC Genomics 8: 59. doi: 10.1186/1471-2164-8-59 17324281

127. Stamm S, Zhu J, Nakai K, Stoilov P, Stoss O, et al. (2000) An alternative-exon database and its statistical analysis. DNA Cell Biol 19: 739–756. doi: 10.1089/104454900750058107 11177572

128. Tanackovic G, Kramer A (2005) Human splicing factor SF3a, but not SF1, is essential for pre-mRNA splicing in vivo. Mol Biol Cell 16: 1366–1377. doi: 10.1091/mbc.E04-11-1034 15647371

129. Masuhiro Y, Mezaki Y, Sakari M, Takeyama K, Yoshida T, et al. (2005) Splicing potentiation by growth factor signals via estrogen receptor phosphorylation. Proc Natl Acad Sci U S A 102: 8126–8131. doi: 10.1073/pnas.0503197102 15919818

130. Smith LD, Lucas CM, Eperon IC (2013) Intron retention in the alternatively spliced region of RON results from weak 3′ splice site recognition. PLoS One 8: e77208. doi: 10.1371/journal.pone.0077208 24155930

131. Rousseau S, Morrice N, Peggie M, Campbell DG, Gaestel M, et al. (2002) Inhibition of SAPK2a/p38 prevents hnRNP A0 phosphorylation by MAPKAP-K2 and its interaction with cytokine mRNAs. EMBO J 21: 6505–6514. doi: 10.1093/emboj/cdf639 12456657

132. Wu TD, Watanabe CK (2005) GMAP: a genomic mapping and alignment program for mRNA and EST sequences. Bioinformatics 21: 1859–1875. doi: 10.1093/bioinformatics/bti310 15728110

133. Wu TD, Nacu S (2010) Fast and SNP-tolerant detection of complex variants and splicing in short reads. Bioinformatics 26: 873–881. doi: 10.1093/bioinformatics/btq057 20147302

134. Schneider TD, Stephens RM (1990) Sequence logos: a new way to display consensus sequences. Nucleic Acids Res 18: 6097–6100. doi: 10.1093/nar/18.20.6097 2172928

135. Crooks GE, Hon G, Chandonia JM, Brenner SE (2004) WebLogo: a sequence logo generator. Genome Res 14: 1188–1190. doi: 10.1101/gr.849004 15173120

136. R Core Team (2013) R: A Language and Environment for Statistical Computing. Vienna, Austria: R Foundation for Statistical Computing.

137. Anders S, Pyl PT, Huber W (2014) HTSeq – A Python framework to work with high-throughput sequencing data. Preprint of submitted mansucript available at biRxiv: doi: 10.1101/002824.

138. Roberts A, Pimentel H, Trapnell C, Pachter L (2011) Identification of novel transcripts in annotated genomes using RNA-Seq. Bioinformatics 27: 2325–2329. doi: 10.1093/bioinformatics/btr355 21697122

139. Roberts A, Trapnell C, Donaghey J, Rinn JL, Pachter L (2011) Improving RNA-Seq expression estimates by correcting for fragment bias. Genome Biol 12: R22. doi: 10.1186/gb-2011-12-3-r22 21410973

140. Alper S, Laws R, Lackford B, Boyd WA, Dunlap P, et al. (2008) Identification of innate immunity genes and pathways using a comparative genomics approach. Proc Natl Acad Sci USA 105: 7016–7021. doi: 10.1073/pnas.0802405105 18463287

141. Fernandez-Botran R, Větvička V (2001) Methods in Cellular Immunology. Boca Raton: CRC Press. p 8.

142. Schneider CA, Rasband WS, Eliceiri KW (2012) NIH Image to ImageJ: 25 years of image analysis. Nat Methods 9: 671–675. doi: 10.1038/nmeth.2089 22930834

143. Kanehisa M, Goto S (2000) KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res 28: 27–30. doi: 10.1093/nar/28.1.27 10592173

144. Kanehisa M, Goto S, Sato Y, Kawashima M, Furumichi M, et al. (2014) Data, information, knowledge and principle: back to metabolism in KEGG. Nucleic Acids Res 42: D199–205. doi: 10.1093/nar/gkt1076 24214961

Štítky
Genetika Reprodukčná medicína

Článok vyšiel v časopise

PLOS Genetics


2015 Číslo 2
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Aktuální možnosti diagnostiky a léčby litiáz
nový kurz
Autori: MUDr. Tomáš Ürge, PhD.

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#