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INFOBIOMED

INFOBIOMED. WP6.2 Genomics and Microbiology. Partners. IMIM . IEETA, FORTH, INFORMA, ACTA. Objective. To link pathway biology of interferon and infection to clinical and potentially chemical informatics. Interferons and infection.

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INFOBIOMED

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  1. INFOBIOMED WP6.2 Genomics and Microbiology

  2. Partners • IMIM. • IEETA, • FORTH, • INFORMA, • ACTA

  3. Objective • To link pathway biology of interferon and infection to clinical and potentially chemical informatics.

  4. Interferons and infection • Interferons (IFNs) are a large family of multifunctional secreted proteins called cytokines that can be characterised into two distinct types: Type I, which constitutes IFN and IFN, and Type II, which consists only of IFN (Goodbourn et al., 2000; Schroder K et al., 2004). • Both types are important in inducing the immune defence mechanism upon infection and other diseases.

  5. Interferon signalling and regulatory pathways

  6. Linking Bio to Medical • To help facilitate linking pathway biology with medical informatics – identifiers based on genomic/proteomic markers will be used in a complementary approach – this is schematically illustrated in the next slide

  7. GENOMICS & MICROBIOLOGY INTERFERON PATHWAY Medical Informatics Bioinformatics IFN Pathogen Cellular (MØ) • Viral Immunomodulatory Interactions • Protein Interaction Network • Micro RNA • Secretome • Regulatory Network • SNPs / genetic mutations • Omim • Patient profiling microarray / proteomic • Clinical / pathway database Gene a b c

  8. Sub-Systems Approach • Shown in the next slide is a subsystem logic map of the interferon pathway. • Work defined in this work-package will elaborate and extend this to other biological data (for bio content) and medical data (genetic, diagnosis, pathology reports, treatment). • Aim will be to generate a systems level informational pathway map.

  9. Ifng Irf3 Extracellular space Extracellular Antigen Trail TNFa Cytosolic Ag-pep Endocyt. Ag-pep Cell membrane HLA-A/B/C B2m HLA-DRA HLA-DRB Trail-R1/2 Tnfr1 Ingoing endosome Endocytosed Antigen Late outgoing endosome membrane Kpna3 Kpna4 D68 HLA- DRB HLA- DRB HLA- DRB HLA- DRB B2m HLA- A/B/C HLA-DRA HLA-DRB H2-DMa: H2-DMb H2-Oa: H2-Ob Endocyt. Ag-pep Clip Ii Clip Cytosolic Ag-pep D69 Late outgoing endosome lumen D70 D70 D66 Endocyt. Ag-polypep Endocyt. Ag-pep + D67 Ctss Ctsb Ctsd Fadd Psmb8 Psmb8 D71 P Pact Psma(1-7): Psmb(1-4): Psmb(1-4): Psmb(1-7) Psma(1-7): Psmb(1-4): Psmb(1-4): Psma(1-7) Psmb9 Psmb9 D72 dsRNA Psmb10 Psmb10 Ikbke Tbk1 D73 Casp8 Psme1 Psme2 Psme1(7) Psme2 Cytosol B73 B74 D74 Ser51 P P IAD eIF2-a B75 Irf7 Psme1(7) Psme2 P IAD B76 Psmb8 D77 P D76 Stat2 Irf1 D75 P Oas STAT1 Casp7 Irf7 Irf7 P Psma(1-7): Psmb(1-4): Psmb(1-4): Psma(1-7) Psmb10 Psmb9 P Irf3:Irf3 IAD B77 Irf3 Psmb9 Psmb10 P 2,5A + IAD B78 Irf5 NF-kB Complex Psmb8 Psme1(7) Psme2 B79 Apaf-1 STAT1 B61 Casp1 P Ikbke Tbk1 D78 Bax C2ta Irf3:Irf3 B58 B59 Cytosolic Antigen Cytosolic Ag-pep Mitochondrialmembrane Bax P P Ser Ser B60 Irf3 Irf3 Bak Mitochondiral lumen B64 Lysosome membrane Ii B2m HLA- A/B/C HLA- DRB HLA- DRB Ctsd Cytosolic Ag-pep Lysosome lumen Ctsb Endocytosed Antigen Endocytosed Antigen Ctss + D65 Ctsh D64 + Early outgoing endosome membrane HLA- DRB Ii HLA- DRB HLA- DRB Ii HLA- DRB B2m HLA- A/B/C Early outgoing endosome lumen Cytosolic Ag-pep Ctsb Ctss D63 + Golgi membrane B2m HLA- A/B/C Golgi lumen P P Ep300 Cytosolic Ag-pep Ctss P Irf7 Irf1 P P Irf7 Irf5 & ER-cytosol membrane Irf3:Irf3 Crebbp D80 Tap1 Tap2 Tap1: Tap2 D81 P P D60 D82 Irf3 Irf7 P P D79 B2m H2-DMa: H2-DMb B2m Ii & Irf7 Irf7 HLA-DRB HLA-DRA H2-DMa: H2-DMb H2-DMa: H2-DMb H2-DMa: H2-DMb & Cytosolic Ag-pep HLA- A/B/C HLA- A/B/C Cytosolic Ag-pep H2-Oa: H2-Ob H2-Oa: H2-Ob H2-Oa: H2-Ob H2-Oa: H2-Ob D61 D61 D62 ER Lumen Cytosolic Ag-pep HLA-DRA Ii HLA-DRB Ctss HLA-B B2m HLA-C HLA-A Nuclear membrane P P P T Stat1 Ifna14 Stat2 XPO1 + T Ifna7 B63 NES HLA-C HLA-A HLA-B B2m Ii HLA-DRB Tap1 Tap2 HLA-DRA Ctss T Casp8 Ifna4 Bak Bcl-2 Bcl-xL D38 D44 Hmga1 Tap1 Tap2 Ii HLA-DRB HLA-DRA HLA-B D33 HLA-C HLA-A Ctss T T T T D39 D45 RnaseL Irf3:Irf3 B2m & T T T & T & + T T Casp8 T T Bcl-2 Bcl-xl Bak & + T & + D25 D26 D27 D28 D24 D29 B62 D31 D32 D35 D36 D37 D41 D42 D43 D47 D48 D49 D50 D51 D52 D53 D40 D46 D30 D34 Irf1 Irf2 Irf4 TNFRSF6 TNFSF6 Icsbp1 B80 Prkr Atf2:Jun Stat1:Stat1 B87 T Psmb9 Hist4h4 B65 D54 T Psmb9 B88 B66 B89 B83 B84 Prkr B81 T B86 B8 B85 B82 B67 B54 D55 B86 Tnfsf6 Tnfrsf6 B84 ISRE B55 T ISRE Ifna11 T PRDIV | G1p2 T T & D23 Ccl5 Tnfrsf6 T Ifna1 PRDII Tnfsf6 Usf2 + & * T B57 PRDIII Psmb8 Psmb10 Nfya Crebbp Oas Psmb8 Psmb10 Usf1 D13 D15 IRF7 Rfxank Rfxap Myc PRDI Nfkb1 T T ISRE D14 ISRE T Nfyc D56 D57 B11 Usf1 B21 T D16 Oas D11 D9 Ep300 Rela D17 Psme1 Psme2 D19 D10 D22 B22 Rfx5 B56 Psme1 Psme2 T D12 D20 Nfyb Nucleus C2ta Stat2 B47ii T T GAS B1 D21 D18 Creb1 D59 D58 T D6 B30 Irf1 S133 Crebbp Pcaf P Pcaf Irf1 K141 D7 B17 Ac B31 T C2ta K144 D8 Icsbp1 Irf2 Ac GAS T Irf2 Irf4 Ac Ac D1 B39 Tyr220 Tyr226 PEST C2ta P & P Ser P D2 Icsbp1 T & D3 B37 B34 D4 B26 PEST PEST B40 T D5 Stat1 B12 Stat6 Fkbp4 Sfpi1 B42 B27 B35 B36 B41 B47i B13ii B48 CD23b GAS B13i ETS + T B15 * T T Itgam Fcer2a Il1b B33 * T B44 B43 Il12b B14 B46 B45 B38 B52 B49 B29 B24 B16 IRF-E T T Cdkn1a Cybb T Il12a * Ifng A54 Ifna Ifnb A1 & A35 A36 A2 | Tnfsf6 = A37 A3 A4 Y466 P Fnrsf6 Ifngr2 Ifngr1 Ifnar1 Ifnar2 P Y440 A42 A40 A47 A16 A10 A51 A5 A60 A8 A67 Tyk2 Jak1 Jak2 Map2k1/ Map3k1 Ptk2b A44 P A7 P Hrmt1l2 Tradd P Au P A52 A41 P A46 A6 A29 A55 A55 A43 Ifng | PRKR P A53 Pias1 P P P Map2k1 Map2k2 MAPKK (Identity not Known) Vav STAT1 A38 A13 A11 Y701 NLS A12 Prkcd | STAT1 P = A39 A65 A21 SH2 domain Arg31 A56 A56 M Caspases Effectors & & GDP GTP P P S727 A59 Rac1 Mapk1 Mapk3 P + + A48 CASP8 Y690 Camk2a A15 SH2 domain Stat1 Prkr | Casp3 CASP9 A62 A45 A34 A20 | STAT1 Mapk14 A14 A49 A64 A57 A17 Cebpb PRKR I-kB P A58 A58 PRKR 2,5A System Kpna1 & Casp9 A18 & & Ran A19 Isgf3g Isgf3g Caspases Initiators A22 & & WD40 Domain CARD-CARD Interaction NLS NLS Cyt.C A50 A50 NF-kB Complex Bcl-xL Cause Release of Cyt.C Inhibit Release of Cyt.C Bcl-2 Cyt.C Isgf3g Isgf3g Isgf3g Isgf3g T A23 P A24 | & & Stat1 A23 + + A32 A23 A27 Y701 A32 Isgf3g Stat2 P A25 Nmi | P P P P A26 Y701 Stat1 Stat1 Y701 B72 + & + & Tradd A32 A32 ISRE & & + A22 A22 A27 + + MCM5 A27 + T | A27 A33 A33 NF-kB complex Casp7 Casp1 Casp3 Sp1 A28 + | T Casp8 T T Casp8 Casp3 Casp7 Casp1 Casp7 BRCA1 A30 | | STAT1 B9 B32 B6 STAT1 A31 TFII-I A31 STAT1 STAT1 Gtf2i A66 B4 B25 B23 B5 IRF1 IRF1 IRF1 IRF1 IRF1 B10 ICSBP1 B2 Isgf3g Isgf3g Isgf3g Isgf3g GAS GAS B3 T T GATE GATE MSE MSE B50 Protein Synthesis Inhibition DNA Degradation, ,Cell shrinkage and Membrane blebbing etc Apoptosis RNA Degradation

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