Immune response - IFN alpha/beta signaling pathway

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IFN alpha/beta signaling pathway

Interferons (IFNs) are pleiotropic cytokines that exhibit important biologic activities, including antiviral, antiproliferative, antitumor and immunomodulatory effects [1], [2].

IFNs are classified as either Type I or Type II. Type I IFNs include the IFN-alpha family of 13 subtypes, IFN-beta, IFN-omega, IFN-tau, IFN-kappa, IFN-lambda, and IFN-zeta. By contrast, there is only one Type-II IFN, IFN-gamma [2], [3], [4].

IFN-alpha and IFN-beta bind to the type I IFN receptor (IFN-alpha/beta receptor) consisting of two subunits, Interferon (alpha, beta and omega) receptor 1 (IFNAR1) and Interferon (alpha, beta and omega) receptor 2 (IFNAR2) [5].

IFN-alpha/beta receptor lacks intrinsic kinase activity and thus relies on associated Janus kinases (JAK1 and Tyk2) to phosphorylate receptor and signal transducing molecules, such as Signal transducers and activators of transcription 1 (STAT1 and STAT2), after ligand-induced receptor clustering. IFNAR1 is pre-associated with Tyk2, and also binds STAT1 and STAT2. IFNAR2 is pre-associated with JAK1, STAT1 and STAT2 [4].

The tyrosine phosphorylation of STAT1 and STAT2 by JAK1 and Tyk2 leads to the formation of transcriptional complexes that translocate to the nucleus to induce expression of certain genes [2].

An important transcriptional complex that is induced by Type-I IFNs is the ISG Factor-3 complex (ISGF3). The mature ISGF3 complex is composed of phosphorylated forms of STAT1 and STAT2 and Interferon regulatory factor 9 (IRF9), which does not undergo tyrosine phosphorylation [2]. ISGF3 is the only complex that binds specific elements known as IFN-stimulated response elements (ISREs) that are present in the promoters of certain genes, such as Promyelocytic leukemia (PML), ISG15 ubiquitin-like modifier (ISG15), Interferon-induced protein with tetratricopeptide repeats 2 (ISG54) and Interferon alpha-inducible protein 6 (IFI6) [6], [7], [8], [9].

In response to IFN-alpha, STAT1 and STAT2 can also form another transcriptional complex, STAT1/STAT2 heterodimer, that exhibits binding to the gamma-activated sequence (GAS) element of the Interferon regulatory factor 1 (IRF1) gene [10], [11]. IRF1, in turn, can also induce the transcription of ISG15, ISG54 and IFI6 genes, whereas another IFN-alpha-inducible factor, Interferon regulatory factor 2 (IRF2), is involved in the repression of gene transcription [12], [13], [14], [15].

Arginine methylation of STAT1 by Protein arginine methyltransferase 1 (PRMT1) is an additional posttranslational modification that regulates transcription factor function required for proper IFN-alpha/beta-induced transcription [16].

A number of negative regulatory molecules limit the extent of type I IFN signaling. Suppressor of cytokine signaling 1 (SOCS1) inhibits type I IFN signaling via interactions with IFNAR1, JAK1 and Tyk2 [17]. Protein tyrosine phosphatases non-receptor type 6 and 11 (SHP-1 and SHP-2) dephosphorylate JAK1 and STAT1 and suppress their signaling [18], [19]. Protein tyrosine phosphatase non-receptor type 1 (PTP-1B) dephosphorylates Tyk2 and modulates signaling responses to IFN-alpha [20]. A type I IFN-inducible Ubiquitin specific peptidase 18 (UBP43) binds directly to IFNAR2 and blocks the interaction between JAK1 and IFN-alpha/beta receptor [21].

References:

  1. Parmar S, Platanias LC
    Interferons: mechanisms of action and clinical applications. Current opinion in oncology 2003 Nov;15(6):431-9
  2. Platanias LC
    Mechanisms of type-I- and type-II-interferon-mediated signalling. Nature reviews. Immunology 2005 May;5(5):375-86
  3. Chen J, Baig E, Fish EN
    Diversity and relatedness among the type I interferons. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 2004 Dec;24(12):687-98
  4. de Weerd NA, Samarajiwa SA, Hertzog PJ
    Type I interferon receptors: biochemistry and biological functions. The Journal of biological chemistry 2007 Jul 13;282(28):20053-7
  5. Pestka S, Krause CD, Walter MR
    Interferons, interferon-like cytokines, and their receptors. Immunological reviews 2004 Dec;202:8-32
  6. Parrington J, Rogers NC, Gewert DR, Pine R, Veals SA, Levy DE, Stark GR, Kerr IM
    The interferon-stimulable response elements of two human genes detect overlapping sets of transcription factors. European journal of biochemistry / FEBS 1993 Jun 15;214(3):617-26
  7. Au WC, Moore PA, Lowther W, Juang YT, Pitha PM
    Identification of a member of the interferon regulatory factor family that binds to the interferon-stimulated response element and activates expression of interferon-induced genes. Proceedings of the National Academy of Sciences of the United States of America 1995 Dec 5;92(25):11657-61
  8. Stadler M, Chelbi-Alix MK, Koken MH, Venturini L, Lee C, Saib A, Quignon F, Pelicano L, Guillemin MC, Schindler C
    Transcriptional induction of the PML growth suppressor gene by interferons is mediated through an ISRE and a GAS element. Oncogene 1995 Dec 21;11(12):2565-73
  9. Nakaya T, Sato M, Hata N, Asagiri M, Suemori H, Noguchi S, Tanaka N, Taniguchi T
    Gene induction pathways mediated by distinct IRFs during viral infection. Biochemical and biophysical research communications 2001 May 25;283(5):1150-6
  10. Ghislain JJ, Wong T, Nguyen M, Fish EN
    The interferon-inducible Stat2:Stat1 heterodimer preferentially binds in vitro to a consensus element found in the promoters of a subset of interferon-stimulated genes. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 2001 Jun;21(6):379-88
  11. Brierley MM, Fish EN
    Functional relevance of the conserved DNA-binding domain of STAT2. The Journal of biological chemistry 2005 Apr 1;280(13):13029-36
  12. Pine R, Decker T, Kessler DS, Levy DE, Darnell JE Jr
    Purification and cloning of interferon-stimulated gene factor 2 (ISGF2): ISGF2 (IRF-1) can bind to the promoters of both beta interferon- and interferon-stimulated genes but is not a primary transcriptional activator of either. Molecular and cellular biology 1990 Jun;10(6):2448-57
  13. Nelson N, Marks MS, Driggers PH, Ozato K
    Interferon consensus sequence-binding protein, a member of the interferon regulatory factor family, suppresses interferon-induced gene transcription. Molecular and cellular biology 1993 Jan;13(1):588-99
  14. Masumi A, Ozato K
    Coactivator p300 acetylates the interferon regulatory factor-2 in U937 cells following phorbol ester treatment. The Journal of biological chemistry 2001 Jun 15;276(24):20973-80
  15. Meraro D, Gleit-Kielmanowicz M, Hauser H, Levi BZ
    IFN-stimulated gene 15 is synergistically activated through interactions between the myelocyte/lymphocyte-specific transcription factors, PU.1, IFN regulatory factor-8/IFN consensus sequence binding protein, and IFN regulatory factor-4: characterization of a new subtype of IFN-stimulated response element. Journal of immunology (Baltimore, Md. : 1950) 2002 Jun 15;168(12):6224-31
  16. Mowen KA, Tang J, Zhu W, Schurter BT, Shuai K, Herschman HR, David M
    Arginine methylation of STAT1 modulates IFNalpha/beta-induced transcription. Cell 2001 Mar 9;104(5):731-41
  17. Fenner JE, Starr R, Cornish AL, Zhang JG, Metcalf D, Schreiber RD, Sheehan K, Hilton DJ, Alexander WS, Hertzog PJ
    Suppressor of cytokine signaling 1 regulates the immune response to infection by a unique inhibition of type I interferon activity. Nature immunology 2006 Jan;7(1):33-9
  18. David M, Chen HE, Goelz S, Larner AC, Neel BG
    Differential regulation of the alpha/beta interferon-stimulated Jak/Stat pathway by the SH2 domain-containing tyrosine phosphatase SHPTP1. Molecular and cellular biology 1995 Dec;15(12):7050-8
  19. You M, Yu DH, Feng GS
    Shp-2 tyrosine phosphatase functions as a negative regulator of the interferon-stimulated Jak/STAT pathway. Molecular and cellular biology 1999 Mar;19(3):2416-24
  20. Myers MP, Andersen JN, Cheng A, Tremblay ML, Horvath CM, Parisien JP, Salmeen A, Barford D, Tonks NK
    TYK2 and JAK2 are substrates of protein-tyrosine phosphatase 1B. The Journal of biological chemistry 2001 Dec 21;276(51):47771-4
  21. Malakhova OA, Kim KI, Luo JK, Zou W, Kumar KG, Fuchs SY, Shuai K, Zhang DE
    UBP43 is a novel regulator of interferon signaling independent of its ISG15 isopeptidase activity. The EMBO journal 2006 Jun 7;25(11):2358-67

  1. Parmar S, Platanias LC
    Interferons: mechanisms of action and clinical applications. Current opinion in oncology 2003 Nov;15(6):431-9
  2. Platanias LC
    Mechanisms of type-I- and type-II-interferon-mediated signalling. Nature reviews. Immunology 2005 May;5(5):375-86
  3. Chen J, Baig E, Fish EN
    Diversity and relatedness among the type I interferons. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 2004 Dec;24(12):687-98
  4. de Weerd NA, Samarajiwa SA, Hertzog PJ
    Type I interferon receptors: biochemistry and biological functions. The Journal of biological chemistry 2007 Jul 13;282(28):20053-7
  5. Pestka S, Krause CD, Walter MR
    Interferons, interferon-like cytokines, and their receptors. Immunological reviews 2004 Dec;202:8-32
  6. Parrington J, Rogers NC, Gewert DR, Pine R, Veals SA, Levy DE, Stark GR, Kerr IM
    The interferon-stimulable response elements of two human genes detect overlapping sets of transcription factors. European journal of biochemistry / FEBS 1993 Jun 15;214(3):617-26
  7. Au WC, Moore PA, Lowther W, Juang YT, Pitha PM
    Identification of a member of the interferon regulatory factor family that binds to the interferon-stimulated response element and activates expression of interferon-induced genes. Proceedings of the National Academy of Sciences of the United States of America 1995 Dec 5;92(25):11657-61
  8. Stadler M, Chelbi-Alix MK, Koken MH, Venturini L, Lee C, Saib A, Quignon F, Pelicano L, Guillemin MC, Schindler C
    Transcriptional induction of the PML growth suppressor gene by interferons is mediated through an ISRE and a GAS element. Oncogene 1995 Dec 21;11(12):2565-73
  9. Nakaya T, Sato M, Hata N, Asagiri M, Suemori H, Noguchi S, Tanaka N, Taniguchi T
    Gene induction pathways mediated by distinct IRFs during viral infection. Biochemical and biophysical research communications 2001 May 25;283(5):1150-6
  10. Ghislain JJ, Wong T, Nguyen M, Fish EN
    The interferon-inducible Stat2:Stat1 heterodimer preferentially binds in vitro to a consensus element found in the promoters of a subset of interferon-stimulated genes. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 2001 Jun;21(6):379-88
  11. Brierley MM, Fish EN
    Functional relevance of the conserved DNA-binding domain of STAT2. The Journal of biological chemistry 2005 Apr 1;280(13):13029-36
  12. Pine R, Decker T, Kessler DS, Levy DE, Darnell JE Jr
    Purification and cloning of interferon-stimulated gene factor 2 (ISGF2): ISGF2 (IRF-1) can bind to the promoters of both beta interferon- and interferon-stimulated genes but is not a primary transcriptional activator of either. Molecular and cellular biology 1990 Jun;10(6):2448-57
  13. Nelson N, Marks MS, Driggers PH, Ozato K
    Interferon consensus sequence-binding protein, a member of the interferon regulatory factor family, suppresses interferon-induced gene transcription. Molecular and cellular biology 1993 Jan;13(1):588-99
  14. Masumi A, Ozato K
    Coactivator p300 acetylates the interferon regulatory factor-2 in U937 cells following phorbol ester treatment. The Journal of biological chemistry 2001 Jun 15;276(24):20973-80
  15. Meraro D, Gleit-Kielmanowicz M, Hauser H, Levi BZ
    IFN-stimulated gene 15 is synergistically activated through interactions between the myelocyte/lymphocyte-specific transcription factors, PU.1, IFN regulatory factor-8/IFN consensus sequence binding protein, and IFN regulatory factor-4: characterization of a new subtype of IFN-stimulated response element. Journal of immunology (Baltimore, Md. : 1950) 2002 Jun 15;168(12):6224-31
  16. Mowen KA, Tang J, Zhu W, Schurter BT, Shuai K, Herschman HR, David M
    Arginine methylation of STAT1 modulates IFNalpha/beta-induced transcription. Cell 2001 Mar 9;104(5):731-41
  17. Fenner JE, Starr R, Cornish AL, Zhang JG, Metcalf D, Schreiber RD, Sheehan K, Hilton DJ, Alexander WS, Hertzog PJ
    Suppressor of cytokine signaling 1 regulates the immune response to infection by a unique inhibition of type I interferon activity. Nature immunology 2006 Jan;7(1):33-9
  18. David M, Chen HE, Goelz S, Larner AC, Neel BG
    Differential regulation of the alpha/beta interferon-stimulated Jak/Stat pathway by the SH2 domain-containing tyrosine phosphatase SHPTP1. Molecular and cellular biology 1995 Dec;15(12):7050-8
  19. You M, Yu DH, Feng GS
    Shp-2 tyrosine phosphatase functions as a negative regulator of the interferon-stimulated Jak/STAT pathway. Molecular and cellular biology 1999 Mar;19(3):2416-24
  20. Myers MP, Andersen JN, Cheng A, Tremblay ML, Horvath CM, Parisien JP, Salmeen A, Barford D, Tonks NK
    TYK2 and JAK2 are substrates of protein-tyrosine phosphatase 1B. The Journal of biological chemistry 2001 Dec 21;276(51):47771-4
  21. Malakhova OA, Kim KI, Luo JK, Zou W, Kumar KG, Fuchs SY, Shuai K, Zhang DE
    UBP43 is a novel regulator of interferon signaling independent of its ISG15 isopeptidase activity. The EMBO journal 2006 Jun 7;25(11):2358-67

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