Pathway maps

Immune response_IFN alpha/beta signaling pathway
Immune response_IFN alpha/beta signaling pathway

Object List (links open in MetaCore):

STAT1/STAT2, PML, JAK1, IRF2, ISG15, IRF1, ISGF3, ISG54, SHP-1, USP18, IFN-alpha/beta receptor, IFNAR2, STAT2, IFN-beta, IFI6, PTP-1B, IFN-alpha, IRF9, PRMT1, STAT1, IFNAR1, SHP-2, SOCS1, Tyk2

Description

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 [3], [2], [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 May 18;