Immune response IFN alpha/beta signaling pathway
IFN alpha/beta signaling pathway Interferons (IFNs) are pleiotropic cytokines that exhibit important biologicactivities, including antiviral, antiproliferative, antitumor and immunomodulatoryeffects , . IFNs are classified as either Type I or Type II. Type I IFNs include theIFN-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 , , . IFN-alpha and IFN-beta bind to the type I IFN receptor (IFN-alpha/beta receptor ) consisting of two subunits, Interferon (alpha, beta andomega) receptor 1 ( IFNAR1 ) and Interferon (alpha, beta and omega) receptor 2 (IFNAR2 ) . IFN-alpha/beta receptor lacks intrinsic kinase activity and thus relies onassociated Janus kinases ( JAK1 and Tyk2 ) to phosphorylate receptor andsignal transducing molecules, such as Signal transducers and activators of transcription1 ( STAT1 and STAT2 ), after ligand-induced receptor clustering.IFNAR1 is pre-associated with Tyk2, and also binds STAT1 andSTAT2. IFNAR2 is pre-associated with JAK1, STAT1 andSTAT2 . The tyrosine phosphorylation of STAT1 and STAT2 by JAK1 andTyk2 leads to the formation of transcriptional complexes that translocate to thenucleus to induce expression of certain genes . An important transcriptional complex that is induced by Type-I IFNs is the ISGFactor-3 complex ( ISGF3 ). The mature ISGF3 complex is composed ofphosphorylated forms of STAT1 and STAT2 and Interferon regulatory factor 9( IRF9 ), which does not undergo tyrosine phosphorylation .ISGF3 is the only complex that binds specific elements known as IFN-stimulatedresponse elements (ISREs) that are present in the promoters of certain genes, such asPromyelocytic leukemia ( PML ), ISG15 ubiquitin-like modifier ( ISG15 ),Interferon-induced protein with tetratricopeptide repeats 2 ( ISG54 ) andInterferon alpha-inducible protein 6 ( IFI6 ) , ,, . In response to IFN-alpha, STAT1 and STAT2 can also form anothertranscriptional complex, STAT1/STAT2 heterodimer, that exhibits binding to thegamma-activated sequence (GAS) element of the Interferon regulatory factor 1 (IRF1 ) gene , . IRF1, in turn, can alsoinduce the transcription of ISG15, ISG54 and IFI6 genes, whereasanother IFN-alpha-inducible factor, Interferon regulatory factor 2 ( IRF2 ), isinvolved in the repression of gene transcription , , , . Arginine methylation of STAT1 by Protein arginine methyltransferase 1 (PRMT1 ) is an additional posttranslational modification that regulatestranscription factor function required for proper IFN-alpha/beta-induced transcription. 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 viainteractions with IFNAR1, JAK1 and Tyk2 . Proteintyrosine phosphatases non-receptor type 6 and 11 ( SHP-1 and SHP-2 )dephosphorylate JAK1 and STAT1 and suppress their signaling , . Protein tyrosine phosphatase non-receptor type 1 (PTP-1B ) dephosphorylates Tyk2 and modulates signaling responses toIFN-alpha . A type I IFN-inducible Ubiquitin specific peptidase 18( UBP43 ) binds directly to IFNAR2 and blocks the interaction betweenJAK1 and IFN-alpha/beta receptor .