EMBO J. J. Immunol. Nature Rev. Platanias, L. Mechanisms of type-I- and type-II-interferon-mediated signalling. In further studies, it was established that p38 is also required for type-I-IFN-driven gene transcription through GAS elements73. After binding of interferon- (IFN-) to the type II IFN receptor, Janus activated kinase 1 (JAK1) and JAK2 are activated and phosphorylate STAT1 (signal transducer and activator of transcription 1) on the tyrosine residue at position 701 (Tyr701). Uggenti C, Lepelley A, Crow YJ. Activation of Mkk3 and Mkk6 by type I interferons. IFN-s mediate antiviral protection through a distinct class II cytokine receptor complex. They also have antiviral properties10, but they are distinct from the type I and type II IFNs and bind a different cell-surface receptor, which is composed of two chains, IFNLR1 (also known as IL-28 receptor-, IL-28R) and IL-10R10. Both possess indirect antiviral properties. The complexity of the IFN system leaves no doubt that extensive effort will be required to precisely define the hierarchical structure of the IFN-mediated signalling machinery. (vCRK). Matikainen, S. et al. Interferon / promotes cell survival by activating nuclear factor B through phosphatidylinositol 3-kinase and Akt. 278, 3935639371 (2003). Through their various downstream effectors, MAPKs regulate diverse functional responses, depending on the stimulus and cellular context. Animals (Basel). Wen, Z., Zhong, Z. The identification of effector kinases that are activated downstream of p38 and mediate its regulatory effects on gene transcription and on the generation of IFN-induced biological properties is of considerable interest. A. 56, 727777 (1987). The structure and activity of a monomeric interferon-:-chain receptor signaling complex. J. Biol. The IRS-pathway operates distinctively from the Stat-pathway in hematopoietic cells and transduces common and distinct signals during engagement of the insulin or interferon- receptors. Uddin, S. et al. However, they block the proliferation of type-2 T helper cells. 276, 1375613761 (2001). Proc. Liang, T. J., Rehermann, B., Seeff, L. B. USP22 crucial for type III interferon signaling and SARS-CoV-2 infection 295, 173182 (2004). The TOR pathway: a target for cancer therapy. There is no doubt that the PI3KAKTMTOR-signalling pathway is activated by growth factors and other mitogenic stimuli to transduce pro-survival and growth-promoting signals127,128,129. Interferon type II. Taken together, these findings indicate that, during responses to IFNs, the PI3K-signalling pathway can mediate either pro-apoptotic or anti-apoptotic signals, depending on the cellular context and, probably, the simultaneous activation or absence of activation of other IFN-dependent signalling pathways. Search for articles by this author , Y. Jiang 1. x. Y. Jiang . EMBO J. Role of the Akt pathway in mRNA translation of interferon-stimulated genes. Interferon downregulates tight junction function, which is rescued by J. Biol. Chem. Here, we use a mouse model of SARS-CoV-2 infection, facilitating viral entry by intranasal recombinant Adeno-Associated Virus (rAAV) transduction of hACE2 in wildtype (WT) and type I IFN-signalling-deficient (Ifnar1-/-) mice, to study type I IFN signalling deficiency and innate immune responses during SARS-CoV-2 infection. Google Scholar. Platanias, L. C. Map kinase signaling pathways and hematologic malignancies. government site. The work provided further evidence on how the virus may interact with the neurovascular unit, resulting in enhanced inflammatory signaling in affected cells. Mol. Interferon- excess leads to pathogenic accumulation of follicular helper T cells and germinal centers. Interestingly, the IFN-dependent activation of p38 is preserved in MEFs that are deficient in either MAPKK3 or MAPKK6, indicating that these kinases have redundant roles in IFN-mediated signalling82. 1). IFN-, the only type II IFN, initiates signalling by binding a distinct receptor at the cell surface. 7, 13951402 (1988). Chem. Two contact regions between Stat1 and CBP/p300 in interferon signaling. Chem. Protein domains that are commonly found in signal-transduction molecules. Mol. Amino-acid sequences that are present in several signalling proteins that mediate their function through binding phosphatidylinositols. The gene that encodes this cytokine is located on chromosome 12 in humans and chromosome 10 in mice, and the protein does not have marked structural homology with type I IFNs1,2,3,4,5,6. Mechanisms of type I interferon signaling in normal and malignant cells. The IFN-dependent phosphorylation (activation) of CRKL also results in induction of the GEF activity of C3G. J. Biol. Subsequent studies showed that CRKL is also tyrosine phosphorylated during IFN--mediated signalling51. Semin. An important transcriptional complex that is induced by type I IFNs is the ISG factor 3 (ISGF3) complex5,6,19,20,21 (Fig. Interactions of STATs with co-activators. Platanias, L. C. The p38 mitogen-activated protein kinase pathway and its role in interferon signaling. J. Biol. Despite the benefits from mouse models, human ADs are chronic inflammation processes instead of short-term and self-limited diseases induced in preclinical models. interferon-induced interferon regulatory factor 1-dependent antiviral response inhibits vaccinia virus replication in mouse but not human fibroblasts. Subsequent studies showed that a member of the PKC family of proteins, PKC-, is activated by treatment of cells with either type I (IFN-, IFN- or IFN-)32 or type II (IFN-)33 IFNs and associates with STAT1 (Refs 32,33). Garber, K. Rapamycin's resurrection: a new way to target the cancer cell cycle. MB), Redistribute or republish the final article, Reuse portions or extracts from the article in other works. IFN signals through the IFN receptor, a protein complex that mediates downstream signaling events. R. Soc. here we reveal that aging leads to increased interferon signaling and elevated concentrations of chemokines in the lung, which is associated with infiltration of monocytes into the lung parenchyma. Phospho-IRF-7 (Ser471/472) Antibody | Cell Signaling Technology David, M. et al. Such activation seems to be important for IFN-dependent transcriptional activation, as shown by the requirement for this kinase in IFN-dependent transcription of Isg15 (IFN-stimulated protein of 15 kDa)82 and in induction of the antiviral properties of type I IFNs75. Lipid microdomains are required sites for the selective endocytosis and nuclear translocation of IFN-, its receptor chain IFN- receptor-1, and the phosphorylation and nuclear translocation of STAT1. 2017. The high-affinity IFN-gamma receptor complex is made up of two type I transmembrane proteins, IFN-gamma R1 (IFN-gamma R alpha) and IFN-gamma R2 (IFN-gamma R beta). Although IFN is the central mediator of the adaptive immune response to pathogens, it has been shown to be involved in several non-infectious physiological processes. 112, 327336 (2001). IFNs have had a considerable impact on clinical medicine, and their use has changed the outcome of various malignancies, viral infections and autoimmune disorders (Box 3). 279, 1228612292 (2004). Chem. Inhibition of the kinase activity of PKC- was found to block phosphorylation of STAT1 on Ser727, as well as STAT1-mediated gene transcription through ISREs or GAS elements, indicating a crucial role for this kinase in IFN-dependent gene transcription. Curr. Interaction of p59fyn with interferon-activated Jak kinases. 51) in a CRKL-dependent manner58. MCE PMID: 20712453 The discovery and initial description of the interferon-lambda (IFN-lambda) family in early 2003 opened an exciting new chapter in the field of IFN research. The biologically active form of IFN-gamma is a noncovalently-linked homodimer. Biol. Proc. Other studies have shown that disruption of the p38 gene results in defective transcription of genes that are regulated by ISREs and/or GAS elements75 but that IFN--dependent serine phosphorylation of STAT1 and formation of DNA-binding complexes are intact in p38-deficient cells75, which firmly establishes that the regulatory effects of the p38-signalling pathway on type-I-IFN-dependent transcriptional regulation are not linked to any direct effects on the function of STATs. sst2 Somatostatin receptor inhibits cell proliferation through Ras-, Rap1-, and B-Raf-dependent ERK2 activation. Using a human . Sci. The most ex-tensively studied IL-12-based immunotherapy consists of a plasmid-encoded human IL-12 gene injected and elec- Uddin, S., Sweet, M. E., Colamonici, O. R., Krolewski, J. J. IFNGR1, IFN- receptor subunit 1; IFNGR2, IFN- receptor subunit 2. In the canonical pathway of IFN signaling, IFN dimerizes and binds to the two IFNGR1 receptors. The observation that IFN is capable of inducing gene expression in STAT1. Get the latest news, product updates, and promotions: We currently do not offer products for this molecule. Mariana Puntel, Robert Barrett, . Interestingly, after the original finding that PKC- is an IFN-activated serine kinase for STAT1 (Ref. 18, 19261945 (2004). Kotlyarov, A. Improved mouse models to assess tumour immunity and irAEs after combination cancer immunotherapies. Chronic expression of interferon leads to murine autoimmune cholangitis with a female predominance. There is accumulating evidence that several other IFN-regulated signalling elements and cascades are required for the generation of many of the responses to IFNs. Cancer Res. However, PI3K activity can be detected in IFN--treated cells106, indicating that other unknown phosphoproteins have analogous roles in type-II-IFN-mediated signalling to those of IRS proteins in type-I-IFN-mediated signalling. An excellent review of the mechanisms of STAT activation and the regulatory effects of STATs on gene transcription. Nature 385, 169172 (1997). Activation of a CrkLStat5 signaling complex by type I interferons. It seems that the function of enzymes that promote or impede histone acetylation can modify the transcriptional capacity of STATs, underscoring the complexity of the process. Res. Other studies have also established that p38 and its downstream effector MAPKAPK2 are activated in a type-I-IFN-dependent manner in primitive haematopoietic precursors, to mediate haematopoietic-suppressive signals90. Article Definitive evidence that the type-I-IFN-activated p38-signalling pathway is required for transcriptional regulation. Parmar, S. & Platanias, L. C. Interferons: mechanisms of action and clinical applications. Zhu, M., John, S., Berg, M. & Leonard, W. J. Functional association of Nmi with Stat5 and Stat1 in IL-2- and IFN-mediated signaling. The genes that encode type I IFNs are clustered on chromosome 9 in humans2 and on chromosome 4 in mice4. Activation of the JAKs that are associated with the type I IFN receptor results in tyrosine phosphorylation of STAT2 (signal transducer and activator of transcription 2) and STAT1; this leads to the formation of STAT1STAT2IRF9 (IFN-regulatory factor 9) complexes, which are known as ISGF3 (IFN-stimulated gene (ISG) factor 3) complexes. The first report that CRKL forms DNA-binding complexes with STAT5 and functions as a nuclear adaptor for STAT5 in type-I-IFN-mediated signalling. Bos, J. L., de Rooij, J. For example, it is known that both. It is anticipated that an increased understanding of the contributions of these recently identified pathways will advance our current thinking about how interferons work. Tumor promotion by depleting cells of protein kinase C-. 81), followed by VAV-dependent exchange of GDP for GTP in RAC1, ultimately leading to activation of downstream MAPK kinases (MAPKKs; also known as MKKs) that phosphorylate p38 (Fig. Finally, another putative p38-dependent effector for the generation of responses to IFNs is the MAPK-interacting protein kinase 1 (MNK1) (Fig. Nature Rev. J. Biol. 2005 Aug 11;436(7052):871-5. doi: 10.1038/nature03869. Interferon Signaling | Pathway - PubChem Oncogene 23, 28192824 (2004). While it does not share structural homology or a common receptor with the type I IFNs, it too has antiviral and immunomodulatory properties. 73). Science 297, 20632066 (2002). These other proteins include the transcriptional co-activator general control non-depressible 5 (GCN5)42 and the chromatin-remodelling factor brahma-related gene 1 (BRG1)43, which interact with STAT2, and they also include NMI (nMYC and STAT interactor), which interacts with all STATs, except STAT2 (Ref. Modern Clinical Mycobacterium tuberculosis Strains Leverage Type I IFN Pathway for a Proinflammatory Response in the Host. Cell Res. image, Download .pdf (.12 Roy, S. K. et al. Interferon type II is a family of interferons involved in immune system regulation. In addition to IRS1, IRS2 was subsequently shown to undergo phosphorylation in a type-I-IFN-dependent manner and to provide docking sites for PI3K103,104. Previous Article in Journal. Mayer, B. J., Hamaguchi, M. & Hanafusa, H. A novel viral oncogene with structural homology to phospholipase C. Nature 332, 272275 (1988). Sci. N, any nucleotide. Conversely, in the presence of Stat1, activation of canonical and non-canonical pathways could happen simultaneously (. As well as activation of classical JAKSTAT (signal transducer and activator of transcription)-signalling pathways (discussed later), activation of IFN-receptor-associated JAKs seems to regulate, either directly or indirectly, several other downstream cascades. Activation of protein kinase C by IFN-. Dataset - interferome.org Chem. STATs interact, in the nucleus, with several co-activator proteins that have important roles in the regulation of transcription. The absence of STAT2 required multiple complementary early phase mechanisms. 139, 155159 (2003). Fu, X. Y., Schindler, C., Improta, T., Aebersold, R. & Darnell, J. E. The proteins of ISGF-3, the interferon -induced transcriptional activator, define a gene family involved in signal transduction. As in the case of ISRE-driven transcription, this was unrelated to effects on the tyrosine phosphorylation of STAT1, STAT3 or STAT5, or the formation of sis-inducible factor (SIF) complexes (that is, STAT1STAT1, STAT1STAT3 and STAT3STAT3) or CRKLSTAT5 DNA-binding complexes73. In addition, in studies using SB203580, a pharmacological inhibitor of p38, or overexpression of a kinase-inactive p38 mutant, it was shown that inhibition of p38 activity blocks IFN--dependent transcription of genes that are regulated by ISREs71. Science 269, 17211723 (1995). This provided evidence for a link between the IFN receptors and the GEF C3G, with which CRKL associates through its N-terminal SH3 domain5,49. Chem. One involves activation of p70 S6 kinase and phosphorylation of ribosomal protein S6, and the other involves phosphorylation and deactivation of the translational repressor 4EBP1 (eukaryotic translation-initiation factor 4E (EIF4E)-binding protein 1). Cumulative evidence indicates that activation of innate immune responses in the central nervous system (CNS) induces the expression of type 1 interferons (T1 IFNs), a family of cytokines. Biochem. Zhang, J. J. et al. It is probable that the list of new elements involved in IFN-mediated signalling will continue to grow during the next few years, whereas the contributions of known pathways might need to be re-evaluated. IFNAR1, type I IFN receptor subunit 1; IFNAR2, type I IFN receptor subunit 2; TYK2, tyrosine kinase 2. 2C, type I IFN treatment resulted in the phosphorylation of both STAT1 and STAT2, while type II . Department of Health and Human Services. Commun. Google Scholar. 277, 40624068 (2002). Natl Acad. Traditionally, high serum levels of IFN (referred herein as IFN levels) are associated with pro-inflammatory active disease, whereas low IFN levels are associated with anti-inflammatory inactive autoimmune disease. 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