STAT2 is exclusive among the STAT family of transcription factors in

STAT2 is exclusive among the STAT family of transcription factors in that its activation is driven predominantly by only two classes of cell surface receptors: Type I and III interferon receptors. of an ever-changing viral community. Keywords: interferon, transmission transducer and activator of transcription, STAT2, viral antagonism, comparative genomics, interferon stimulated gene Viral infections result in a cascade of intracellular events that lead to the secretion of pro-inflammatory and anti-viral cytokines. For example, ssRNAs from viruses such as influenza activate the intracellular detectors TLR7, RIG-I-like receptors (RLRs) and nucleotide-binding website and leucine-rich-repeat-containing proteins (NLRs).1 Collectively, these detectors promote the transcription and translation of two classes of cytokines that mobilize cells of the innate and adaptive immune system and create a state of viral resistance in neighboring cells and cells. Pro-inflammatory cytokines, such as IL-1, TNF- and IL-8, recruit and activate innate cells such as neutrophils and macrophages that take action early in the response to limit the infection. The anti-viral cytokines IFN-/ and IFN- (type I and III interferons, respectively) take action locally to prevent viral replication and spread. In professional antigen showing cells, such as plasmacytoid dendritic cells, TLR7 activation drives manifestation of IFN- along with numerous members of the IFN- subtype genes.2,3 These cells act both locally and regionally within lymph nodes to perfect T cells and drive the adaptive immune response. In parallel, somatic cells, such as lung epithelial cells, secrete both type I and III interferons that inhibit viral replication within infected cells and create a state of resistance in non-infected cells, effectively limiting viral spread. Type I and III interferons, while signaling through unique receptors, share STAT2 like a common signaling intermediate.4,5 Over 300 genes have been identified as direct transcriptional targets of STAT2 activation, Spry2 many of which remain to be characterized.6 Many of the IFN-induced genes that have been characterized perform an almost exclusive role in the anti-viral response and remain silenced in the absence of infection. Therefore, STAT2 is definitely a pivotal regulator of the interferon-regulated anti-viral response, and the lack of redundancy with this pathway creates an Achilles back heel the sponsor, as a varieties, must protect. Receptor-Mediated STAT2 Activation and the Interferon Response In humans, type I interferons are encoded by ~16 genes and individual genes encoding , , and . Their gene products are highly structurally related and all bind to a single receptor (IFNAR) consisting of heterodimeric R1 and R2 subunits.7 In contrast, IFN- consists of 3 genes, IFN-1, 2 and 3 (formally, IL-29, IL-28a and IL-28b) that are more related to the IL-10 family than to interferon.8,9 IFN- binds a receptor (IFNLR) composed of a unique IFNLR1 and a shared IL-10R2 subunit. Both IFNLR and IFNAR recruit and activate STATs 1, 2 and 3. While STATs 1 and 3 are promiscuously turned on by a number of various other development and cytokines aspect receptors, STAT2 is recruited towards the IFNAR and IFNLR selectively. STAT2 recruitment and activation by both receptors consists of tyrosine phosphorylation of STAT2 by JAK kinases and following oligomerization with STAT1 and IRF-9.10,11 Although a fraction of STAT1:STAT2 heterodimers can translocate towards the nucleus and bind atypical gamma activated series (GAS)-like components,12 the canonical interferon-stimulated gene aspect-3 (ISGF3) organic of STAT2:STAT1:IRF-9 regulates a big fraction of the interferon pathway genes.13 Thus, STAT2 is central towards the induction of the genes in response to both IFN- and IFN-/. In some full cases, type II interferon, IFN-, can mobilize the antiviral response within a STAT2-reliant way.14 Although there is absolutely no proof for direct recruitment of STAT2 towards the IFN-R, MP470 IFN- signaling may drive the forming of an ISGF3-like organic containing STAT2,14 inhibit viral replication15 and induce expression of IFN-/ focus on genes,15,16 through the pairing of phosphorylated STAT1 with latent STAT2 perhaps. Of its setting and path of activation Irrespective, STAT2 serves as the gatekeeper towards the antiviral response, which is normally underscored with the severe susceptibility of STAT2 knockout mice to viruses ranging from influenza to dengue.17-19 Type I and III interferon, while produced in different amounts by unique cell populations, regulate the expression of an overlapping set of interferon stimulated genes (ISGs). Some examples include 2C5-oligoadenylate synthase (OAS), which decorates viral RNAs with branched polyadenosine, and RNA endonuclease L, which promptly MP470 degrades RNAs comprising these polyadenosine modifications.20 Most ISGs, however, have not been well characterized, and some of these genes are so enigmatic that they do not consist of any canonical secondary structures that could aid in predicting their function. Over 300 MP470 ISGs have been recognized by microarray and genomic analysis,6,21 which is definitely curious given the magnitude of antiviral activity.

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