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Interferons (IFNs) represent a group of proteins with notable antiviral capabilities. Recently, the discovery of type IV IFN, i.e. IFN-υ has created a new avenue for research on class II cytokines. In the present study, IFN-υ was identified in blunt snout bream to possess conserved sequence CXXXXX[W/L] and gene locus. In the bream, IFN-υ was expressed in examined tissues and was induced significantly following poly(I:C) stimulation. With the stimulation of recombinant IFN-υ in vivo, transcriptome was sequenced in head kidney, and 814 DEGs were identified with 165 possible IFN-stimulated genes (ISGs) characterized through comparison with type I IFN induced ISGs in zebrafish. Furthermore, IFN-υ was found to show high affinity with CRFB12, but no interaction was observed between IFN-υ and CRFB4, through surface plasmon resonance (SPR) and coimmunoprecipitation (Co-IP) analyses. These results should contribute to the understanding of IFN-υ and its receptor complex, and importantly its immune function in inducing ISGs. • IFN-υ was cloned in blunt snout bream with conserved features. • The type IV IFN was constitutively expressed and was induced by poly(I:C). • Transcriptome induced by recombinant IFN-υ contains about 170 ISGs. • IFN-υ was found to interact with CRFB12, but not CRFB4. [ABSTRACT FROM AUTHOR]

Toll-like receptors (TLRs) are essential for the protection of the host from pathogen infections by initiating the integration of contextual cues to regulate inflammation and immunity. However, without tightly controlled immune responses, the host will be subjected to detrimental outcomes. Therefore, it is important to balance the positive and negative regulations of TLRs to eliminate pathogen infection, yet avert harmful immunological consequences. This study revealed a distinct mechanism underlying the regulation of the TLR network. The expression of sex-determining region Y-box 4 (Sox4) is induced by virus infection in viral infected patients and cultured cells, which subsequently represses the TLR signaling network to facilitate viral replication at multiple levels by a distinct mechanism. Briefly, Sox4 inhibits the production of myeloid differentiation primary response gene 88 (MyD88) and most of the TLRs by binding to their promoters to attenuate gene transcription. In addition, Sox4 blocks the activities of the TLR/MyD88/IRAK4/TAK1 and TLR/TRIF/TRAF3/TBK1 pathways by repressing their key components. Moreover, Sox4 represses the activation of the nuclear factor kappa-B (NF-κB) through interacting with IKKα/α, and attenuates NF-kB and IFN regulatory factors 3/7 (IRF3/7) abundances by promoting protein degradation. All these contributed to the down-regulation of interferons (IFNs) and IFN-stimulated gene (ISG) expression, leading to facilitate the viral replications. Therefore, we reveal a distinct mechanism by which viral pathogens evade host innate immunity and discover a key regulator in host defense.

Toll-like receptors (TLRs) are essential for the protection of the host from pathogen infections by initiating the integration of contextual cues to regulate inflammation and immunity. However, without tightly controlled immune responses, the host will be subjected to detrimental outcomes. Therefore, it is important to balance the positive and negative regulations of TLRs to eliminate pathogen infection, yet avert harmful immunological consequences. This study revealed a distinct mechanism underlying the regulation of the TLR network. The expression of sex-determining region Y-box 4 (Sox4) is induced by virus infection in viral infected patients and cultured cells, which subsequently represses the TLR signaling network to facilitate viral replication at multiple levels by a distinct mechanism. Briefly, Sox4 inhibits the production of myeloid differentiation primary response gene 88 (MyD88) and most of the TLRs by binding to their promoters to attenuate gene transcription. In addition, Sox4 blocks the activities of the TLR/MyD88/IRAK4/TAK1 and TLR/TRIF/TRAF3/TBK1 pathways by repressing their key components. Moreover, Sox4 represses the activation of the nuclear factor kappa-B (NF-κB) through interacting with IKKα/α, and attenuates NF-kB and IFN regulatory factors 3/7 (IRF3/7) abundances by promoting protein degradation. All these contributed to the down-regulation of interferons (IFNs) and IFN-stimulated gene (ISG) expression, leading to facilitate the viral replications. Therefore, we reveal a distinct mechanism by which viral pathogens evade host innate immunity and discover a key regulator in host defense. [ABSTRACT FROM AUTHOR]

Type I interferon (IFN-I) is a pluripotent cytokine that modulates innate and adaptive immunity. We have previously shown that STAT3 suppresses IFN-I response in a manner dependent on its N-terminal domain (NTD), but independent of its DNA-binding and transactivation ability. Using the yeast two-hybrid system, we have identified phospholipid scramblase 2 (PLSCR2) as a STAT3 NTD-binding partner and a suppressor of IFN-I response. Overexpression of PLSCR2 attenuates ISRE-driven reporter activity, which is further aggravated by co-expression of STAT3. Moreover, PLSCR2 deficiency enhances IFN-I-induced gene expression and antiviral activity without affecting the activation or nuclear translocation of STAT1 and STAT2 or the assembly of ISGF3 complex. Instead, PLSCR2 impedes promoter occupancy by ISGF3, an effect further intensified by the presence of STAT3. Moreover, palmitoylation of PLSCR2 is required for its binding to STAT3 and for this suppressive activity. In addition to STAT3, PLSCR2 also interacts with STAT2, which facilitates the suppressive effect on ISGF3-mediated transcriptional activity. Together, these results define the role of a novel STAT3–PLSCR2 axis in fine-tuning IFN-I response.

Type I interferon (IFN-I) is a pluripotent cytokine that modulates innate and adaptive immunity. We have previously shown that STAT3 suppresses IFN-I response in a manner dependent on its N-terminal domain (NTD), but independent of its DNA-binding and transactivation ability. Using the yeast two-hybrid system, we have identified phospholipid scramblase 2 (PLSCR2) as a STAT3 NTD-binding partner and a suppressor of IFN-I response. Overexpression of PLSCR2 attenuates ISRE-driven reporter activity, which is further aggravated by co-expression of STAT3. Moreover, PLSCR2 deficiency enhances IFN-I-induced gene expression and antiviral activity without affecting the activation or nuclear translocation of STAT1 and STAT2 or the assembly of ISGF3 complex. Instead, PLSCR2 impedes promoter occupancy by ISGF3, an effect further intensified by the presence of STAT3. Moreover, palmitoylation of PLSCR2 is required for its binding to STAT3 and for this suppressive activity. In addition to STAT3, PLSCR2 also interacts with STAT2, which facilitates the suppressive effect on ISGF3-mediated transcriptional activity. Together, these results define the role of a novel STAT3–PLSCR2 axis in fine-tuning IFN-I response. [ABSTRACT FROM AUTHOR]

Variants of the RNA-editing enzyme ADAR1 cause Aicardi-Goutières syndrome (AGS), in which severe inflammation occurs in the brain due to innate immune activation. Here, we analyze the RNA-editing status and innate immune activation in an AGS mouse model that carries the Adar P195A mutation in the N terminus of the ADAR1 p150 isoform, the equivalent of the P193A human Zα variant causal for disease. This mutation alone can cause interferon-stimulated gene (ISG) expression in the brain, especially in the periventricular areas, reflecting the pathologic feature of AGS. However, in these mice, ISG expression does not correlate with an overall decrease in RNA editing. Rather, the enhanced ISG expression in the brain due to the P195A mutant is dose dependent. Our findings indicate that ADAR1 can regulate innate immune responses through Z-RNA binding without changing overall RNA editing. [Display omitted] • The ADAR1 P195A mutation alone causes brain innate immune response in Adar P195A/ P195A mice • Haploinsufficiency of ADAR1 P195A mutation dramatically enhances ISG expression in the brain • ISGs are highly expressed in the periventricular areas in the brains of P195A mutant mice • The ADAR1 P195A mutation does not affect the overall RNA-editing levels in the brain Guo et al. analyze a mouse model carrying the ADAR1 Zα domain P195A mutation and find that this specific mutation does not affect the overall RNA-editing activity of ADAR1, while it results in activation of the MDA5-dependent RNA-sensing signaling pathway, leading to robust ISG expression in the brain. [ABSTRACT FROM AUTHOR]

Interferons (IFNs) are pleotropic cytokines secreted upon encounter of pathogens and tumors. Applying their antipathogenic, antiproliferative, and immune stimulatory capacities, recombinant IFNs are frequently prescribed as drugs to treat different diseases. IFNs act by changing the gene expression profile of cells. Due to characteristics such as rapid gene induction and signaling, IFNs also represent prototypical model systems for various aspects of biomedical research (e.g., signal transduction). In regard to the signaling and activated promoters, IFNs can be subdivided into two groups. Here, alterations of the cellular proteome of human cells treated with IFNα and IFNγ were elucidated in a time-resolved manner by quantitative proteome analysis. The majority of protein regulations were strongly IFN type and time dependent. In addition to the expected upregulation of IFN-responsive proteins, an astonishing number of proteins became profoundly repressed especially by IFNγ. Thus, our comprehensive analysis revealed important insights into the human IFN-regulated proteome and its dynamics of protein induction and repression. Interestingly, the new class of IFN-repressed genes comprises known host factors for highly relevant pathogens such as HIV, dengue virus, and hepatitis C virus.

By interfering with the type I interferon (IFN1) response, human immunodeficiency virus 1 (HIV-1) can circumvent host antiviral signalling and establish persistent viral reservoirs. HIV-1-mediated defects in the IFN pathway are numerous, and include the impairment of protein receptors involved in pathogen detection, downstream signalling cascades required for IFN1 upregulation, and expression or function of key IFN1-inducible, antiviral proteins. Despite this, the activation of IFN1-inducible, antiviral proteins has been shown to facilitate the killing of latently HIV-infected cells in vitro . Understanding how IFN1 signalling is blocked in physiologically-relevant models of HIV-1 infection, and whether these defects can be reversed, is therefore of great importance for the development of novel therapeutic strategies aimed at eradicating the HIV-1 reservoir. [ABSTRACT FROM AUTHOR]

Interferons (IFNs) are pleotropic cytokines secreted upon encounter of pathogens and tumors. Applying their antipathogenic, antiproliferative, and immune stimulatory capacities, recombinant IFNs are frequently prescribed as drugs to treat different diseases. IFNs act by changing the gene expression profile of cells. Due to characteristics such as rapid gene induction and signaling, IFNs also represent prototypical model systems for various aspects of biomedical research (e.g., signal transduction). In regard to the signaling and activated promoters, IFNs can be subdivided into two groups. Here, alterations of the cellular proteome of human cells treated with IFNα and IFNγ were elucidated in a time-resolved manner by quantitative proteome analysis. The majority of protein regulations were strongly IFN type and time dependent. In addition to the expected upregulation of IFNresponsive proteins, an astonishing number of proteins became profoundly repressed especially by IFNγ. Thus, our comprehensive analysis revealed important insights into the human IFN-regulated proteome and its dynamics of protein induction and repression. Interestingly, the new class of IFN-repressed genes comprises known host factors for highly relevant pathogens such as HIV, dengue virus, and hepatitis C virus. [ABSTRACT FROM AUTHOR]

Viperin is an IFN-inducible radical S-adenosylmethionine (SAM) enzyme that inhibits viral replication. We determined crystal structures of an anaerobically prepared fragment of mouse viperin (residues 45-362) complexed with S-adenosylhomocysteine (SAH) or 5'-deoxyadenosine (5'-dAdo) and L-methionine (L-Met). Viperin contains a partial (βα)6-barrel fold with a disordered N-terminal extension (residues 45-74) and a partially ordered C-terminal extension (residues 285-362) that bridges the partial barrel to form an overall closed barrel structure. Cys84, Cys88, and Cys91 located after the first β-strand bind a [4Fe-4S] cluster. The active site architecture of viperin with bound SAH (a SAM analog) or 5'-dAdo and L-Met (SAM cleavage products) is consistent with the canonical mechanism of 5'-deoxyadenosyl radical generation. The viperin structure, together with sequence alignments, suggests that vertebrate viperins are highly conserved and that fungi contain a viperin-like ortholog. Many bacteria and archaebacteria also express viperin-like enzymes with conserved active site residues. Structural alignments show that viperin is similar to several other radical SAM enzymes, including the molybdenum cofactor biosynthetic enzyme MoaA and the RNA methyltransferase RlmN, which methylates specific nucleotides in rRNA and tRNA. The viperin putative active site contains several conserved positively charged residues, and a portion of the active site shows structural similarity to the GTPbinding site of MoaA, suggesting that the viperin substrate may be a nucleoside triphosphate of some type. [ABSTRACT FROM AUTHOR]

Influenza A virus (IAV) is an important pathogen that has a wide range of hosts and represents a threat to the health of humans and several animal species. IAV infection can induce the transcription of many genes in the host. In the present study, we demonstrated for the first time that three different strains of H1N1 IAV induce the expression of an IFN-stimulated gene, ISG20. We determined the antiviral activity of ISG20 against IAV because ISG20 inhibited viral protein expression and reduced the progeny viral titer dependent upon its exonuclease activity. To elucidate the detailed mechanism of ISG20, we further demonstrated that ISG20 impairs the polymerase activity and inhibits both the replication and transcription levels of the M1 and NP genes. Notably, we identified that ISG20 colocalizes and interacts with NP during IAV infection, while exonuclease-inactive mutant ISG20 lacked association with NP, indicating that ISG20 inhibits IAV replication by interacting with NP. Together, these data provide a detailed explanation for the specific antiviral action of ISG20 and suggest that ISG20 may act as a promising antiviral drug candidate against IAV. [ABSTRACT FROM AUTHOR]

Abstract: Viperin is an antiviral protein that is induced by different viruses, type I interferon, poly(I:C) and lipopolysaccharide, which is localized to the endoplasmic reticulum and lipid droplets. Recently, our knowledge on the mechanism by which viperin inhibits viral replication has strongly increased. Interestingly, it also became clear that viperin can be used by viruses to increase their infectivity. Here, our current knowledge on the induction of viperin and its effect on virus replication will be reviewed. [Copyright &y& Elsevier]

[Display omitted] Thrombocytopenia is common among patients with viral hepatitis, limiting the use of antiviral therapy. Eltrombopag (EP) is a thrombopoietin receptor (TPO-R) agonist that has been approved for treatment of immune thrombocytopenia patients with hepatitis virus infection. Interferon-α (IFN-α) plays a crucial role in the antiviral response, and is recommended as the first-line agent for chronic hepatitis B patients. Here, we investigated whether EP inhibits the production of IFN-stimulated genes (ISGs) induced by IFN-α through the TPO-R-independent pathway by mediating reactive oxygen species production by iron chelation. Our results assessed the inhibitory effect of EP on IFN-α signaling, which contributes to the downregulation of ISGs produced by monocytes and sheds light on the underlying mechanisms using iron chelation to treat patients with hepatitis-related immunological thrombocytopenia. [ABSTRACT FROM AUTHOR]

The immune system is tasked with identifying malignant cells to eliminate or prevent cancer spread. This involves a complex orchestration of many immune cell types that together recognize different aspects of tumor transformation and growth. In response, tumors have developed mechanisms to circumvent immune attack. Type I interferons (IFN-Is) are a class of proinflammatory cytokines produced in response to viruses and other environmental stressors. IFN-Is are also emerging as essential drivers of antitumor immunity, potently stimulating the ability of immune cells to eliminate tumor cells. However, a more complicated role for IFN-Is has arisen, as prolonged stimulation can promote feedback inhibitory mechanisms that contribute to immune exhaustion and other deleterious effects that directly or indirectly permit cancer cells to escape immune clearance. We review the fundamental and opposing functions of IFN-Is that modulate tumor growth and impact immune function and ultimately how these functions can be harnessed for the design of new cancer therapies.

Peste des petits ruminants virus (PPRV) is a morbillivirus which causes severe disease in ruminants. Since interferons (IFNs) serve as the important defense line against viral infection, we have investigated the roles of types I and III IFNs in PPRV infection in vitro. Upon PPRV infection, IFN-λ3 was strongly induced, while IFN-β and IFN-λ2 were moderately induced at transcriptional level in human embryonic kidney 293 T (HEK293T) cells. Although the transcription of type I and III IFNs were triggered, the production of functional IFN products was not detected. Importantly, the replication of PPRV was strongly inhibited in HEK293T cells treated by the exogenous IFNs (IFN-α-2b, IFN-β and IFN-λ3). Consistently, these IFNs significantly activate a panel of IFN-stimulated genes (ISGs). The inhibition of JAK-STAT pathway by JAK I inhibitor can abrogate the anti-PPRV activity of IFNs. Thus, our study shall contribute to better understanding of the complex PPRV-host interactions and provide rationale for therapeutic development of IFN-based treatment against PPRV infection. • The transcription of type I and III IFNs were triggered upon PPRV infection in HEK293T cells. • PPRV is sensitive to Exogenous IFNs (IFN-α-2b and IFN-λ3) treatment. • The JAK-STAT signaling pathway mediates the anti-PPRV effect of IFN-α-2b. [ABSTRACT FROM AUTHOR]

• Human cervical epithelial cells (HCEs) express the functional IL-22 receptor. • IL-22 inhibits HSV-2 replication in HCEs. • IL-22 induces the expression of ISGs and the tight junction proteins in HCEs. • IL-22 has potential as a therapeutic agent to inhibit HSV-2 infection. Interleukin (IL)-22, a member of the IL-10 family, plays a role in antiviral immune responses to a number of viral infections. However, it is unclear whether IL-22 is involved in the mucosal immunity against herpes simplex virus 2 (HSV-2) infection in the female reproductive tract (FRT). In this study, we studied whether IL-22 could inhibit HSV-2 infection of human cervical epithelial cells (End1/E6E7 cells). We showed that End1/E6E7 cells express the functional IL-22 receptor complex (IL-22R1 and IL-10R2). When treated with IL-22, End1/E6E7 cells expressed the higher levels of IFN-stimulated genes (ISGs: ISG15, ISG56, OAS-1, OAS-2, and Mx2) than untreated cells. In addition, IL-22-treated cells produced higher levels of the tight junction proteins (ZO-1 and Occludin) than untreated cells. Mechanistically, IL-22 could activate the JAK/STAT signaling pathway by inducing the phosphorylation of STAT1 and STAT3. These observations indicate the potential of IL-22 as an anti-HSV-2 agent in the FRT mucosal innate immunity against HSV-2 infection. [ABSTRACT FROM AUTHOR]

γ-interferon-inducible protein-16 (IFI16), a key DNA sensor, triggers downstream STING-dependent type I interferon (IFN-I) production and antiviral immunity. However, it is still unclear how to negatively regulate IFI16 to avoid excessive IFN-I production and autoimmunity. Here, we find that STING directly interacts with IFI16 and facilitates IFI16 degradation via the ubiquitin-proteasome pathway by recruiting the E3 ligase TRIM21. The 1-pyrin region of IFI16 is responsible for the IFI16-STING interaction, and the first three lysines in the N-terminal region of IFI16 are the key sites that lead to STING-mediated IFI16 ubiquitination and degradation. Compared to wild-type IFI16, a higher level of viral DNA triggered IFN-β and antiviral IFN-stimulated gene expression, and thus less HSV-1 infection, was observed in the cells transfected with IFI16-K3/4/6R, an IFI16 mutant that is resistant to degradation. STING-mediated negative feedback regulation of IFI16 restricts IFN-I overproduction during antiviral immunity to avoid autoimmune diseases. • Overexpression of STING facilitates IFI16 degradation • E3 ligase TRIM21 plays a role in STING-mediated IFI16 degradation • IFI16-K3/4/6R mutation stabilizes IFI16 protein • IFI16-K3/4/6R facilitates type I IFN production Li et al. show that STING mediates negative feedback regulation of IFI16 and restricts type I IFN overproduction during immune responses to viruses such as HSV-1. [ABSTRACT FROM AUTHOR]

Type I interferon (IFN) plays a crucial role in establishing the cellular antiviral state by inducing transcription of IFN-stimulated genes (ISGs). Generally, histone acetyltransferases (HATs) are positive regulators of transcription, but histone deacetylase (HDAC) activity is essential for transcriptional induction of ISGs. pp32 is known to be a key component of the inhibitor of acetyltransferase (INHAT) complex that inhibits HAT-dependent transcriptional activation. Here, we show that pp32 is involved in the positive regulation of ISG transcription. pp32 interacted with signal transducer and activator of transcription 1 (STAT1) and STAT2 in an IFN-dependent manner. pp32 was not required for tyrosine phosphorylation and nuclear translocation of STATs, but was needed for binding of transcriptional complexes with ISG promoters and, thereby, for maximal transcription activation. pp32 was found to be associated with ISG promoters in IFN-untreated cells, and its binding amount fluctuated as a function of time after IFN treatment. short interfering RNA (siRNA)-mediated knockdown of pp32 expression reduced the histone acetylation level on ISG promoters, suggesting that pp32 plays a role in ISG transcription by a function other than that of INHAT. Taking these findings together, we propose that pp32 is involved in the formation of ISG transcription initiation complexes, possibly as their recruiter. [ABSTRACT FROM AUTHOR]

Human cytomegalovirus (HCMV) is a member of the β-herpesvirus family that invariably occupies hosts for life despite a consistent multi-pronged antiviral immune response that targets the infection. This persistence is enabled by the large viral genome that encodes factors conferring a wide assortment of sophisticated, often redundant phenotypes that disable or otherwise manipulate impactful immune effector processes. The type I interferon system represents a first line of host defense against infecting viruses. The physiological reactions induced by secreted interferon act to effectively block replication of a broad spectrum of virus types, including HCMV. As such, the virus must exhibit counteractive mechanisms to these responses that involve their inhibition, tolerance, or re-purposing. The goal of this review is to describe the impact of the type I interferon system on HCMV replication and to showcase the number and diversity of strategies employed by the virus that allow infection of hosts in the presence of interferon-dependent activity., (© 2013.)

Arenaviruses are enveloped, negative-stranded RNA viruses that belong to the family Arenaviridae. This diverse family can be further classified into OW (Old World) and NW (New World) arenaviruses based on their antigenicity, phylogeny, and geographical distribution. Many of the NW arenaviruses are highly pathogenic viruses that cause systemic human infections characterized by hemorrhagic fever and/or neurological manifestations, constituting public health problems in their endemic regions. NW arenavirus infection induces a variety of host innate immune responses, which could contribute to the viral pathogenesis and/or influence the final outcome of virus infection in vitro and in vivo. On the other hand, NW arenaviruses have also developed several strategies to counteract the host innate immune response. We will review current knowledge regarding the interplay between the host innate immune response and NW arenavirus infection in vitro and in vivo, with emphasis on viral-encoded proteins and their effect on the type I interferon response., (© 2013.)