MAVS Cys508 palmitoylation promotes its aggregation on the mitochondrial outer membrane and antiviral innate immunity.

Cysteine palmitoylation or S-palmitoylation catalyzed by the ZDHHC family of acyltransferases regulates the biological function of numerous mammalian proteins as well as viral proteins. However, understanding of the role of S-palmitoylation in antiviral immunity against RNA viruses remains very limited. The adaptor protein MAVS forms functionally essential prion-like aggregates upon activation by viral RNA-sensing RIG-I-like receptors. Here, we identify that MAVS, a C-terminal tail-anchored mitochondrial outer membrane protein, is S-palmitoylated by ZDHHC7 at Cys508, a residue adjacent to the tail-anchor transmembrane helix. Using superresolution microscopy and other biochemical techniques, we found that the mitochondrial localization of MAVS at resting state mainly depends on its transmembrane tail-anchor, without regulation by Cys508 S-palmitoylation. However, upon viral infection, MAVS S-palmitoylation stabilizes its aggregation on the mitochondrial outer membrane and thus promotes subsequent propagation of antiviral signaling. We further show that inhibition of MAVS S-palmitoylation increases the host susceptibility to RNA virus infection, highlighting the importance of S-palmitoylation in the antiviral innate immunity. Also, our results indicate ZDHHC7 as a potential therapeutic target for MAVS-related autoimmune diseases.

Listerin promotes cGAS protein degradation through the ESCRT pathway to negatively regulate cGAS-mediated immune response.

The enzyme cyclic GMP-AMP synthase (cGAS) is a key sensor for detecting misplaced double-stranded DNA (dsDNA) of genomic, mitochondrial, and microbial origin. It synthesizes 2'3'-cGAMP, which in turn activates the stimulator of interferon genes pathway, leading to the initiation of innate immune responses. Here, we identified Listerin as a negative regulator of cGAS-mediated innate immune response. We found that Listerin interacts with cGAS on endosomes and promotes its K63-linked ubiquitination through recruitment of the E3 ligase TRIM27. The polyubiquitinated cGAS is then recognized by the endosomal sorting complexes required for transport machinery and sorted into endosomes for degradation. Listerin deficiency enhances the innate antiviral response to herpes simplex virus 1 infection. Genetic deletion of Listerin also deteriorates the neuroinflammation and the ALS disease progress in an ALS mice model; overexpression of Listerin can robustly ameliorate disease progression in ALS mice. Thus, our work uncovers a mechanism for cGAS regulation and suggests that Listerin may be a promising therapeutic target for ALS disease.

HSV-1 reactivation results in post-herpetic neuralgia by upregulating Prmt6 and inhibiting cGAS-STING.

Chronic varicella zoster virus (VZV) infection induced neuroinflammatory condition is the critical pathology of post-herpetic neuralgia (PHN). The immune escape mechanism of VZV remains elusive. As to mice have no VZV infection receptor, herpes simplex virus type 1 (HSV-1) infection is a well established PHN mice model. Transcriptional expression analysis identified that the protein arginine methyltransferases 6 (Prmt6) was upregulated upon HSV-1 infection, which was further confirmed by immunofluorescence staining in spinal dorsal horn. Prmt6 deficiency decreased HSV-1-induced neuroinflammation and PHN by enhancing antiviral innate immunity and decreasing HSV-1 load in vivo and in vitro. Overexpression of Prmt6 in microglia dampened antiviral innate immunity and increased HSV-1 load. Mechanistically, Prmt6 methylated and inactivated STING, resulting in reduced phosphorylation of TANK binding kinase-1 (TBK1) and interferon regulatory factor 3 (IRF3), diminished production of type I interferon (IFN-I) and antiviral innate immunity. Furthermore, intrathecal or intraperitoneal administration of the Prmt6 inhibitor EPZ020411 decreased HSV-1-induced neuroinflammation and PHN by enhancing antiviral innate immunity and decreasing HSV-1 load. Our findings revealed that HSV-1 escapes antiviral innate immunity and results in PHN by upregulating Prmt6 expression and inhibiting the cGAS-STING pathway, providing novel insights and a potential therapeutic target for PHN.

Impaired innate antiviral defenses in COVID-19: Causes, consequences and therapeutic opportunities.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a recently emerged pathogen that has caused coronavirus disease 2019 (COVID-19), the worst pandemic of our times leading to tremendous loss of human life and unprecedented measures of social distancing. COVID-19 symptom manifestations range from asymptomatic disease to severe and lethal outcomes. Lack of previous exposure and immunity to SARS-CoV-2, and high infectivity of the virus have contributed to its broad spread across the globe. In the absence of specific adaptive immunity, innate immune mechanisms are crucial for efficient antiviral defenses and control of the infection. Accumulating evidence now suggests that the remarkable heterogeneity in COVID-19 disease manifestations is due to variable degrees of impairment of innate immune mechanisms. In this review, we summarize recent findings describing both viral and host intrinsic factors that have been linked to defective innate immune responses and account for severe COVID-19. We also discuss emerging therapeutic opportunities for targeting innate immunity for the treatment of COVID-19.

Endocytosis triggers V-ATPase-SYK-mediated priming of cGAS activation and innate immune response.

The current view of nucleic acid-mediated innate immunity is that binding of intracellular sensors to nucleic acids is sufficient for their activation. Here, we report that endocytosis of virus or foreign DNA initiates a priming signal for the DNA sensor cyclic GMP-AMP synthase (cGAS)-mediated innate immune response. Mechanistically, viral infection or foreign DNA transfection triggers recruitment of the spleen tyrosine kinase (SYK) and cGAS to the endosomal vacuolar H+ pump (V-ATPase), where SYK is activated and then phosphorylates human cGASY214/215 (mouse cGasY200/201) to prime its activation. Upon binding to DNA, the primed cGAS initiates robust cGAMP production and mediator of IRF3 activation/stimulator of interferon genes-dependent innate immune response. Consistently, blocking the V-ATPase-SYK axis impairs DNA virus- and transfected DNA-induced cGAMP production and expression of antiviral genes. Our findings reveal that V-ATPase-SYK-mediated tyrosine phosphorylation of cGAS following endocytosis of virus or other cargos serves as a priming signal for cGAS activation and innate immune response.

Sirt1 Negatively Regulates Cellular Antiviral Responses by Preventing the Cytoplasmic Translocation of Interferon-Inducible Protein 16 in Human Cells.

Interferon-inducible protein 16 (IFI16) plays a critical role in antiviral innate immune responses against DNA viruses. Although the acetylation of IFI16 is crucial to its cytoplasmic translocation and downstream signal transduction, the regulation of IFI16 acetylation remains unclear. In this study, we demonstrated that the NAD-dependent deacetylase silent information regulatory 1 (Sirtuin1, Sirt1) interacted with IFI16 and decreased the acetylation of IFI16, resulting in the inhibition of IFI16 cytoplasmic localization and antiviral responses against DNA virus and viral DNA in human cells. Meantime, Sirt1 could not inhibit RNA virus-triggered signal transduction. Interestingly, even p204, the murine ortholog of human IFI16, barely interacted with Sirt1. Thus, Sirt1 could not negatively regulate the acetylation of p204 and subsequent signal transduction upon herpes simplex virus 1 (HSV-1) infection in mouse cells. Taken together, our research work showed a new mechanism by which Sirt1 manipulated IFI16-mediated host defense. Our study also demonstrated a difference in the regulation of antiviral host defense between humans and mice, which might be considered in preclinical studies for antiviral treatment. IMPORTANCE DNA viruses, such as hepatitis B virus (HBV), human papillomavirus (HPV), human cytomegalovirus (HCMV), Epstein-Barr virus (EBV), and herpes simplex virus (HSV), can cause a wide range of diseases and are considered a global threat to human health. Interferon-inducible protein 16 (IFI16) binds virus DNA and triggers antiviral innate immune responses to restrict viral infection. In this study, we identified that silent information regulatory 1 (Sirtuin1, Sirt1) interacted with IFI16 and regulated IFI16-mediated innate host defense. Therefore, the activator or inhibitor of Sirt1 may have the potential to be used as a novel strategy to treat DNA virus-associated diseases. We also found that Sirt1 barely interacted with p204, the murine ortholog of human IFI16, and could not negatively regulate innate immune responses upon HSV-1 infection in mouse cells. This difference between humans and mice in the regulation of antiviral host defense might be considered in preclinical studies for antiviral treatment.

O-GlcNAc of STING mediates antiviral innate immunity.

BACKGROUND: O-GlcNAcylation modification affects multiple physiological and pathophysiolocal functions of cells. Altered O-GlcNAcylation was reported to participate in antivirus response. Stimulator of interferon genes (STING) is an adaptor mediating DNA virus-induced innate immune response. Whether STING is able to be modified by O-GlcNAcylation and how O-GlcNAcylation affects STING-mediated anti-DNA virus response remain unknown. METHODS: Metabolomics analysis was used for detecting metabolic alterations in HSV-1 infection cells. Succinylated wheat germ agglutinin (sWGA), co-immunoprecipitation, and pull-down assay were employed for determining O-GlcNAcylation. Mutagenesis PCR was applied for the generation of STING mutants. WT and Sting1-/- C57BL/6 mice (KOCMP-72512-Sting1-B6NVA) were infected with HSV-1 and treated with O-GlcNAcylation inhibitor for validating the role of STING O-GlcNAcylation in antiviral response. RESULTS: STING was functionally activated by O-GlcNAcylation in host cells challenged with HSV-1. We demonstrated that this signaling event was initiated by virus infection-enhanced hexosamine biosynthesis pathway (HBP). HSV-1 (or viral DNA mimics) promotes glucose metabolism of host cells with a marked increase in HBP, which provides donor glucosamine for O-GlcNAcylation. STING was O-GlcNAcylated on threonine 229, which led to lysine 63-linked ubiquitination of STING and activation of antiviral immune responses. Mutation of STING T229 to alanine abrogated STING activation and reduced HSV-1 stimulated production of interferon (IFN). Application of 6-diazo-5-oxonorleucine (DON), an agent that blocks the production of UDP-GlcNAc and inhibits O-GlcNAcylation, markedly attenuated the removal of HSV-1 in wild type C57BL/6 mice, leading to an increased viral retention, elevated infiltration of inflammatory cells, and worsened tissue damages to those displayed in STING gene knockout mice. Together, our data suggest that STING is O-GlcNAcylated in HSV-1, which is crucial for an effective antiviral innate immune response. CONCLUSION: HSV-1 infection activates the generation of UDP-Glc-NAc by upregulating the HBP metabolism. Elevated UDP-Glc-NAc promotes the O-GlcNAcylation of STING, which mediates the anti-viral function of STING. Targeting O-GlcNAcylation of STING could be a useful strategy for antiviral innate immunity.

Identification of pigeon mitochondrial antiviral signaling protein (MAVS) and its role in antiviral innate immunity.

Pigeons can be infected with various RNA viruses, and their innate immune system responds to viral infection to establish an antiviral response. Mitochondrial antiviral signaling protein (MAVS), an important adaptor protein in signal transduction, plays a pivotal role in amplifying the innate immune response. In this study, we successfully cloned pigeon MAVS (piMAVS) and performed a bioinformatics analysis. The results showed that the caspase recruitment domain (CARD) and transmembrane (TM) domain are highly conserved in poultry and mammals but poorly conserved in other species. Furthermore, we observed that MAVS expression is upregulated both in pigeons and pigeon embryonic fibroblasts (PEFs) upon RNA virus infection. Overexpression of MAVS resulted in increased levels of ß-interferon (IFN-ß), IFN-stimulated genes (ISGs), and interleukin (ILs) mRNA and inhibited Newcastle disease virus (NDV) replication. We also found that piMAVS and human MAVS (huMAVS) induced stronger expression of IFN-ß and ISGs when compared to chicken MAVS (chMAVS), and this phenomenon was also reflected in the degree of inhibition of NDV replication. Our findings demonstrate that piMAVS plays an important role in repressing viral replication by regulating the activation of the IFN signal pathway in pigeons. This study not only sheds light on the function of piMAVS in innate immunity but also contributes to a more comprehensive understanding of the innate immunity system in poultry. Our data also provide unique insights into the differences in innate immunity between poultry and mammal.

The emerging roles of IFIT3 in antiviral innate immunity and cellular biology.

The interferon-inducible protein with tetrapeptide repeats 3 (IFIT3) is one of the most important members in both the IFIT family and interferon-stimulated genes family. IFIT3 has typical features of the IFIT family in terms of gene and protein structures, and is able to be activated through the classical PRRs-IFN-JAK/STAT pathway. A variety of viruses can induce the expression of IFIT3, which in turn inhibits the replication of viruses, with the underlying mechanism showing its crucial role in antiviral innate immunity. Emerging studies have also identified that IFIT3 is involved in cellular biology changes, including cell proliferation, apoptosis, differentiation, and cancer development. In this review, we summarize the characteristics of IFIT3 with respect to molecular structure and regulatory pathways, highlighting the role of IFIT3 in antiviral innate immunity, as well as its diverse biological roles. We also discuss the potential of IFIT3 as a biomarker in disease diagnosis and therapy.

SARS-CoV-2 NSP13 interacts with host IRF3, blocking antiviral immune responses.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), poses an unprecedented threat to human health since late 2019. Notably, the progression of the disease is associated with impaired antiviral interferon (IFN) responses. Although multiple viral proteins were identified as potential IFN antagonists, the underlying molecular mechanisms remain to be fully elucidated. In this study, we firstly demonstrate that SARS-CoV-2 NSP13 protein robustly antagonizes IFN response induced by the constitutively active form of transcription factor IRF3 (IRF3/5D). This induction of IFN response by IRF3/5D is independent of the upstream kinase, TBK1, a previously reported NSP13 target, thus indicating that NSP13 can act at the level of IRF3 to antagonize IFN production. Consistently, NSP13 exhibits a specific, TBK1-independent interaction with IRF3, which, moreover, is much stronger than that of NSP13 with TBK1. Furthermore, the NSP13-IRF3 interaction was shown to occur between the NSP13 1B domain and IRF3 IRF association domain (IAD). In agreement with the strong targeting of IRF3 by NSP13, we then found that NSP13 blocks IRF3-directed signal transduction and antiviral gene expression, counteracting IRF3-driven anti-SARS-CoV-2 activity. These data suggest that IRF3 is likely to be a major target of NSP13 in antagonizing antiviral IFN responses and provide new insights into the SARS-CoV-2-host interactions that lead to viral immune evasion.

Bacterial vesicles block viral replication in macrophages via TLR4-TRIF-axis.

Gram-negative bacteria naturally secrete nano-sized outer membrane vesicles (OMVs), which are important mediators of communication and pathogenesis. OMV uptake by host cells activates TLR signalling via transported PAMPs. As important resident immune cells, alveolar macrophages are located at the air-tissue interface where they comprise the first line of defence against inhaled microorganisms and particles. To date, little is known about the interplay between alveolar macrophages and OMVs from pathogenic bacteria. The immune response to OMVs and underlying mechanisms are still elusive. Here, we investigated the response of primary human macrophages to bacterial vesicles (Legionella pneumophila, Klebsiella pneumoniae, Escherichia coli, Salmonella enterica, Streptococcus pneumoniae) and observed comparable NF-κB activation across all tested vesicles. In contrast, we describe differential type I IFN signalling with prolonged STAT1 phosphorylation and strong Mx1 induction, blocking influenza A virus replication only for Klebsiella, E.coli and Salmonella OMVs. OMV-induced antiviral effects were less pronounced for endotoxin-free Clear coli OMVs and Polymyxin-treated OMVs. LPS stimulation could not mimic this antiviral status, while TRIF knockout abrogated it. Importantly, supernatant from OMV-treated macrophages induced an antiviral response in alveolar epithelial cells (AEC), suggesting OMV-induced intercellular communication. Finally, results were validated in an ex vivo infection model with primary human lung tissue. In conclusion, Klebsiella, E.coli and Salmonella OMVs induce antiviral immunity in macrophages via TLR4-TRIF-signaling to reduce viral replication in macrophages, AECs and lung tissue. These gram-negative bacteria induce antiviral immunity in the lung through OMVs, with a potential decisive and tremendous impact on bacterial and viral coinfection outcome. Video Abstract.

Bmp4 in Zebrafish Enhances Antiviral Innate Immunity through p38 MAPK (Mitogen-Activated Protein Kinases) Pathway.

Bone morphogenetic proteins (BMPs) are a group of structurally and functionally related signaling molecules that comprise a subfamily, belonging to the TGF-ß superfamily. Most BMPs play roles in the regulation of embryonic development, stem cell differentiation, tumor growth and some cardiovascular and cerebrovascular diseases. Although evidence is emerging for the antiviral immunity of a few BMPs, more BMPs are needed to determine whether this function is universal. Here, we identified the zebrafish bmp4 ortholog, whose expression is up-regulated through challenge with grass carp reovirus (GCRV) or its mimic poly(I:C). The overexpression of bmp4 in epithelioma papulosum cyprini (EPC) cells significantly decreased the viral titer of GCRV-infected cells. Moreover, compared to wild-type zebrafish, viral load and mortality were significantly increased in both larvae and adults of bmp4-/- mutant zebrafish infected with GCRV virus. We further demonstrated that Bmp4 promotes the phosphorylation of Tbk1 and Irf3 through the p38 MAPK pathway, thereby inducing the production of type I IFNs in response to virus infection. These data suggest that Bmp4 plays an important role in the host defense against virus infection. Our study expands the understanding of BMP protein functions and opens up new targets for the control of viral infection.

Epigenetic regulation in antiviral innate immunity.

Emerging life-threatening viruses have posed great challenges to public health. It is now increasingly clear that epigenetics plays a role in shaping host-virus interactions and there is a great need for a more thorough understanding of these intricate interactions through the epigenetic lens, which may represent potential therapeutic opportunities in the clinic. In this review, we highlight the current understanding of the roles of key epigenetic regulators - chromatin remodeling and histone modification - in modulating chromatin openness during host defense against virus. We also discuss how the RNA modification m6A (N6-methyladenosine) affects fundamental aspects of host-virus interactions. We conclude with future directions for uncovering more detailed functions that epigenetic regulation exerts on both host cells and viruses during infection.

The emerging roles of the CDK/cyclin complexes in antiviral innate immunity.

More than 20 members of the human cyclin-dependent kinases (CDKs) family share the feature of being activated by cyclins. CDKs have been involved in diverse biological processes, such as cell cycle, transcription, DNA damage response, and apoptosis. If CDKs are not properly regulated, they can cause diseases like cancer. CDKs are Ser/Thr kinases that work with cyclins to control cell cycle progression. Various CDK-cyclin complexes phosphorylate particular target proteins and drive different cell cycle stages. Accumulating evidence demonstrated that CDKs play an essential role in the cell cycle; however, their roles in antiviral innate immunity are just emerging. This minireview summarizes how CDKs play their roles in antiviral innate immunity. Our goal is to draw attention to the involvement of CDKs in antiviral innate immunity, whether as separate entities or as components of CDK/cyclin complexes that have gotten less attention in the past.

UNC93B1 attenuates the cGAS-STING signaling pathway by targeting STING for autophagy-lysosome degradation.

Stimulator of interferon genes (STING) is a pivotal innate immune adaptor, and its functions during DNA virus infections have been extensively documented. However, its homeostatic regulation is not well understood. Our study demonstrates that Unc-93 homolog B1 (UNC93B1) is a crucial checker for STING to prevent hyperactivation. Ectopic expression of UNC93B1 attenuates IFN-ß promoter activity and the transcriptions of IFN-ß, ISG54, and ISG56 genes. Moreover, UNC93B1 also blocks the IRF3 nuclear translocation induced by ectopic expression of both cyclic GMP-AMP synthase (cGAS) and STING and reduces the stability of STING by facilitating its autophagy-lysosome degradation, which can be reversed by lysosome inhibitors. Mechanistically, UNC93B1 interacts with STING and suppresses STING-activated downstream signaling by delivering STING to the lysosomes for degradation, depending on its trafficking capability. UNC93B1 knockout in human embryonic kidney 293T cells facilitates IFN-ß promoter activity, IFN-ß, ISG54, and ISG56 transcriptions, and IRF3 nuclear translocation induced by ectopic expression of cGAS and STING. Infected with herpes simplex virus-1 (HSV-1), UNC93B1 knockdown BJ cells or primary peritoneal macrophages from Unc93b1-deficient (Unc93b1-/- ) mice show enhanced IFN-ß, ISG54, and ISG56 transcriptions, TBK1 phosphorylation, and reduced STING degradation and viral replication. In addition, Unc93b1-/-  mice exhibit higher IFN-ß, ISG54, and ISG56 transcriptions and lower mortality upon HSV-1 infection in vivo. Collectively, these findings demonstrate that UNC93B1 attenuates the cGAS-STING signaling pathway by targeting STING for autophagy-lysosome degradation and provide novel insights into the function of UNC93B1 in antiviral innate immunity.

The molecular mechanism of SARS-CoV-2 evading host antiviral innate immunity.

The newly identified Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has resulted in a global health emergency (COVID-19) because of its rapid spread and high mortality. Since the virus epidemic, many pathogenic mechanisms have been revealed, and virus-related vaccines have been successfully developed and applied in clinical practice. However, the pandemic is still developing, and new mutations are still emerging. Virus pathogenicity is closely related to the immune status of the host. As innate immunity is the body's first defense against viruses, understanding the inhibitory effect of SARS-CoV-2 on innate immunity is of great significance for determining the target of antiviral intervention. This review summarizes the molecular mechanism by which SARS-CoV-2 escapes the host immune system, including suppressing innate immune production and blocking adaptive immune priming. Here, on the one hand, we devoted ourselves to summarizing the combined action of innate immune cells, cytokines, and chemokines to fine-tune the outcome of SARS-CoV-2 infection and the related immunopathogenesis. On the other hand, we focused on the effects of the SARS-CoV-2 on innate immunity, including enhancing viral adhesion, increasing the rate of virus invasion, inhibiting the transcription and translation of immune-related mRNA, increasing cellular mRNA degradation, and inhibiting protein transmembrane transport. This review on the underlying mechanism should provide theoretical support for developing future molecular targeted drugs against SARS-CoV-2. Nevertheless, SARS-CoV-2 is a completely new virus, and people's understanding of it is in the process of rapid growth, and various new studies are also being carried out. Although we strive to make our review as inclusive as possible, there may still be incompleteness.

A glimpse on metazoan ZNFX1 helicases, ancient players of antiviral innate immunity.

The human zinc finger NFX1-type containing 1 (ZNFX1) is an interferon-stimulated protein associated to the outer mitochondrial membrane, able to bind dsRNAs and interact with MAVS proteins, promoting type I IFN response in the early stage of viral infection. An N-terminal Armadillo (ARM)-type fold and a large helicase core (P-loop) and zinc fingers confer RNA-binding and ATPase activities to ZNFX1. We studied the phylogenetic distribution of metazoan ZNFX1s, ZNFX1 gene expression trends and genomic and protein signatures during viral infection of invertebrates. Based on 221 ZNFX1 sequences, we obtained a polyphyletic tree with a taxonomy-consistent branching at the phylum-level only. In metazoan genomes, ZNFX1 genes were found either in single copy, with up to some tens of exons in vertebrates, or in multiple copies, with one or a few exons and one of them sometimes encompassing most of the coding sequence, in invertebrates like sponges, sea urchins and mollusks. Structural analyses of selected ZNFX1 proteins showed high conservation of the helicase region (P-loop), an overall conserved region and domain architecture, an ARM-fold mostly traceable, and the presence of intrinsically disordered regions of varying length and position. The remarkable over-expression of ZNFX1 in bivalve and gastropod mollusks infected with dsDNA viruses underscores the antiviral role of ZNFX1, whereas nothing similar was found in virus-infected nematodes and corals. Whether the functional diversification reported in the C. elegans ZNFX1 occurs in other metazoan proteins remains to be established.

DExD/H-box helicases: multifunctional regulators in antiviral innate immunity.

DExD/H-box helicases play critical roles in multiple cellular processes, including transcription, cellular RNA metabolism, translation, and infections. Several seminal studies over the past decades have delineated the distinct functions of DExD/H-box helicases in regulating antiviral innate immune signaling pathways, including Toll-like receptors, retinoic acid-inducible gene I-like receptors, cyclic GMP-AMP synthase-the stimulator of interferon gene, and NOD-like receptors signaling pathways. Besides the prominent regulatory roles, there is increasing attention on their functions as nucleic acid sensors involved in antiviral innate immunity. Here we summarize the complex regulatory roles of DExD/H-box helicases in antiviral innate immunity. A better understanding of the underlying molecular mechanisms of DExD/H-box helicases' regulatory roles is vital for developing new therapeutics targeting DExD/H-box helicases and their mediated signaling transduction in viral infectious diseases.

A Novel Cognition of Decitabine: Insights into Immunomodulation and Antiviral Effects.

DNA methylation, as one of the major means of epigenesis change, makes a large difference in the spatial structure of chromatin, transposable element activity and, fundamentally, gene transcription. It has been confirmed that DNA methylation is closely related to innate immune responses. Decitabine, the most efficient available DNA methyltransferase inhibitor, has demonstrated exhilarating immune activation and antiviral effects on multiple viruses, including HIV, HBV, HCV, HPV and EHV1. This review considers the role of decitabine in regulating innate immune responses and antiviral ability. Understanding the complex transcriptional and immune regulation of decitabine could help to identify and validate therapeutic methods to reduce pathogen infection-associated morbidity, especially virus infection-induced morbidity and mortality.

NMI Facilitates Influenza A Virus Infection by Promoting Degradation of IRF7 through TRIM21.

Acute respiratory infections caused by influenza A virus (IAV) spread widely and lead to substantial morbidity and mortality. Host cell induction of type I interferon (IFN-I) plays a fundamental role in eliminating the virus during the innate antiviral response. The potential role of N-myc and STAT interactor (NMI) and its underlying mechanisms of action during IAV infection, however, remain elusive. In this study, we found that the expression of NMI increased after IAV infection. Nmi-knockout mice infected with IAV displayed increased survival rate, decreased weight loss, lower viral replication, and attenuated lung inflammation when compared with wild-type mice. Deficiency of NMI promoted the production of IFN-I and IFN-stimulated genes in vivo and in vitro. Reduced levels of NMI also resulted in an increase of the expression of IFN regulator factor (IRF) 7. Further studies have revealed that NMI could interact with IRF7 after IAV infection, and this interaction involved its NID1 and NID2 domain. In addition, NMI facilitated ubiquitination and proteasome-dependent degradation of IRF7 through recruitment of the E3 ubiquitin ligase TRIM21 (tripartite motif-containing 21) to limit the IAV-triggered innate immunity. Our findings reveal a clearer understanding of the role of NMI in regulating the host innate antiviral response and provide a potential therapeutic target for controlling IAV infection.