RESUMO
Defining monogenic drivers of autoinflammatory syndromes elucidates mechanisms of disease in patients with these inborn errors of immunity and can facilitate targeted therapeutic interventions. Here, we describe a cohort of patients with a Behçet's- and inflammatory bowel disease (IBD)-like disorder termed "deficiency in ELF4, X-linked" (DEX) affecting males with loss-of-function variants in the ELF4 transcription factor gene located on the X chromosome. An international cohort of fourteen DEX patients was assessed to identify unifying clinical manifestations and diagnostic criteria as well as collate findings informing therapeutic responses. DEX patients exhibit a heterogeneous clinical phenotype including weight loss, oral and gastrointestinal aphthous ulcers, fevers, skin inflammation, gastrointestinal symptoms, arthritis, arthralgia, and myalgia, with findings of increased inflammatory markers, anemia, neutrophilic leukocytosis, thrombocytosis, intermittently low natural killer and class-switched memory B cells, and increased inflammatory cytokines in the serum. Patients have been predominantly treated with anti-inflammatory agents, with the majority of DEX patients treated with biologics targeting TNFα.
Assuntos
Artrite , Síndrome de Behçet , Produtos Biológicos , Doenças Inflamatórias Intestinais , Masculino , Humanos , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/genética , Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/genética , Artralgia , Proteínas de Ligação a DNA , Fatores de Transcrição/genéticaRESUMO
Ionic liquids have been widely used to improve the efficiency and stability of perovskite solar cells (PSCs), and are generally believed to passivate defects on the grain boundaries of perovskites. However, few studies have focused on the relevant effects of ionic liquids on intragrain defects in perovskites which have been shown to be critical for the performance of PSCs. In this work, the effect of ionic liquid 1-hexyl-3-methylimidazolium iodide (HMII) on intragrain defects of formamidinium lead iodide (FAPbI3) perovskite is investigated. Abundant {111}c intragrain planar defects in pure FAPbI3 grains are found to be significantly reduced by the addition of the ionic liquid HMII, shown by using ultra-low-dose selected area electron diffraction. As a result, longer charge carrier lifetimes, higher photoluminescence quantum yield, better charge carrier transport properties, lower Urbach energy, and current-voltage hysteresis are achieved, and the champion power conversion efficiency of 24.09% is demonstrated. These observations suggest that ionic liquids significantly improve device performance resulting from the elimination of {111}c intragrain planar defects.
RESUMO
Patients with DEX (deficiency in ELF4, X-linked) were recently reported by our team and others, and cases are very limited worldwide. Our knowledge of this new disease is currently preliminary. In this study, we described 5 more cases presenting mainly with oral ulcer, inflammatory bowel disease-like symptoms, fever of unknown origin, anemia, or systemic lupus erythematosus. Whole exome sequencing identified potential pathogenic ELF4 variants in all cases. The pathogenicity of these variants was confirmed by the detection of ELF4 expression in peripheral blood mononuclear cells from patients and utilizing a simple IFN-b luciferase reporter assay, as previously reported. Our findings significantly contribute to the current understanding of DEX.
Assuntos
Doenças do Sistema Imunitário , Lúpus Eritematoso Sistêmico , Humanos , Leucócitos Mononucleares , China , Estudos de Coortes , Proteínas de Ligação a DNA , Fatores de TranscriçãoRESUMO
The dedicator of cytokinesis 2(DOCK2) protein, an atypical guanine nucleotide exchange factor (GEFs), is a member of the DOCKA protein subfamily. DOCK2 protein deficiency is characterized by early-onset lymphopenia, recurrent infections, and lymphocyte dysfunction, which was classified as combined immune deficiency with neutrophil abnormalities as well. The only cure is hematopoietic stem cell transplantation. Here, we report two patients harboring four novel DOCK2 mutations associated with recurrent infections including live attenuated vaccine-related infections. The patient's condition was partially alleviated by symptomatic treatment or intravenous immunoglobulin. We also confirmed defects in thymic T cell output and T cell proliferation, as well as aberrant skewing of T/B cell subset TCR-Vß repertoires. In addition, we noted neutrophil defects, the weakening of actin polymerization, and BCR internalization under TCR/BCR activation. Finally, we found that the DOCK2 protein affected antibody affinity although with normal total serum immunoglobulin. The results reported herein expand the clinical phenotype, the pathogenic DOCK2 mutation database, and the immune characteristics of DOCK2-deficient patients.
Assuntos
Proteínas Ativadoras de GTPase , Síndromes de Imunodeficiência , Humanos , Vacinas Atenuadas , Proteínas Ativadoras de GTPase/genética , Reinfecção , Fatores de Troca do Nucleotídeo Guanina/genética , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/terapia , Mutação , Receptores de Antígenos de Linfócitos T/genéticaRESUMO
PURPOSE: CD81 deficiency is an extremely rare primary immunodeficiency disease characterized by severe and recurrent infections, IgA-related nephropathy, and profound hypogammaglobulinemia. Only one patient has been reported so far, and the pathogenesis remains unclear. Here, we identified a new case of CD81 deficiency and described its pathogenesis. METHODS: We analyzed the clinical, genetic, and immunological features of the patient with CD81 deficiency, and explored the pathogenesis of her antibody deficiencies. RESULTS: The major manifestation of this patient was unexpectedly not recurrent infections but IgA nephropathy with aberrant serum galactose-deficient IgA1. Whole-exome sequencing revealed novel biallelic mutations in CD81 gene that abolished the surface expression of CD81. B cells from the patient lack membrane CD19 and showed reduced switched memory B cells and transitional B cells. Decreased expression of key molecules pY and pBTK in BCR signaling were demonstrated by confocal microscopy. RNA sequencing revealed that genes associated with BCR signaling and immunoglobulins were downregulated in CD81-deficient B cells. In addition, the patient showed increased frequency of T follicular helper cells that biased to Th1-like subsets. CONCLUSION: We reported the second patient with CD81 deficiency in the world and illustrated aberrant BCR signaling in the patient, therefore helping to unravel the mechanism of antibody deficiency in CD81-deficient patients.
Assuntos
Glomerulonefrite por IGA , Tetraspanina 28 , Feminino , Humanos , Antígenos CD19/metabolismo , Linfócitos B , China , Glomerulonefrite por IGA/diagnóstico , Glomerulonefrite por IGA/genética , Glomerulonefrite por IGA/metabolismo , Imunoglobulina A/genética , Mutação , Tetraspanina 28/genéticaRESUMO
Monogenic autoinflammatory diseases (mAIDs) are a heterogeneous group of diseases affecting primarily innate immunity, with various genetic causes. Genetic diagnosis of mAIDs can assist in the patient's management and therapy. However, a large number of sporadic and familial cases remain genetically uncharacterized. Deficiency in ELF4, X-linked (DEX) is recently identified as a novel mAID. Here, we described a pediatric patient suffering from recurrent viral and bacterial respiratory infection, refractory oral ulcer, constipation, and arthritis. Whole-exome sequencing found a hemizygous variant in ELF4 (chrX:129205133 A > G, c.691 T > C, p.W231R). Using cells from patient and point mutation mice, we showed mutant cells failed to restrict viral replication effectively and produced more pro-inflammatory cytokines. RNA-seq identified several potential critical antiviral and anti-inflammation genes with decreased expression, and ChIP-qPCR assay suggested mutant ELF4 failed to bind to the promoters of these genes. Thus, we presented the second report of DEX.
Assuntos
Doenças Hereditárias Autoinflamatórias , Síndromes de Imunodeficiência , Síndrome de Imunodeficiência Adquirida Murina , Animais , Criança , Proteínas de Ligação a DNA/genética , Doenças Hereditárias Autoinflamatórias/diagnóstico , Doenças Hereditárias Autoinflamatórias/genética , Humanos , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/genética , Mutação com Perda de Função , Camundongos , Mutação/genética , Fatores de Transcrição/genética , Sequenciamento do ExomaRESUMO
BACKGROUND: TYK2 deficiency is a rare primary immunodeficiency disease caused by loss-of-function mutations of TYK2 gene, which is initially proposed as a subset of hyper-IgE syndrome (HIES). However, accumulating evidence suggests TYK2-deficient patients do not necessarily present with HIES characteristics, indicating a vacuum of knowledge on the exact roles of TYK2 in human immune system. METHOD: Pathogenic effects of patients were confirmed by qRT-PCR, Western blot, and protein stability assays. The responses to cytokines including IFN-α/ß/γ, IL-6, IL-10, IL-12, and IL-23 of peripheral blood mononuclear cells (PBMCs) from these patients were detected by Western blot, qRT-PCR, and flow cytometry. The differentiation of T and B cells was detected by flow cytometry. RESULTS: We described five more TYK2-deficient cases presenting with or without hyper-IgE levels, atopy, and distinct pathogen infection profile, which are caused by novel TYK2 mutations. These mutations were all found by high-throughput sequencing and confirmed by Sanger sequencing. The patients showed heterogeneous responses to various cytokine treatments, including IFN-α/ß/γ, IL-6, IL-10, IL-12, and IL-23. The homeostasis of lymphocytes is also disrupted. CONCLUSION: Based on our findings, we propose that TYK2 works as a multi-tasker in orchestrating various cytokine signaling pathways, differentially combined defects which account for the expressed clinical manifestations.
Assuntos
Síndrome de Job , Leucócitos Mononucleares , TYK2 Quinase , Humanos , Síndrome de Job/genética , Leucócitos Mononucleares/metabolismo , Mutação , Fenótipo , TYK2 Quinase/genética , TYK2 Quinase/metabolismoRESUMO
RNA and protein are interconnected biomolecules that can influence each other's life cycles and functions through physical interactions. Abnormal RNA-protein interactions lead to cell dysfunctions and human diseases. Therefore, mapping networks of RNA-protein interactions is crucial for understanding cellular processes and pathogenesis of related diseases. Different practical protein-centric methods for studying RNA-protein interactions have been reported, but few robust RNA-centric methods exist. Here, we developed CRISPR-based RNA proximity proteomics (CBRPP), a new RNA-centric method to identify proteins associated with an endogenous RNA of interest in native cellular context without pre-editing of the target RNA, cross-linking or RNA-protein complexes manipulation in vitro. CBRPP is based on a fusion of dCas13 and proximity-based labelling (PBL) enzyme. dCas13 can deliver PBL enzyme to the target RNA with high specificity, while PBL enzyme labels the surrounding proteins of the target RNA, which are then identified by mass spectrometry.
Assuntos
Espectrometria de Massas/métodos , Mapeamento de Interação de Proteínas , Proteínas de Ligação a RNA/metabolismo , RNA/metabolismo , Biotinilação , Células HEK293 , Humanos , Ligação Proteica , RNA/genética , Proteínas de Ligação a RNA/genética , Coloração e RotulagemRESUMO
Toxoplasma gondii is an important neurotropic pathogen that establishes latent infections in humans that can cause toxoplasmosis in immunocompromised individuals. It replicates inside host cells and has developed several strategies to manipulate host immune responses. However, the cytoplasmic pathogen-sensing pathway that detects T. gondii is not well-characterized. Here, we found that cyclic GMP-AMP synthase (cGAS), a sensor of foreign dsDNA, is required for activation of anti-T. gondii immune signaling in a mouse model. We also found that mice deficient in STING (Stinggt/gt mice) are much more susceptible to T. gondii infection than WT mice. Of note, the induction of inflammatory cytokines, type I IFNs, and interferon-stimulated genes in the spleen from Stinggt/gt mice was significantly impaired. Stinggt/gt mice exhibited more severe symptoms than cGAS-deficient mice after T. gondii infection. Interestingly, we found that the dense granule protein GRA15 from T. gondii is secreted into the host cell cytoplasm and then localizes to the endoplasmic reticulum, mediated by the second transmembrane motif in GRA15, which is essential for activating STING and innate immune responses. Mechanistically, GRA15 promoted STING polyubiquitination at Lys-337 and STING oligomerization in a TRAF protein-dependent manner. Accordingly, GRA15-deficient T. gondii failed to elicit robust innate immune responses compared with WT T. gondii. Consequently, GRA15-/-T. gondii was more virulent and caused higher mortality of WT mice but not Stinggt/gt mice upon infection. Together, T. gondii infection triggers cGAS/STING signaling, which is enhanced by GRA15 in a STING- and TRAF-dependent manner.
Assuntos
Imunidade Inata , Proteínas de Membrana/metabolismo , Proteínas de Protozoários/metabolismo , Toxoplasma/metabolismo , Animais , Modelos Animais de Doenças , Células HEK293 , Humanos , Interferon gama/metabolismo , Subunidade p35 da Interleucina-12/genética , Subunidade p35 da Interleucina-12/metabolismo , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nucleotidiltransferases/deficiência , Nucleotidiltransferases/genética , Multimerização Proteica , Proteínas de Protozoários/química , Proteínas de Protozoários/genética , Baço/metabolismo , Taxa de Sobrevida , Toxoplasma/patogenicidade , Toxoplasmose/mortalidade , Toxoplasmose/parasitologia , Toxoplasmose/patologia , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/metabolismo , UbiquitinaçãoRESUMO
Wiskott-Aldrich syndrome protein (WASp) is a hematopoietic-specific regulator of actin nucleation. Wiskott-Aldrich syndrome (WAS) patients show immunodeficiencies, most of which have been attributed to defective T-cell functions. T follicular helper (Tfh) cells are the major CD4(+) T-cell subset with specialized B-cell helper capabilities. Aberrant Tfh cells activities are involved in immunopathologies such as autoimmunity, immunodeficiencies, and lymphomas. We found that in WAS patients, the number of circulating Tfh cells was significantly reduced due to reduced proliferation and increased apoptosis, and Tfh cells were Th2 and Th17 polarized. The expression of inducible costimulator (ICOS) in circulating Tfh cells was higher in WAS patients than in controls. BCL6 expression was decreased in total CD4(+) T and Tfh cells of WAS patients. Mirroring the results in patients, the frequency of Tfh cells in WAS knockout (KO) mice was decreased, as was the frequency of BCL6(+) Tfh cells, but the frequency of ICOS(+) Tfh cells was increased. Using WAS chimera mice, we found that the number of ICOS(+) Tfh cells was decreased in WAS chimera mice, indicating that the increase in ICOS(+) Tfh cells in WAS KO mice was cell extrinsic. The data from in vivo CD4(+) naive T-cell adoptive transfer mice as well as in vitro coculture of naive B and Tfh cells showed that the defective function of WASp-deficient Tfh cells was T-cell intrinsic. Consistent findings in both WAS patients and WAS KO mice suggested an essential role for WASp in the development and memory response of Tfh cells and that WASp deficiency causes a deficient differentiation defect in Tfh cells by downregulating the transcription level of BCL6.
Assuntos
Centro Germinativo/patologia , Linfócitos T Auxiliares-Indutores/patologia , Linfócitos T Auxiliares-Indutores/fisiologia , Síndrome de Wiskott-Aldrich/imunologia , Animais , Linfócitos B , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD4-Positivos/fisiologia , Estudos de Casos e Controles , Diferenciação Celular , Células Cultivadas , Centro Germinativo/imunologia , Humanos , Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo , Interleucinas/metabolismo , Linfonodos/imunologia , Linfonodos/patologia , Camundongos , Camundongos Knockout , Fator 1 de Ligação ao Domínio I Regulador Positivo , Receptores CXCR5/metabolismo , Proteínas Repressoras/metabolismo , Síndrome de Wiskott-Aldrich/sangue , Síndrome de Wiskott-Aldrich/patologia , Proteína da Síndrome de Wiskott-Aldrich/genéticaAssuntos
Subpopulações de Linfócitos/citologia , Adolescente , Criança , Pré-Escolar , China , Humanos , Lactente , Recém-Nascido , Contagem de Linfócitos , Valores de ReferênciaRESUMO
BACKGROUND: ELF4 deficiency has been recently recognized as a novel disorder within the spectrum of inborn errors of immunity (IEIs), specifically categorized as a "disease of immune dysregulation." Cases of this condition, reported by our team and others, are very limited worldwide. As such, our current knowledge of this new disease remains preliminary. This review aims to provide a brief overview of the clinical manifestations, pathogenesis, and treatment strategies for this novel IEI. DATA SOURCES: A comprehensive review was conducted after an extensive literature search in the PubMed/Medline database and websites concerning transcriptional factor ELF4 and reports concerning patients with ELF4 deficiency. Our search strategy was "ELF4 OR ETS-related transcription factor Elf-4 OR EL4-like factor 4 OR myeloid Elf-1-like factor" as of the time of manuscript submission. RESULTS: The current signature manifestations of ELF4 deficiency disorder are recurrent and prolonged oral ulcer, abdominal pain, and diarrhea in pediatric males. In some cases, immunodeficiency and autoimmunity can also be prominent. Targeted Sanger sequencing or whole exome sequencing can be used to detect variation in ELF4 gene. Western blotting for ELF4 expression of the patient's cells can confirm the pathogenic effect of the variant. To fully confirm the pathogenicity of the variant, further functional test is strongly advised. Glucocorticoid and biologics are the mainstream management of ELF4 deficiency disorder. CONCLUSIONS: Pediatric males presenting with recurring ulcerations in digestive tract epithelium with or without recurrent fever should be suspected of DEX. When atypical presentations are prominent, variations in ELF4 gene should be carefully evaluated functionally due to the complex nature of ELF4 function. Experience of treating DEX includes use of glucocorticoid and biologics and more precise treatment needs more patients to identify and further mechanistic study.
Assuntos
Proteínas de Ligação a DNA , Fatores de Transcrição , Humanos , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/imunologia , Proteínas Proto-Oncogênicas c-ets/genética , Fatores de Transcrição/genética , Fatores de Transcrição/imunologia , Doenças do Sistema Imunitário/genéticaRESUMO
The metal halide (BX6)4- octahedron, where B represents a metal cation and X represents a halide anion, is regarded as the fundamental structural and functional unit of metal halide perovskites. However, the influence of the way the (BX6)4- octahedra connect to each other has on the structural stability and optoelectronic properties of metal halide perovskite is still unclear. Here, the octahedral connectivity, including corner-, edge-, and face-sharing, of various CsxFA1-xPbI3 (0 ≤ x ≤ 0.3) perovskite films is tuned and reliably characterized through compositional and additive engineering, and with ultralow-dose transmission electron microscopy. It is found that the overall solar cell device performance, the charge carrier lifetime, the open-circuit voltage, and the current density-voltage hysteresis are all improved when the films consist of corner-sharing octahedra, and non-corner sharing phases are suppressed, even in films with the same chemical composition. Additionally, it is found that the structural, optoelectronic, and device performance stabilities are similarly enhanced when non-corner-sharing connectivities are suppressed. This approach, combining macroscopic device tests and microscopic material characterization, provides a powerful tool enabling a thorough understanding of the impact of octahedral connectivity on device performance, and opens a new parameter space for designing high-performance photovoltaic metal halide perovskite devices.
RESUMO
Voice conversion has made great progress in the past few years under the studio-quality test scenario in terms of speech quality and speaker similarity. However, in real applications, test speech from source speaker or target speaker can be corrupted by various environment noises, which seriously degrade the speech quality and speaker similarity. In this paper, we propose a novel encoder-decoder based noise-robust voice conversion framework, which consists of a speaker encoder, a content encoder, a decoder, and two domain adversarial neural networks. Specifically, we integrate disentangling speaker and content representation technique with domain adversarial training technique. Domain adversarial training makes speaker representations and content representations extracted by speaker encoder and content encoder from clean speech and noisy speech in the same space, respectively. In this way, the learned speaker and content representations are noise-invariant. Therefore, the two noise-invariant representations can be taken as input by the decoder to predict the clean converted spectrum. The experimental results demonstrate that our proposed method can synthesize clean converted speech under noisy test scenarios, where the source speech and target speech can be corrupted by seen or unseen noise types during the training process. Additionally, both speech quality and speaker similarity are improved.
Assuntos
Aprendizagem , Fala , Redes Neurais de ComputaçãoRESUMO
mRNA m6A modification is heavily involved in modulation of immune responses. However, its function in antiviral immunity is controversial, and how immune responses regulate m6A modification remains elusive. We here find TBK1, a key kinase of antiviral pathways, phosphorylates the core m6A methyltransferase METTL3 at serine 67. The phosphorylated METTL3 interacts with the translational complex, which is required for enhancing protein translation, thus facilitating antiviral responses. TBK1 also promotes METTL3 activation and m6A modification to stabilize IRF3 mRNA. Type I interferon (IFN) induction is severely impaired in METTL3-deficient cells. Mettl3fl/fl-lyz2-Cre mice are more susceptible to influenza A virus (IAV)-induced lethality than control mice. Consistently, Ythdf1-/- mice show higher mortality than wild-type mice due to decreased IRF3 expression and subsequently attenuated IFN production. Together, we demonstrate that innate signals activate METTL3 via TBK1, and METTL3-mediated m6A modification secures antiviral immunity by promoting mRNA stability and protein translation.
Assuntos
Antivirais/imunologia , Imunidade Inata , Metiltransferases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Adenosina/análogos & derivados , Adenosina/metabolismo , Sequência de Aminoácidos , Animais , Linhagem Celular , Humanos , Fator Regulador 3 de Interferon/metabolismo , Interferon Tipo I/metabolismo , Metiltransferases/química , Camundongos Endogâmicos C57BL , Fosforilação , Ligação Proteica , Biossíntese de Proteínas , Proteínas de Ligação a RNA/metabolismo , Viroses/imunologia , Viroses/patologiaRESUMO
Mitochondria not only serve as a platform for innate immune signaling transduction but also enhance immune responses by releasing mitochondrial DNA and RNA into the cytoplasm. However, whether mitochondrial matrix proteins could be liberated and involved in immune responses remains enigmatic. Here, we identify the mitochondrial protein ERA G-protein-like 1 (ERAL1) as a mitochondrial antiviral signaling protein (MAVS)-interacting protein by using proximity-based labeling technology. ERAL1 deficiency markedly reduces the downstream antiviral signaling triggered by RNA viruses. Moreover, ERAL1-deficient mice are more susceptible to lethality following RNA virus infection than wild-type mice. After virus infection, ERAL1 is released from mitochondria through the BAX/BAK pore. The cytosolic ERAL1 facilitates lysine 63 (K63)-linked ubiquitination of retinoicacid inducible gene-1 (RIG-I)/melanoma differentiation-associated gene 5 (MDA5) and promotes downstream MAVS polymerization, thus positively regulating antiviral responses.
Assuntos
Proteína DEAD-box 58/imunologia , Proteínas de Ligação ao GTP/imunologia , Proteínas Mitocondriais/metabolismo , Infecções por Vírus de RNA/imunologia , Proteínas de Ligação a RNA/imunologia , Receptores Imunológicos/imunologia , Animais , Células HEK293 , Células HeLa , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Infecções por Vírus de RNA/genética , Infecções por Vírus de RNA/metabolismo , Transdução de SinaisRESUMO
Ulcerative colitis (UC) is a chronic inflammatory bowel disease, characterized by relapsing and remitting colon mucosal inflammation. For patients suffering from UC, a higher risk of colon cancer has been widely recognized. Here, we found that Elf4 -/- mice developed colon tumors with 3 cycles of dextran sulfate sodium salt (DSS) treatment alone. We further showed that ELF4 suppression was prevalent in both patients with UC and DSS-induced mice models, and this suppression was caused by promoter region methylation. ELF4, upon PARylation by PARP1, transcriptionally regulated multiple DNA damage repair machinery components. Consistently, ELF4 deficiency leads to more severe DNA damage both in vitro and in vivo. Oral administration of montmorillonite powder can prevent the reduction of ELF4 in DSS-induced colitis models and lower the risk of colon tumor development during azoxymethane (AOM) and DSS induced colitis-associated cancer (CAC). These data provided additional mechanism of CAC initiation and supported the "epigenetic priming model of tumor initiation".
RESUMO
Pathogen pattern recognition receptors (PRRs) trigger innate immune responses to invading pathogens. All known PRRs for viral RNA have extranuclear localization. However, for many viruses, replication generates dsRNA in the nucleus. Here, we show that the nuclear matrix protein SAFA (also known as HnRNPU) functions as a nuclear viral dsRNA sensor for both DNA and RNA viruses. Upon recognition of viral dsRNA, SAFA oligomerizes and activates the enhancers of antiviral genes, including IFNB1. Moreover, SAFA is required for the activation of super-enhancers, which direct vigorous immune gene transcription to establish the antiviral state. Myeloid-specific SAFA-deficient mice were more susceptible to lethal HSV-1 and VSV infection, with decreased type I IFNs. Thus, SAFA functions as a nuclear viral RNA sensor and trans-activator to bridge innate sensing with chromatin remodeling and potentiate robust antiviral responses.
Assuntos
Antivirais/imunologia , Ribonucleoproteínas Nucleares Heterogêneas Grupo U/imunologia , Proteínas Associadas à Matriz Nuclear/imunologia , RNA Viral/metabolismo , Receptores de Reconhecimento de Padrão/imunologia , Adenosina Trifosfatases/genética , Animais , Proteínas Cromossômicas não Histona/genética , DNA Topoisomerases Tipo I/genética , Vírus de DNA , Células HEK293 , Células HeLa , Herpesvirus Humano 1 , Ribonucleoproteínas Nucleares Heterogêneas Grupo U/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Inata/genética , Fator Regulador 3 de Interferon , Fator Regulador 7 de Interferon , Camundongos , Proteínas Associadas à Matriz Nuclear/metabolismo , Proteínas Serina-Treonina Quinases , Vírus de RNA , RNA de Cadeia Dupla , VírusRESUMO
The innate immune system plays a critical role in the initial antiviral response. However, the timing and duration of these responses must be tightly regulated during infection to ensure appropriate immune cell activation and anti-viral defenses. Here we demonstrate that during antiviral response, a negative regulator miR-221 was also induced in an ELF4-dependent manner. We further show that ELF4 promotes miR-221 expression through direct binding to its promoter. Overexpression and knockdown assay show that miR-221 can negatively regulate IFNß production in time of virus infection. RNA-seq analysis of miR-221 overexpressed cells revealed multiple candidate targets. Taken together, our study identified a novel negative microRNA regulator of innate antiviral response, which is dependent on ELF4.
Assuntos
Imunidade Inata/genética , MicroRNAs/metabolismo , Infecções por Rhabdoviridae/imunologia , Animais , Antagomirs/metabolismo , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Regulação para Baixo , Células HEK293 , Herpesvirus Humano 1/fisiologia , Humanos , Interferon beta/genética , Interferon beta/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/virologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Regiões Promotoras Genéticas , Proteínas Serina-Treonina Quinases/genética , Infecções por Rhabdoviridae/patologia , Infecções por Rhabdoviridae/virologia , Fatores de Transcrição/deficiência , Fatores de Transcrição/genética , Vesiculovirus/genética , Vesiculovirus/imunologiaRESUMO
E. fischeriana has long been used as a traditional Chinese medicine. Recent studies reported that some compounds of E. fischeriana exhibited antimicrobial and immune enhance activity. Innate immune system is essential for the immune surveillance of inner and outer threats, initial host defense responses and immune modulation. The role of natural drug compounds, including E. fischeriana, in innate immune regulation is largely unknown. Here we demonstrated that E. fischeriana compound Dpo is involved in antiviral signaling. The genome wide RNA-seq analysis revealed that the induction of ISGs by viral infection could be synergized by Dpo. Consistently, Dpo enhanced the antiviral immune responses and protected the mice from death during viral infection. Dpo however was not able to rescue STING deficient mice lethality caused by HSV-1 infection. The enhancement of ISG15 by Dpo was also impaired in STING, IRF3, IRF7, or ELF4 deficient cells, demonstrating that Dpo activates innate immune responses in a STING/IRFs/ELF4 dependent way. The STING/IRFs/ELF4 axis is therefore important for Dpo induced ISGs expression, and can be used by host to counteract infection.