RESUMO
The inflammasome is an intracellular signaling complex, which on recognition of pathogens and physiological aberration, drives activation of caspase-1, pyroptosis, and the release of the pro-inflammatory cytokines IL-1ß and IL-18. Bacterial ligands must secure entry into the cytoplasm to activate inflammasomes; however, the mechanisms by which concealed ligands are liberated in the cytoplasm have remained unclear. Here, we showed that the interferon-inducible protein IRGB10 is essential for activation of the DNA-sensing AIM2 inflammasome by Francisella novicida and contributed to the activation of the LPS-sensing caspase-11 and NLRP3 inflammasome by Gram-negative bacteria. IRGB10 directly targeted cytoplasmic bacteria through a mechanism requiring guanylate-binding proteins. Localization of IRGB10 to the bacterial cell membrane compromised bacterial structural integrity and mediated cytosolic release of ligands for recognition by inflammasome sensors. Overall, our results reveal IRGB10 as part of a conserved signaling hub at the interface between cell-autonomous immunity and innate immune sensing pathways.
Assuntos
Proteínas de Ligação a DNA/metabolismo , Francisella/imunologia , GTP Fosfo-Hidrolases/metabolismo , Infecções por Bactérias Gram-Negativas/imunologia , Interações Hospedeiro-Patógeno/imunologia , Inflamassomos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Linfócitos B/imunologia , Caspases/metabolismo , Caspases Iniciadoras , Citosol/imunologia , Citosol/microbiologia , GTP Fosfo-Hidrolases/genética , Infecções por Bactérias Gram-Negativas/microbiologia , Imunidade Celular , Imunidade Inata , Inflamassomos/metabolismo , Ligantes , Camundongos , Camundongos Mutantes , Células Mieloides/imunologia , Linfócitos T/imunologiaRESUMO
The IL-1 family of cytokines follows an unconventional pathway of secretion mostly associated with inflammatory cell death. In this issue of Immunity, (Evavold et al., 2017) report gasdermin D pores as channels for active IL-1 release in live phagocytic cells.
Assuntos
Inflamassomos , Piroptose , Citocinas , Interleucina-1 , Proteínas de NeoplasiasRESUMO
Z-DNA-binding protein 1 (ZBP1), initially reported as an interferon (IFN)-inducible tumor-associated protein, harbors nucleic acid-binding domains for left-handed helix (Z-form) and receptor-interacting protein homotypic interaction motif (RHIM) domains for protein homotypic interactions. Recent studies have identified ZBP1 as an innate sensor of viral infections and a target of viral evasion strategies, regulating cell death, inflammasome activation, and proinflammatory responses. ZBP1 also functions during development and can trigger perinatal lethality when its RHIM-dependent interactions are not restricted. Here we review the history and emergence of ZBP1 as a pathogen sensor and a central regulator of cell death and inflammatory responses. We also discuss the gaps in our knowledge regarding the regulation and functions of ZBP1 and highlight potential avenues for future research.
Assuntos
Morte Celular/imunologia , Proteínas de Ligação a DNA/metabolismo , Inflamação/imunologia , Viroses/imunologia , Animais , DNA Forma Z/metabolismo , Proteínas de Ligação a DNA/genética , Humanos , Evasão da Resposta Imune , Imunidade Inata , Imunomodulação , Domínios Proteicos/genética , Proteínas de Ligação a RNA , Transdução de SinaisRESUMO
Pyroptosis is a form of lytic, programmed cell death that functions as an innate immune effector mechanism to facilitate host defense against pathogenic microorganisms, including viruses. This type of proinflammatory cell death is orchestrated by proteolytic activation of human or mouse caspase-1, mouse caspase-11 and human caspase-4 and caspase-5 in response to infectious and inflammatory stimuli. Induction of pyroptosis requires either a canonical inflammasome responsible for caspase-1 activation or a noncanonical complex composed of caspase-11 in mice or caspase-4 or caspase-5 in humans. Recent studies have identified the pore-forming protein gasdermin D, a substrate of these inflammatory caspases, as an executioner of pyroptosis. The membrane pores formed by gasdermin D facilitate release of proinflammatory cytokines IL-1ß and IL-18 and consequent biologic effects of these cytokines together with other released components. Pyroptosis, like other forms of programmed cell death, helps eliminate infected cells and thereby restricts the replicative niche, undermining survival and proliferation of intracellular pathogens. This includes viruses as well as bacteria, where ample evidence supports a critical role for inflammasome effector functions and cell death in host defense. Viruses have evolved their own mechanisms to modulate inflammasome signaling and pyroptosis. Here, we review the current literature regarding the role of pyroptosis in antiviral immune responses.
RESUMO
Innate immune sensing of influenza A virus (IAV) induces activation of various immune effector mechanisms, including the nucleotide and oligomerization domain, leucine-rich repeat-containing protein family, pyrin domain containing 3 (NLRP3) inflammasome and programmed cell death pathways. Although type I IFNs are identified as key mediators of inflammatory and cell death responses during IAV infection, the involvement of various IFN-regulated effectors in facilitating these responses are less studied. In this study, we demonstrate the role of IFN regulatory factor (IRF)1 in promoting NLRP3 inflammasome activation and cell death during IAV infection. Both inflammasome-dependent responses and induction of apoptosis and necroptosis are reduced in cells lacking IRF1 infected with IAV. The observed reduction in inflammasome activation and cell death in IRF1-deficient cells during IAV infection correlates with reduced levels of Z-DNA binding protein 1 (ZBP1), a key molecule mediating IAV-induced inflammatory and cell death responses. We further demonstrate IRF1 as a transcriptional regulator of ZBP1. Overall, our study identified IRF1 as an upstream regulator of NLRP3 inflammasome and cell death during IAV infection and further highlights the complex and multilayered regulation of key molecules controlling inflammatory response and cell fate decisions during infections.
Assuntos
Regulação da Expressão Gênica/imunologia , Glicoproteínas/biossíntese , Inflamassomos/imunologia , Fator Regulador 1 de Interferon/imunologia , Infecções por Orthomyxoviridae/imunologia , Animais , Morte Celular/imunologia , Imunidade Inata/imunologia , Vírus da Influenza A , Fator Regulador 1 de Interferon/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Proteínas de Ligação a RNARESUMO
Pathogen recognition receptors are vital components of the immune system. Engagement of these receptors is important not only for instigation of innate immune responses to invading pathogens but also for initiating the adaptive immune response. Members of the NOD-like receptor (NLR) family of pathogen recognition receptors have important roles in orchestrating this response. The NLR family member NLRC5 regulates major histocompatibility complex class I (MHC-I) expression during various types of infections, but its role in immunity to influenza A virus (IAV) is not well studied. Here we show that Nlrc5-/- mice exhibit an altered CD8+ T cell response during IAV infection compared to that of wild-type (WT) mice. Nlrc5-/- mice have decreased MHC-I expression on hematopoietic cells and fewer CD8+ T cells prior to infection. NLRC5 deficiency does not affect the generation of antigen-specific CD8+ T cells following IAV infection; however, a change in epitope dominance is observed in Nlrc5-/- mice. Moreover, IAV-specific CD8+ T cells from Nlrc5-/- mice have impaired effector functions. This change in the adaptive immune response is associated with impaired viral clearance in Nlrc5-/- mice. Collectively, our results demonstrate an important role for NLRC5 in regulation of antiviral immune responses and viral clearance during IAV infection.IMPORTANCE The NOD-like receptor family member NLRC5 is known to regulate expression of MHC-I as well as other genes required for antigen processing. In addition, NLRC5 also regulates various immune signaling pathways. In this study, we investigated the role of NLRC5 during influenza virus infection and found a major role for NLRC5 in restricting virus replication and promoting viral clearance. The observed increases in viral titers in NLRC5-deficient mice correlated with impaired effector CD8+ T cell responses. Although NLRC5-deficient mice were defective at clearing the virus, they did not show an increase in morbidity or mortality following influenza virus infection because of other compensatory immune mechanisms. Therefore, our study highlights how NLRC5 regulates multiple immune effector mechanisms to promote the host defense during influenza virus infection.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Células Matadoras Naturais/imunologia , Infecções por Orthomyxoviridae/imunologia , Animais , Citocinas/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Imunidade Inata , Vírus da Influenza A , Peptídeos e Proteínas de Sinalização Intracelular/genética , Pulmão/patologia , Pulmão/virologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infecções por Orthomyxoviridae/virologia , Transdução de Sinais , Carga ViralRESUMO
Mitogen-activated protein kinase (MAP) cascades are important in antiviral immunity through their regulation of interferon (IFN) production as well as virus replication. Although the serine-threonine MAP kinase tumor progression locus 2 (Tpl2/MAP3K8) has been implicated as a key regulator of Type I (IFNα/ß) and Type II (IFNγ) IFNs, remarkably little is known about how Tpl2 might contribute to host defense against viruses. Herein, we investigated the role of Tpl2 in antiviral immune responses against influenza virus. We demonstrate that Tpl2 is an integral component of multiple virus sensing pathways, differentially regulating the induction of IFNα/ß and IFNλ in a cell-type specific manner. Although Tpl2 is important in the regulation of both IFNα/ß and IFNλ, only IFNλ required Tpl2 for its induction during influenza virus infection both in vitro and in vivo. Further studies revealed an unanticipated function for Tpl2 in transducing Type I IFN signals and promoting expression of interferon-stimulated genes (ISGs). Importantly, Tpl2 signaling in nonhematopoietic cells is necessary to limit early virus replication. In addition to early innate alterations, impaired expansion of virus-specific CD8+ T cells accompanied delayed viral clearance in Tpl2-/- mice at late time points. Consistent with its critical role in facilitating both innate and adaptive antiviral responses, Tpl2 is required for restricting morbidity and mortality associated with influenza virus infection. Collectively, these findings establish an essential role for Tpl2 in antiviral host defense mechanisms.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Influenza Humana/imunologia , Interferon gama/biossíntese , MAP Quinase Quinase Quinases/imunologia , Proteínas Proto-Oncogênicas/imunologia , Animais , Humanos , Imunidade Inata/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Orthomyxoviridae/imunologia , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Signal transduction via NFκB and MAP kinase cascades is a universal response initiated upon pathogen recognition by Toll-like receptors (TLRs). How activation of these divergent signaling pathways is integrated to dictate distinct immune responses to diverse pathogens is still incompletely understood. Herein, contrary to current perception, we demonstrate that a signaling pathway defined by the inhibitor of κB kinase ß (IKKß), MAP3 kinase tumor progression locus 2 (Tpl2/MAP3K8), and MAP kinase ERK is differentially activated by TLRs. TLRs 2, 4, and 7 directly activate this inflammatory axis, inducing immediate ERK phosphorylation and early TNFα secretion. In addition to TLR adaptor proteins, IKKß-Tpl2-ERK activation by TLR4 is regulated by the TLR4 co-receptor CD14 and the tyrosine kinase Syk. Signals from TLRs 3 and 9 do not initiate early activation of IKKß-Tpl2-ERK pathway but instead induce delayed, NADPH-oxidase-dependent ERK phosphorylation and TNFα secretion via autocrine reactive oxygen species signaling. Unexpectedly, Tpl2 is an essential regulator of ROS production during TLR signaling. Overall, our study reveals distinct mechanisms activating a common inflammatory signaling cascade and delineates differences in MyD88-dependent signaling between endosomal TLRs 7 and 9. These findings further confirm the importance of Tpl2 in innate host defense mechanisms and also enhance our understanding of how the immune system tailors pathogen-specific gene expression patterns.
Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , MAP Quinase Quinase Quinases/fisiologia , Processamento de Proteína Pós-Traducional , Proteínas Proto-Oncogênicas/fisiologia , Receptor 3 Toll-Like/metabolismo , Receptor Toll-Like 9/metabolismo , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Animais , Comunicação Autócrina , Células Cultivadas , Quinase I-kappa B/metabolismo , Interleucina-10/genética , Interleucina-10/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Receptores de Lipopolissacarídeos/metabolismo , Lipopolissacarídeos/farmacologia , Sistema de Sinalização das MAP Quinases , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/metabolismo , Fosforilação , Proteínas Tirosina Quinases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Explosão Respiratória , Quinase Syk , Receptor 4 Toll-Like/metabolismo , Ativação Transcricional , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
In autoimmune diseases, the accumulation of activated leukocytes correlates with inflammation and disease progression, and, therefore, the disruption of leukocyte trafficking is an active area of research. The serine/threonine protein kinase Tpl2 (MAP3K8) regulates leukocyte inflammatory responses and is also being investigated for therapeutic inhibition during autoimmunity. Here we addressed the contribution of Tpl2 to the regulation of macrophage chemokine receptor expression and migration in vivo using a mouse model of Tpl2 ablation. LPS stimulation of bone marrow-derived macrophages induced early CCR1 chemokine receptor expression but repressed CCR2 and CCR5 expression. Notably, early induction of CCR1 expression by LPS was dependent upon a signaling pathway involving Tpl2, PI3K, and ERK. On the contrary, Tpl2 was required to maintain the basal expression of CCR2 and CCR5 as well as to stabilize CCR5 mRNA expression. Consistent with impairments in chemokine receptor expression, tpl2(-/-) macrophages were defective in trafficking to the peritoneal cavity following thioglycollate-induced inflammation. Overall, this study demonstrates a Tpl2-dependent mechanism for macrophage expression of select chemokine receptors and provides further insight into how Tpl2 inhibition may be used therapeutically to disrupt inflammatory networks in vivo.
Assuntos
Quimiocinas/imunologia , Inflamação/imunologia , MAP Quinase Quinase Quinases/imunologia , Macrófagos/imunologia , Proteínas Proto-Oncogênicas/imunologia , Receptores de Quimiocinas/imunologia , Doença Aguda , Proteínas Adaptadoras de Transporte Vesicular/genética , Animais , Movimento Celular/imunologia , Quimiocinas/metabolismo , Feminino , Lipopolissacarídeos/farmacologia , MAP Quinase Quinase Quinases/genética , MAP Quinase Quinase Quinases/metabolismo , Sistema de Sinalização das MAP Quinases/imunologia , Macrófagos/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Receptores CCR1/genética , Receptores CCR1/imunologia , Receptores CCR1/metabolismo , Receptores CCR2/genética , Receptores CCR2/imunologia , Receptores CCR2/metabolismo , Receptores CCR5/genética , Receptores CCR5/imunologia , Receptores CCR5/metabolismo , Receptores de Quimiocinas/genética , Receptores de Quimiocinas/metabolismoRESUMO
BACKGROUND: Pediatric high-grade glioma (pHGG) is largely incurable and accounts for most brain tumor-related deaths in children. Radiation is a standard therapy, yet the benefit from this treatment modality is transient, and most children succumb to disease within 2 years. Recent large-scale genomic studies suggest that pHGG has alterations in DNA damage response (DDR) pathways that induce resistance to DNA damaging agents. The aim of this study was to evaluate the therapeutic potential and molecular consequences of combining radiation with selective DDR inhibition in pHGG. METHODS: We conducted an unbiased screen in pHGG cells that combined radiation with clinical candidates targeting the DDR and identified the ATM inhibitor AZD1390. Subsequently, we profiled AZD1390 + radiation in an extensive panel of early passage pHGG cell lines, mechanistically characterized response to the combination in vitro in sensitive and resistant cells and evaluated the combination in vivo using TP53 wild-type and TP53 mutant orthotopic xenografts. RESULTS: AZD1390 significantly potentiated radiation across molecular subgroups of pHGG by increasing mutagenic nonhomologous end joining and augmenting genomic instability. In contrast to previous reports, ATM inhibition significantly improved the efficacy of radiation in both TP53 wild-type and TP53 mutant isogenic cell lines and distinct orthotopic xenograft models. Furthermore, we identified a novel mechanism of resistance to AZD1390 + radiation that was marked by an attenuated ATM pathway response which dampened sensitivity to ATM inhibition and induced synthetic lethality with ATR inhibition. CONCLUSIONS: Our study supports the clinical evaluation of AZD1390 in combination with radiation in pediatric patients with HGG.
Assuntos
Neoplasias Encefálicas , Glioma , Humanos , Criança , Glioma/tratamento farmacológico , Glioma/genética , Glioma/radioterapia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/radioterapia , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Dano ao DNA , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismoRESUMO
In an outbreak of highly pathogenic H5 and H7 avian influenza, rapid analysis of a large number of clinical samples with the potential to rapidly identify the virus subtype is extremely important. Herein, we report on the development of a rapid multiplex microsphere assay for the simultaneous detection of all avian influenza viruses (AIV) as well as the differentiation of H5, H7, N1, and N2 subtypes. A reverse transcriptase-PCR (RT-PCR) reaction, followed by hybridization of the amplified product with specific oligonucleotide probe-coated microspheres, was conducted in a multiplex format. Following incubation with a reporter dye, the fluorescence intensity was measured using a suspension array system. The limit of detection of the probe-coupled microspheres ranged from 1 x 10(5) to 1 x 10(9) copies of RT-PCR amplified product and the sensitivity of the multiplex assay ranged from 1 x 10(2.5) to 1 x 10(3.2) 50% embryo infectious doses of virus. The diagnostic accuracy of the assay, compared to the standard real-time RT-PCR, was evaluated using 102 swab samples from chickens exposed to low pathogenic AIV, and 97.05% of samples gave identical results with both the assays. The calculated specificity of the assay was 97.43%. Although the assay still needs to be validated, it appears to be a suitable diagnostic tool for detection and differentiation of avian influenza virus H5, H7, N1, and N2 subtypes.
Assuntos
Galinhas , Vírus da Influenza A/classificação , Vírus da Influenza A/isolamento & purificação , Influenza Aviária/diagnóstico , Microesferas , Doenças das Aves Domésticas/diagnóstico , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Animais , Cloaca/virologia , Vírus da Influenza A/genética , Influenza Aviária/virologia , Orofaringe/virologia , Doenças das Aves Domésticas/virologia , RNA Viral/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa/veterinária , Sensibilidade e EspecificidadeRESUMO
Interferon effector functions and autophagy are evolutionarily conserved arms of cell-autonomous immunity that restrict replication of intracellular pathogens. In this issue of Cell Host and Microbe, Biering et al., (2017) demonstrate how host cells co-opt sequential action of autophagy proteins and IFN-inducible GTPases to inhibit replication of positive-sense RNA viruses.
Assuntos
GTP Fosfo-Hidrolases/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Vírus/metabolismo , Autofagia/imunologia , GTP Fosfo-Hidrolases/imunologia , Interações Hospedeiro-Patógeno/imunologia , Interações Hospedeiro-Patógeno/fisiologia , Humanos , Imunidade Celular , Imunidade Inata , Interferons/imunologia , Interferons/metabolismo , Viroses/imunologia , Viroses/metabolismo , Replicação Viral/efeitos dos fármacos , Vírus/imunologiaRESUMO
In this issue of JEM, Swanson et al. (https://doi.org/10.1084/jem.20171749) report an unanticipated role for cGAMP in priming and activation of inflammasomes in addition to its well-characterized function as an endogenous second messenger inducing type I interferons in the cytosolic DNA-sensing pathway.
Assuntos
Inflamassomos , Nucleotídeos CíclicosRESUMO
The NLRP3 inflammasome constitutes a major antiviral host defense mechanism during influenza virus infection. Inflammasome assembly in virus-infected cells facilitates autocatalytic processing of pro-caspase-1 and subsequent cleavage and secretion of proinflammatory cytokines IL-1ß and IL-18. The NLRP3 inflammasome is critical for induction of both innate and adaptive immune responses during influenza virus infection. Inflammasome-dependent antiviral responses also regulate immunopathology and tissue repair in the infected lungs. The regulation of NLRP3 inflammasome assembly is an area of active research and recent studies have unraveled multiple cellular and viral factors involved in inflammasome assembly. Emerging studies have also identified the cross talk between inflammasome activation and programmed cell death pathways in influenza virus-infected cells. Here, we review the current literature regarding regulation and functions of NLRP3 inflammasome during influenza virus infection.
Assuntos
Imunidade Inata , Inflamassomos/imunologia , Vírus da Influenza A/imunologia , Influenza Humana/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Caspase 1/metabolismo , Proteínas de Ligação a DNA/metabolismo , Humanos , Inflamassomos/metabolismo , Vírus da Influenza A/patogenicidade , Influenza Humana/patologia , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Piroptose , Proteínas de Ligação a RNA , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismoRESUMO
Guanylate-binding proteins (GBPs) are essential components of cell-autonomous immunity. In response to IFN signaling, GBPs are expressed in the cytoplasm of immune and nonimmune cells, where they unleash their antimicrobial activity toward intracellular bacteria, viruses, and parasites. Recent studies have revealed that GBPs are essential for mediating activation of the caspase-1 inflammasome in response to the gram-negative bacteria Salmonella enterica serovar Typhimurium, Francisella novicida, Chlamydia muridarum, Chlamydia trachomatis, Legionella pneumophila, Vibrio cholerae, Enterobacter cloacae, and Citrobacter koseri During infection with vacuolar-restricted gram-negative bacteria, GBPs disrupt the vacuolar membrane to ensure liberation of LPS for cytoplasmic detection by caspase-11 and the noncanonical NLRP3 inflammasome. In response to certain cytosolic bacteria, GBPs liberate microbial DNA for activation of the DNA-sensing AIM2 inflammasome. GBPs also promote the recruitment of antimicrobial proteins, including NADPH oxidase subunits and autophagy-associated proteins to the Mycobacterium-containing vacuole to mediate intracellular bacterial killing. Here, we provide an overview on the emerging relationship between GBPs and activation of the inflammasome in innate immunity to microbial pathogens.
Assuntos
Proteínas de Ligação ao GTP/metabolismo , Imunidade Celular , Inflamassomos/metabolismo , Interferons/metabolismo , Animais , Doenças Transmissíveis/microbiologia , Doenças Transmissíveis/parasitologia , Doenças Transmissíveis/virologia , Humanos , Modelos BiológicosRESUMO
Innate sensing of influenza virus infection induces activation of programmed cell death pathways. We have recently identified Z-DNA-binding protein 1 (ZBP1) as an innate sensor of influenza A virus (IAV). ZBP1-mediated IAV sensing is critical for triggering programmed cell death in the infected lungs. Surprisingly, little is known about the mechanisms regulating ZBP1 activation to induce programmed cell death. Here, we report that the sensing of IAV RNA by retinoic acid inducible gene I (RIG-I) initiates ZBP1-mediated cell death via the RIG-I-MAVS-IFN-ß signaling axis. IAV infection induces ubiquitination of ZBP1, suggesting potential regulation of ZBP1 function through posttranslational modifications. We further demonstrate that ZBP1 senses viral ribonucleoprotein (vRNP) complexes of IAV to trigger cell death. These findings collectively indicate that ZBP1 activation requires RIG-I signaling, ubiquitination, and vRNP sensing to trigger activation of programmed cell death pathways during IAV infection. The mechanism of ZBP1 activation described here may have broader implications in the context of virus-induced cell death.
Assuntos
Morte Celular/fisiologia , Glicoproteínas/fisiologia , Ribonucleoproteínas/metabolismo , Animais , Glicoproteínas/metabolismo , Vírus da Influenza A/fisiologia , Proteínas de Membrana/fisiologia , Camundongos Endogâmicos BALB C , Camundongos Knockout , Proteínas do Tecido Nervoso/fisiologia , Infecções por Orthomyxoviridae/metabolismo , Proteínas de Ligação a RNA , Receptores de Superfície Celular , Transdução de Sinais/fisiologia , UbiquitinaçãoRESUMO
The interferon-inducible protein Z-DNA binding protein 1 (ZBP1, also known as DNA-dependent activator of IFN-regulatory factors (DAI) and DLM-1) was identified as a dsDNA sensor, which instigates innate immune responses. However, this classification has been disputed and whether ZBP1 functions as a pathogen sensor during an infection has remained unknown. Herein, we demonstrated ZBP1-mediated sensing of the influenza A virus (IAV) proteins NP and PB1, triggering cell death and inflammatory responses via the RIPK1-RIPK3-Caspase-8 axis. ZBP1 regulates NLRP3 inflammasome activation as well as induction of apoptosis, necroptosis and pyroptosis in IAV-infected cells. Importantly, ZBP1 deficiency protected mice from mortality during IAV infection owing to reduced inflammatory responses and epithelial damage. Overall, these findings indicate that ZBP1 is an innate immune sensor of IAV and highlight its importance in the pathogenesis of IAV infection.