scholarly journals The Zα2 domain of ZBP1 is a molecular switch regulating influenza-induced PANoptosis and perinatal lethality during development

2020 ◽  
Vol 295 (24) ◽  
pp. 8325-8330 ◽  
Author(s):  
Sannula Kesavardhana ◽  
R. K. Subbarao Malireddi ◽  
Amanda R. Burton ◽  
Shaina N. Porter ◽  
Peter Vogel ◽  
...  
Keyword(s):  
Cell Death ◽  
Nucleic Acids ◽  
Influenza A Virus ◽  
Nlrp3 Inflammasome ◽  
Influenza A ◽  
Defense Responses ◽  
Innate Immune ◽  
Inflammasome Activation ◽  
Perinatal Lethality

Z-DNA-binding protein 1 (ZBP1) is an innate immune sensor of nucleic acids that regulates host defense responses and development. ZBP1 activation triggers inflammation and pyroptosis, necroptosis, and apoptosis (PANoptosis) by activating receptor-interacting Ser/Thr kinase 3 (RIPK3), caspase-8, and the NLRP3 inflammasome. ZBP1 is unique among innate immune sensors because of its N-terminal Zα1 and Zα2 domains, which bind to nucleic acids in the Z-conformation. However, the specific role of these Zα domains in orchestrating ZBP1 activation and subsequent inflammation and cell death is not clear. Here we generated Zbp1ΔZα2/ΔZα2 mice that express ZBP1 lacking the Zα2 domain and demonstrate that this domain is critical for influenza A virus–induced PANoptosis and underlies perinatal lethality in mice in which the RIP homotypic interaction motif domain of RIPK1 has been mutated (Ripk1mRHIM/mRHIM). Deletion of the Zα2 domain in ZBP1 abolished influenza A virus–induced PANoptosis and NLRP3 inflammasome activation. Furthermore, deletion of the Zα2 domain of ZBP1 was sufficient to rescue Ripk1mRHIM/mRHIM mice from perinatal lethality caused by ZBP1-driven cell death and inflammation. Our findings identify the essential role of the Zα2 domain of ZBP1 in several physiological functions and establish a link between Z-RNA sensing via the Zα2 domain and promotion of influenza-induced PANoptosis and perinatal lethality.

scholarly journals Zα2 domain of ZBP1 is a molecular switch regulating Influenza-induced PANoptosis and perinatal lethality during development

2020 ◽  
Author(s):  
Sannula Kesavardhana ◽  
R. K. Subbarao Malireddi ◽  
Amanda R. Burton ◽  
Shaina N. Porter ◽  
Peter Vogel ◽  
...  
Keyword(s):  
Cell Death ◽  
Nlrp3 Inflammasome ◽  
Influenza A ◽  
Dna Binding Protein ◽  
Defense Responses ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation ◽  
Perinatal Lethality ◽  
Nucleic Acid Sensor

ABSTRACTZ-DNA-binding protein 1 (ZBP1) is an innate nucleic acid sensor which regulates host defense responses and development. ZBP1 activation triggers inflammation and pyroptosis, necroptosis, and apoptosis (PANoptosis) by activating RIPK3, caspase-8, and the NLRP3 inflammasome. ZBP1 is unique among innate sensors because of its N-terminal Zα1 and Zα2 domains, which bind to nucleic acids in the Z-conformation. However, the specific role of these Zα domains in orchestrating ZBP1 activation and subsequent inflammation and cell death is not clear. Here we have generated Zbp1ΔZα2/ΔZα2 mice that lack the Zα2 domain of ZBP1 and demonstrate that this domain is critical for influenza A virus (IAV)-induced PANoptosis and perinatal lethality in RIPK1-RHIM mutated (Ripk1RHIM/RHIM) mice. Deletion of the Zα2 domain in ZBP1 abolished IAV-induced PANoptosis and NLRP3 inflammasome activation. Furthermore, deletion of the Zα2 domain of ZBP1 was sufficient to rescue Ripk1RHIM/RHIM mice from the perinatal lethality which is caused by ZBP1-driven cell death and inflammation. Our findings identify the essential role of the Zα2 domain of ZBP1 in physiological functions and establish a link between sensing of Z-RNAs via the Zα2 domain and the promotion of influenza-induced PANoptosis and perinatal lethality.

scholarly journals Influenza A Virus Infection Activates NLRP3 Inflammasome through Trans-Golgi Network Dispersion

Viruses ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 88
Author(s):  
Kannu Priya Pandey ◽  
Yan Zhou
Keyword(s):  
Influenza A Virus ◽  
Nlrp3 Inflammasome ◽  
Influenza A ◽  
Innate Immune ◽  
Proton Channel ◽  
Inflammasome Activation ◽  
Channel Activity ◽  
Trans Golgi Network ◽  
Nlrp3 Inflammasome Activation ◽  
Golgi Network

The NLRP3 inflammasome consists of NLRP3, ASC, and pro-caspase-1 and is an important arm of the innate immune response against influenza A virus (IAV) infection. Upon infection, the inflammasome is activated, resulting in the production of IL-1β and IL-18, which recruits other immune cells to the site of infection. It has been suggested that in the presence of stress molecules such as nigericin, the trans-Golgi network (TGN) disperses into small puncta-like structures where NLRP3 is recruited and activated. Here, we investigated whether IAV infection could lead to TGN dispersion, whether dispersed TGN (dTGN) is responsible for NLRP3 inflammasome activation, and which viral protein is involved in this process. We showed that the IAV causes dTGN formation, which serves as one of the mechanisms of NLRP3 inflammasome activation in response to IAV infection. Furthermore, we generated a series of mutant IAVs that carry mutations in the M2 protein. We demonstrated the M2 proton channel activity, specifically His37 and Trp41 are pivotal for the dispersion of TGN, NLRP3 conformational change, and IL-1β induction. The results revealed a novel mechanism behind the activation and regulation of the NLRP3 inflammasome in IAV infection.

scholarly journals The NS1 Protein of Influenza A Virus Participates in Necroptosis by Interacting with MLKL and Increasing Its Oligomerization and Membrane Translocation

2018 ◽  
Vol 93 (2) ◽  
Author(s):  
Amit Gaba ◽  
Fang Xu ◽  
Yao Lu ◽  
Hong-Su Park ◽  
GuanQun Liu ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Influenza A Virus ◽  
Nlrp3 Inflammasome ◽  
Influenza A ◽  
Ion Homeostasis ◽  
Inflammasome Activation ◽  
Ns1 Protein ◽  
Membrane Translocation ◽  
Nlrp3 Inflammasome Activation

ABSTRACT Elimination of infected cells by programmed cell death is a well-recognized host defense mechanism to control the spread of infection. In addition to apoptosis, necroptosis is also one of the mechanisms of cell death that can be activated by viral infection. Activation of necroptosis leads to the phosphorylation of mixed-lineage kinase domain-like protein (MLKL) by receptor-interacting protein kinase 3 (RIPK3) and results in MLKL oligomerization and membrane translocation, leading to membrane disruption and a loss of cellular ion homeostasis. It has recently been reported that influenza A virus (IAV) infection induces necroptosis. However, the underlying mechanism of the IAV-mediated necroptosis process, particularly the roles of IAV proteins in necroptosis, remains unexplored. Here, we report that IAV infection induces necroptosis in macrophages and epithelial cells. We demonstrate that the NS1 protein of IAV interacts with MLKL. Coiled-coil domain 2 of MLKL has a predominant role in mediating the MLKL interaction with NS1. The interaction of NS1 with MLKL increases MLKL oligomerization and membrane translocation. Moreover, the MLKL-NS1 interaction enhances MLKL-mediated NLRP3 inflammasome activation, leading to increased interleukin-1β (IL-1β) processing and secretion. IMPORTANCE Necroptosis is a programmed cell death that is inflammatory in nature owing to the release of danger-associated molecular patterns from the ruptured cell membrane. However, necroptosis also constitutes an important arm of host immune responses. Thus, a balanced inflammatory response determines the disease outcome. We report that the NS1 protein of IAV participates in necroptosis by interacting with MLKL, resulting in increased MLKL oligomerization and membrane translocation. These results reveal a novel function of the NS1 protein and the mechanism by which IAV induces necroptosis. Moreover, we show that this interaction enhances NLRP3 inflammasome activation and IL-1β processing and secretion. This information may contribute to a better understanding of the role of necroptosis in IAV-induced inflammation.

scholarly journals NS1 Protein of 2009 Pandemic Influenza A Virus Inhibits Porcine NLRP3 Inflammasome-Mediated Interleukin-1 Beta Production by Suppressing ASC Ubiquitination

2018 ◽  
Vol 92 (8) ◽  
Author(s):  
Hong-Su Park ◽  
GuanQun Liu ◽  
Sathya N. Thulasi Raman ◽  
Shelby L. Landreth ◽  
Qiang Liu ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Nlrp3 Inflammasome ◽  
Influenza A ◽  
Adaptor Protein ◽  
Influenza Viruses ◽  
Innate Immune ◽  
Inflammasome Activation ◽  
Pandemic H1n1 ◽  
Ns1 Protein ◽  
C Terminus

ABSTRACT The inflammasome represents a molecular platform for innate immune regulation and controls proinflammatory cytokine production. The NLRP3 inflammasome is comprised of NLRP3, ASC, and procaspase-1. When the NLRP3 inflammasome is activated, it causes ASC speck formation and caspase-1 activation, resulting in the maturation of interleukin-1β (IL-1β). The NLRP3 inflammasome is regulated at multiple levels, with one level being posttranslational modification. Interestingly, ubiquitination of ASC has been reported to be indispensable for the activation of the NLRP3 inflammasome. Influenza A virus (IAV) infection induces NLRP3 inflammasome-dependent IL-1β secretion, which contributes to the host antiviral defense. However, IAVs have evolved multiple antagonizing mechanisms, one of which is executed by viral NS1 protein to suppress the NLRP3 inflammasome. In this study, we compared IL-1β production in porcine alveolar macrophages in response to IAV infection and found that the 2009 pandemic H1N1 induced less IL-1β than swine influenza viruses (SIVs). Further study revealed that the NS1 C terminus of pandemic H1N1 but not that of SIV was able to significantly inhibit NLRP3 inflammasome-mediated IL-1β production. This inhibitory function was attributed to impaired ASC speck formation and suppression of ASC ubiquitination. Moreover, we identified two target lysine residues, K110 and K140, which are essential for both porcine ASC ubiquitination and NLRP3 inflammasome-mediated IL-1β production. These results revealed a novel mechanism by which the NS1 protein of the 2009 pandemic H1N1 suppresses NLRP3 inflammasome activation. IMPORTANCE Influenza A virus (IAV) infection activates the NLRP3 inflammasome, resulting in the production of IL-1β, which contributes to the host innate immune response. ASC, an adaptor protein of NLRP3, forms specks that are critical for inflammasome activation. Here, we report that the NS1 C terminus of the 2009 pandemic H1N1 has functions to suppress porcine IL-1β production by inhibiting ASC speck formation and ASC ubiquitination. Furthermore, the ubiquitination sites on porcine ASC were identified. The information gained here may contribute to an in-depth understanding of porcine inflammasome activation and regulation in response to different IAVs, helping to further enhance our knowledge of innate immune responses to influenza virus infection in pigs.

scholarly journals PA-X Decreases the Pathogenicity of Highly Pathogenic H5N1 Influenza A Virus in Avian Species by Inhibiting Virus Replication and Host Response

2015 ◽  
Vol 89 (8) ◽  
pp. 4126-4142 ◽  
Author(s):  
Jiao Hu ◽  
Yiqun Mo ◽  
Xiaoquan Wang ◽  
Min Gu ◽  
Zenglei Hu ◽  
...  
Keyword(s):  
Cell Death ◽  
Influenza A Virus ◽  
Host Response ◽  
Influenza A ◽  
H1n1 Virus ◽  
Innate Immune ◽  
Avian Species ◽  
Accessory Proteins ◽  
Highly Pathogenic

ABSTRACTPA-X is a newly discovered protein that decreases the virulence of the 1918 H1N1 virus in a mouse model. However, the role of PA-X in the pathogenesis of highly pathogenic avian influenza viruses (HPAIV) of the H5N1 subtype in avian species is totally unknown. By generating two PA-X-deficient viruses and evaluating their virulence in different animal models, we show here that PA-X diminishes the virulence of the HPAIV H5N1 strain A/Chicken/Jiangsu/k0402/2010 (CK10) in mice, chickens, and ducks. Expression of PA-X dampens polymerase activity and virus replication bothin vitroandin vivo. Using microarray analysis, we found that PA-X blunts the global host response in chicken lungs, markedly downregulating genes associated with the inflammatory and cell death responses. Correspondingly, a decreased cytokine response was recapitulated in multiple organs of chickens and ducks infected with the wild-type virus relative to those infected with the PA-X-deficient virus. In addition, the PA-X protein exhibits antiapoptotic activity in chicken and duck embryo fibroblasts. Thus, our results demonstrated that PA-X acts as a negative virulence regulator and decreases virulence by inhibiting viral replication and the host innate immune response. Therefore, we here define the role of PA-X in the pathogenicity of H5N1 HPAIV, furthering our understanding of the intricate pathogenesis of influenza A virus.IMPORTANCEInfluenza A virus (IAV) continues to pose a huge threat to global public health. Eight gene segments of the IAV genome encode as many as 17 proteins, including 8 main viral proteins and 9 accessory proteins. The presence of these accessory proteins may further complicate the pathogenesis of IAV. PA-X is a newly identified protein in segment 3 that acts to decrease the virulence of the 1918 H1N1 virus in mice by modulating host gene expression. Our study extends these functions of PA-X to H5N1 HPAIV. We demonstrated that loss of PA-X expression increases the virulence and replication of an H5N1 virus in mice and avian species and alters the host innate immune and cell death responses. Our report is the first to delineate the role of the novel PA-X protein in the pathogenesis of H5N1 viruses in avian species and promotes our understanding of H5N1 HPAIV.

scholarly journals Molecular Events Involved in Influenza A Virus-Induced Cell Death

2022 ◽  
Vol 12 ◽  
Author(s):  
Rui Gui ◽  
Quanjiao Chen
Keyword(s):  
Cell Death ◽  
Influenza A Virus ◽  
Influenza A ◽  
Regulatory Networks ◽  
Molecular Mechanisms ◽  
Tissue Destruction ◽  
Inflammatory Reactions ◽  
Molecular Events ◽  
Host Death

Viral infection usually leads to cell death. Moderate cell death is a protective innate immune response. By contrast, excessive, uncontrolled cell death causes tissue destruction, cytokine storm, or even host death. Thus, the struggle between the host and virus determines whether the host survives. Influenza A virus (IAV) infection in humans can lead to unbridled hyper-inflammatory reactions and cause serious illnesses and even death. A full understanding of the molecular mechanisms and regulatory networks through which IAVs induce cell death could facilitate the development of more effective antiviral treatments. In this review, we discuss current progress in research on cell death induced by IAV infection and evaluate the role of cell death in IAV replication and disease prognosis.

scholarly journals NLRP3 Inflammasome Activation Enhanced by TRIM25 is Targeted by the NS1 Protein of 2009 Pandemic Influenza A Virus

2021 ◽  
Vol 12 ◽  
Author(s):  
Hong-Su Park ◽  
Yao Lu ◽  
Kannupriya Pandey ◽  
GuanQun Liu ◽  
Yan Zhou
Keyword(s):  
Influenza A Virus ◽  
Nlrp3 Inflammasome ◽  
Influenza A ◽  
Inflammatory Responses ◽  
Interleukin 1 ◽  
Inflammasome Activation ◽  
Ns1 Protein ◽  
Structural Protein ◽  
Caspase 1 ◽  
C Terminus

Nucleotide-binding domain and leucine-rich repeat-containing protein 3 (NLRP3) inflammasome-mediated interleukin-1 beta (IL-1β) production is one of the crucial responses in innate immunity upon infection with viruses including influenza A virus (IAV) and is modulated by both viral and host cellular proteins. Among host proteins involved, we identified tripartite motif-containing protein 25 (TRIM25) as a positive regulator of porcine NLRP3 inflammasome-mediated IL-1β production. TRIM25 achieved this function by enhancing the pro-caspase-1 interaction with apoptosis-associated speck-like protein containing caspase recruitment domain (ASC). The N-terminal RING domain, particularly residues predicted to be critical for the E3 ligase activity of TRIM25, was responsible for this enhancement. However, non-structural protein 1 (NS1) C-terminus of 2009 pandemic IAV interfered with this action by interacting with TRIM25, leading to diminished association between pro-caspase-1 and ASC. These findings demonstrate that TRIM25 promotes the IL-1β signaling, while it is repressed by IAV NS1 protein, revealing additional antagonism of the NS1 against host pro-inflammatory responses.

scholarly journals The central role of inflammatory signaling in the pathogenesis of myelodysplastic syndromes

Blood ◽  
2019 ◽  
Vol 133 (10) ◽  
pp. 1039-1048 ◽  
Author(s):  
David A. Sallman ◽  
Alan List
Keyword(s):  
Myelodysplastic Syndromes ◽  
Immune Activation ◽  
Nlrp3 Inflammasome ◽  
Cancer Biology ◽  
Innate Immune ◽  
Cell Swelling ◽  
Receptor Protein ◽  
Inflammasome Activation ◽  
Innate Immune Activation

Abstract In cancer biology, tumor-promoting inflammation and an inflammatory microenvironment play a vital role in disease pathogenesis. In the past decade, aberrant innate immune activation and proinflammatory signaling within the malignant clone and the bone marrow (BM) microenvironment were identified as key pathogenic drivers of myelodysplastic syndromes (MDS). In particular, S100A9-mediated NOD-like receptor protein 3 (NLRP3) inflammasome activation directs an inflammatory, lytic form of cell death termed pyroptosis that underlies many of the hallmark features of the disease. This circuit and accompanying release of other danger-associated molecular patterns expands BM myeloid-derived suppressor cells, creating a feed-forward process propagating inflammasome activation. Furthermore, somatic gene mutations of varied functional classes license the NLRP3 inflammasome to generate a common phenotype with excess reactive oxygen species generation, Wnt/β-catenin–induced proliferation, cation flux-induced cell swelling, and caspase-1 activation. Recent investigations have shown that activation of the NLRP3 inflammasome complex has more broad-reaching importance, particularly as a possible disease-specific biomarker for MDS, and, mechanistically, as a driver of cardiovascular morbidity/mortality in individuals with age-related, clonal hematopoiesis. Recognition of the mechanistic role of aberrant innate immune activation in MDS provides a new perspective for therapeutic development that could usher in a novel class of disease-modifying agents.

scholarly journals ZBP1: A STARGᐰTE to decode the biology of Z-nucleic acids in disease

2020 ◽  
Vol 217 (7) ◽  
Author(s):  
Sannula Kesavardhana ◽  
Thirumala-Devi Kanneganti
Keyword(s):  
Cell Death ◽  
Nucleic Acids ◽  
Inflammatory Disease ◽  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation ◽  
Specific Ligand

ZBP1 triggers NLRP3 inflammasome activation/pyroptosis, apoptosis, and necroptosis; the specific ligand for ZBP1 activation remains ambiguous. Recent studies, including Devos et al. in this issue of JEM (https://doi.org/10.1084/jem.20191913), collectively suggest that ZBP1 sensing Z-nucleic acids is critical for cell death/inflammatory disease.

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