Interferon Regulatory Factors and the Atypical IKK-Related Kinases TBK1 and IKK-ε: Essential Players in the Innate Immune Response to RNA Virus Infection

During myelopoiesis, differentiating phagocytes develop functional competence and undergo proliferation arrest and eventual programmed cell death. This process involves transcriptional regulation of genes which mediate the innate immune response, mitotic arrest, and apoptosis. A number of transcription factor families play important roles in regulating such genes, including Hox proteins and interferon regulatory factors (IRFs). Disordered expression of Hox proteins is associated with myeloid leukemogenesis. Hox proteins are homeodomain transcription factors that are organized in four paralog groups (A–D). Expression of HoxA7-11 (the ABD-HOXA genes) is characteristic of myeloid progenitors. ABD-HOXA transcription decreases with CD34+ to CD34− progression, and persistent expression of these genes is found in poor prognosis leukemia. Abd Hox proteins regulate genes that are involved in multiple aspects of myelopoiesis. For example, HoxA10 represses transcription of the genes encoding gp91phox and p67phox in myeloid progenitors (the CYBB and NCF2 genes, respectively). In contrast, HoxA9 activates transcription of these genes as differentiation proceeds. Since these are the rate-limiting NADPH oxidase components, HoxA proteins influence the innate immune response. HoxA10 activates transcription of the gene encoding Beta3 integrin, thereby further facilitating NADPH oxidase activation and influencing adhesion. HoxA10 also activates transcription of DUSP4, the gene encoding MAP kinase phosphatase 2 (Mkp2). Mkp2 antagonizes the activity of c-Jun N-terminal kinases (Jnk). Since HoxA10-activation of DUSP4 decreases during myelopoiesis, decreased Mkp2 expression in mature phagocytes facilitates apoptosis via Jnk. Interferon regulatory factors (IRF) also regulate multiple aspects of myelopoiesis. IRF1 and ICSBP/IRF8 activate transcription of the CYBB and NCF2 genes in cooperation with the ets protein PU.1. ICSBP/IRF8 also contributes to phagocyte function by activating genes encoding TLR4, IL12, and Nramp. Additionally, IRF proteins regulate cell cycle progression and proliferation. IRF2, ICSBP/IRF8, and PU.1 activate transcription of gene encoding Neurofibromin 1, thereby downregulating the proliferative response to cytokines such as GM-CSF, M-CSF, and G-CSF. ICSBP/IRF8 and PU.1 also activate the gene encoding Ink4b, thereby also influencing proliferation. In myeloid progenitors, ICSBP/IRF8 influences cell survival by repressing transcription of PTPN13, the gene encoding Fas-associated phosphatase 1 (Fap1), a Fas-antagonist. Decreased ICSBP/IRF8-induced PTPN13 repression during myelopoiesis increases susceptibility of mature phagocytes to Fas-induced apoptosis. Such studies reveal that multiple aspects of myelopoiesis are regulated by common sets of transcription factors. This may suggest therapeutic targets for myeloid leukemias or other disorders of myeloid development.

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Mitochondrial Antiviral Signaling Protein Plays a Major Role in Induction of the Fish Innate Immune Response against RNA and DNA Viruses

Journal of Virology ◽

10.1128/jvi.00404-09 ◽

2009 ◽

Vol 83 (16) ◽

pp. 7815-7827 ◽

Cited By ~ 170

Author(s):

Stéphane Biacchesi ◽

Monique LeBerre ◽

Annie Lamoureux ◽

Yoann Louise ◽

Emilie Lauret ◽

...

Keyword(s):

Immune Response ◽

Virus Infection ◽

Innate Immune Response ◽

Teleost Fish ◽

Rna Virus ◽

Innate Immune ◽

Antiviral Signaling ◽

Mitochondrial Antiviral Signaling ◽

Fish Cells ◽

Mitochondrial Antiviral Signaling Protein

ABSTRACT Viral infection triggers host innate immune responses through cellular sensor molecules which activate multiple signaling cascades that induce the production of interferons (IFN) and other cytokines. The recent identification of mammalian cytoplasmic viral RNA sensors, such as retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) and their mitochondrial adaptor, the mitochondrial antiviral signaling protein (MAVS), also called IPS-1, VISA, and Cardif, highlights the significance of these molecules in the induction of IFN. Teleost fish also possess a strong IFN system, but nothing is known concerning the RLRs and their downstream adaptor. In this study, we cloned MAVS cDNAs from several fish species (including salmon and zebrafish) and showed that they were orthologs of mammalian MAVS. We demonstrated that overexpression of these mitochondrial proteins in fish cells led to a constitutive induction of IFN and IFN-stimulated genes (ISGs). MAVS-overexpressing cells were almost fully protected against RNA virus infection, with a strong inhibition of both DNA and RNA virus replication (1,000- and 10,000-fold decreases, respectively). Analyses of MAVS deletion mutants showed that both the N-terminal CARD-like and C-terminal transmembrane domains, but not the central proline-rich region, were indispensable for MAVS signaling function. In addition, we cloned the cDNAs encoding a RIG-I-like molecule from salmonid and cyprinid cell lines. Like the case with MAVS, overexpression of RIG-I CARDs in fish cells led to a strong induction of both IFN and ISGs, conferring on fish cells full protection against RNA virus infection. This report provides the first demonstration that teleost fish possess a functional RLR pathway in which MAVS may play a central role in the induction of the innate immune response.

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Control of antiviral innate immune response by protein geranylgeranylation

Science Advances ◽

10.1126/sciadv.aav7999 ◽

2019 ◽

Vol 5 (5) ◽

pp. eaav7999 ◽

Cited By ~ 14

Author(s):

Shigao Yang ◽

Alfred T. Harding ◽

Catherine Sweeney ◽

David Miao ◽

Gregory Swan ◽

...

Keyword(s):

Immune Response ◽

Virus Infection ◽

Innate Immune Response ◽

Influenza A ◽

Rna Virus ◽

Critical Role ◽

Innate Immune ◽

Junction Protein ◽

Mitochondrial Antiviral Signaling ◽

Destructive Inflammation

The mitochondrial antiviral signaling protein (MAVS) orchestrates host antiviral innate immune response to RNA virus infection. However, how MAVS signaling is controlled to eradicate virus while preventing self-destructive inflammation remains obscure. Here, we show that protein geranylgeranylation, a posttranslational lipid modification of proteins, limits MAVS-mediated immune signaling by targeting Rho family small guanosine triphosphatase Rac1 into the mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) at the mitochondria-ER junction. Protein geranylgeranylation and subsequent palmitoylation promote Rac1 translocation into MAMs upon viral infection. MAM-localized Rac1 limits MAVS’ interaction with E3 ligase Trim31 and hence inhibits MAVS ubiquitination, aggregation, and activation. Rac1 also facilitates the recruitment of caspase-8 and cFLIPL to the MAVS signalosome and the subsequent cleavage of Ripk1 that terminates MAVS signaling. Consistently, mice with myeloid deficiency of protein geranylgeranylation showed improved survival upon influenza A virus infection. Our work revealed a critical role of protein geranylgeranylation in regulating antiviral innate immune response.

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Imperative role of particulate matter in innate immunity during RNA virus infection

10.1101/2020.03.28.013169 ◽

2020 ◽

Author(s):

Richa Mishra ◽

K Pandikannan ◽

S Gangamma ◽

Ashwin Ashok Raut ◽

Himanshu Kumar

Keyword(s):

Immune Response ◽

Air Pollution ◽

Particulate Matter ◽

Virus Infection ◽

Innate Immune Response ◽

Rna Virus ◽

Innate Immune ◽

Virus Infectivity ◽

Transcriptomic Profile ◽

H5n1 Influenza

ABSTRACTSensing of pathogens by specialized receptors is the hallmark of the innate immune response. Innate immune response also mounts a defense response against various allergens and pollutants including particulate matter present in the atmosphere. Air pollution has been included as the top threat to global health declared by WHO which aims to cover more than three billion people against health emergencies from 2019-2023. Particulate matter (PM), one of the major components of air pollution, is a significant risk factor for many human diseases and its adverse effects include morbidity and premature deaths throughout the world. Several clinical and epidemiological studies have identified a key link between the PM composition and the prevalence of respiratory and inflammatory disorders. However, the underlying molecular mechanism is not well understood. Here, we investigated the influence of air pollutant, PM10 during RNA virus infections using highly pathogenic avian influenza (HPAI). We thus characterized the transcriptomic profile of lung epithelial cell line, A549 treated with PM10 prior to infection with (HPAI) H5N1 influenza virus, which is known to severely affect the lung and cause respiratory damage. We found that PM10 regulates virus infectivity and enhances overall pathogenic burden in the lung cells. Additionally, the transcriptomic profile highlights the connection of host factors related to various metabolic pathways and immune responses which were dysregulated during virus infection. Overall our findings suggest a strong link between the prevalence of respiratory illness and the air quality.

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Mammalian Orthoreovirus Factories Modulate Stress Granule Protein Localization by Interaction with G3BP1

Journal of Virology ◽

10.1128/jvi.01298-17 ◽

2017 ◽

Vol 91 (21) ◽

Cited By ~ 15

Author(s):

Promisree Choudhury ◽

Luke D. Bussiere ◽

Cathy L. Miller

Keyword(s):

Immune Response ◽

Virus Infection ◽

Innate Immune Response ◽

Nonstructural Protein ◽

Innate Immune ◽

Common Mechanism ◽

Effector Protein ◽

Associated Proteins ◽

Mammalian Orthoreovirus ◽

Late Stages

ABSTRACT Mammalian orthoreovirus (MRV) infection induces phosphorylation of translation initiation factor eIF2α, which promotes the formation of discrete cytoplasmic inclusions, termed stress granules (SGs). SGs are emerging as a component of the innate immune response to virus infection, and modulation of SG assembly is a common mechanism employed by viruses to counter this antiviral response. We previously showed that MRV infection induces SGs early and then interferes with SG formation as infection proceeds. In this work, we found that SG-associated proteins localized to the periphery of virus-encoded cytoplasmic structures, termed virus factories (VFs), where viral transcription, translation, and replication occur. The localization of SG proteins to VFs was dependent on polysome dissociation and occurred via association of the SG effector protein, Ras-GAP SH3-binding protein 1 (G3BP1), with the MRV nonstructural protein σNS, which localizes to VFs via association with VF nucleating protein, μNS. Deletion analysis of the σNS RNA binding domain and G3BP1 RNA (RRM) and ribosomal (RGG) binding domains showed that σNS association and VF localization phenotypes of G3BP1 do not occur solely through RNA or ribosomal binding but require both the RRM and RGG domains of G3BP1 for maximal viral-factory-like structure (VFL) localization and σNS association. Coexpression of σNS and μNS resulted in disruption of normal SG puncta, and in cells lacking G3BP1, MRV replication was enhanced in a manner correlating with strain-dependent induction of host translation shutoff. These results suggest that σNS association with G3BP1 and relocalization of G3BP1 to the VF periphery play roles in SG disruption to facilitate MRV replication in the host translational shutoff environment. IMPORTANCE SGs and SG effector proteins have emerged as important, yet poorly understood, players in the host's innate immune response to virus infection. MRV infection induces SGs early during infection that are dispersed and/or prevented from forming during late stages of infection despite continued activation of the eIF2α signaling pathway. Cellular and viral components involved in disruption of SGs during late stages of MRV infection remain to be elucidated. This work provides evidence that MRV disruption of SGs may be facilitated by association of the MRV nonstructural protein σNS with the major SG effector protein G3BP1 and subsequent localization of G3BP1 and other SG-associated proteins around the peripheries of virus-encoded factories, interrupting the normal formation of SGs. Our findings also reveal the importance of G3BP1 as an inhibitor of MRV replication during infection for the first time.

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