scholarly journals Spatiotemporal dynamics of innate immune signaling via RIG-I–like receptors

2020 ◽  
Vol 117 (27) ◽  
pp. 15778-15788 ◽  
Author(s):  
Katharina Esser-Nobis ◽  
Lauren D. Hatfield ◽  
Michael Gale
Keyword(s):  
Innate Immunity ◽  
Virus Infection ◽  
Rna Virus ◽  
Adaptor Protein ◽  
Innate Immune ◽  
Negative Regulator ◽  
Resting Cells ◽  
Immune Signaling ◽  
Innate Immune Signaling ◽  
Irf3 Activation

RIG-I, MDA5, and LGP2 comprise the RIG-I–like receptors (RLRs). RIG-I and MDA5 are essential pathogen recognition receptors sensing viral infections while LGP2 has been described as both RLR cofactor and negative regulator. After sensing and binding to viral RNA, including double-stranded RNA (dsRNA), RIG-I and MDA5 undergo cytosol-to-membrane relocalization to bind and signal through the MAVS adaptor protein on intracellular membranes, thus directing downstream activation of IRF3 and innate immunity. Here, we report examination of the dynamic subcellular localization of all three RLRs within the intracellular response to dsRNA and RNA virus infection. Observations from high resolution biochemical fractionation and electron microscopy, coupled with analysis of protein interactions and IRF3 activation, show that, in resting cells, microsome but not mitochondrial fractions harbor the central components to initiate innate immune signaling. LGP2 interacts with MAVS in microsomes, blocking the RIG-I/MAVS interaction. Remarkably, in response to dsRNA treatment or RNA virus infection, LGP2 is rapidly released from MAVS and redistributed to mitochondria, temporally correlating with IRF3 activation. We reveal that IRF3 activation does not take place on mitochondria but instead occurs at endoplasmic reticulum (ER)-derived membranes. Our observations suggest ER-derived membranes as key RLR signaling platforms controlled through inhibitory actions of LGP2 binding to MAVS wherein LGP2 translocation to mitochondria releases MAVS inhibition to facilitate RLR-mediated signaling of innate immunity.

scholarly journals Distinct RIG-I and MDA5 Signaling by RNA Viruses in Innate Immunity

2007 ◽  
Vol 82 (1) ◽  
pp. 335-345 ◽  
Author(s):  
Yueh-Ming Loo ◽  
Jamie Fornek ◽  
Nanette Crochet ◽  
Gagan Bajwa ◽  
Olivia Perwitasari ◽  
...  
Keyword(s):  
Gene Expression ◽  
Virus Infection ◽  
Influenza A Virus ◽  
Influenza A ◽  
Rna Viruses ◽  
Adaptor Protein ◽  
Innate Immune ◽  
Influenza B ◽  
Immune Signaling ◽  
Innate Immune Signaling

ABSTRACT Alpha/beta interferon immune defenses are essential for resistance to viruses and can be triggered through the actions of the cytoplasmic helicases retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5). Signaling by each is initiated by the recognition of viral products such as RNA and occurs through downstream interaction with the IPS-1 adaptor protein. We directly compared the innate immune signaling requirements of representative viruses of the Flaviviridae, Orthomyxoviridae, Paramyxoviridae, and Reoviridae for RIG-I, MDA5, and interferon promoter-stimulating factor 1 (IPS-1). In cultured fibroblasts, IPS-1 was essential for innate immune signaling of downstream interferon regulatory factor 3 activation and interferon-stimulated gene expression, but the requirements for RIG-I and MDA5 were variable. Each was individually dispensable for signaling triggered by reovirus and dengue virus, whereas RIG-I was essential for signaling by influenza A virus, influenza B virus, and human respiratory syncytial virus. Functional genomics analyses identified cellular genes triggered during influenza A virus infection whose expression was strictly dependent on RIG-I and which are involved in processes of innate or adaptive immunity, apoptosis, cytokine signaling, and inflammation associated with the host response to contemporary and pandemic strains of influenza virus. These results define IPS-1-dependent signaling as an essential feature of host immunity to RNA virus infection. Our observations further demonstrate differential and redundant roles for RIG-I and MDA5 in pathogen recognition and innate immune signaling that may reflect unique and shared biologic properties of RNA viruses whose differential triggering and control of gene expression may impact pathogenesis and infection.

scholarly journals FIP200 restricts RNA virus infection by facilitating RIG-I activation

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Lingyan Wang ◽  
Kun Song ◽  
Wenzhuo Hao ◽  
Yakun Wu ◽  
Girish Patil ◽  
...  
Keyword(s):  
Virus Infection ◽  
Rna Virus ◽  
Innate Immune ◽  
Host Susceptibility ◽  
In Vivo Studies ◽  
Helicase Domain ◽  
Type I ◽  
Immune Signaling ◽  
Innate Immune Signaling

AbstractRetinoic acid-inducible gene I (RIG-I) senses viral RNA and instigates an innate immune signaling cascade to induce type I interferon expression. Currently, the regulatory mechanisms controlling RIG-I activation remain to be fully elucidated. Here we show that the FAK family kinase-interacting protein of 200 kDa (FIP200) facilitates RIG-I activation. FIP200 deficiency impaired RIG-I signaling and increased host susceptibility to RNA virus infection. In vivo studies further demonstrated FIP200 knockout mice were more susceptible to RNA virus infection due to the reduced innate immune response. Mechanistic studies revealed that FIP200 competed with the helicase domain of RIG-I for interaction with the two tandem caspase activation and recruitment domains (2CARD), thereby facilitating the release of 2CARD from the suppression status. Furthermore, FIP200 formed a dimer and facilitated 2CARD oligomerization, thereby promoting RIG-I activation. Taken together, our study defines FIP200 as an innate immune signaling molecule that positively regulates RIG-I activation.

scholarly journals PSMB1 Negatively Regulates the Innate Antiviral Immunity by Facilitating Degradation of IKK-ε

Viruses ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 99
Author(s):  
Fangyi Wu ◽  
Zhenmin Niu ◽  
Bin Zhou ◽  
Pengcheng Li ◽  
Feng Qian
Keyword(s):  
Viral Infection ◽  
Rna Virus ◽  
Cell Cycle Control ◽  
Ubiquitin Proteasome System ◽  
Innate Immune ◽  
Negative Regulator ◽  
Viral Immunity ◽  
Chemokine Production ◽  
Cellular Processes ◽  
Innate Immune Signaling

Proteasome is a large protein complex, which degrades most intracellular proteins. It regulates numerous cellular processes, including the removal of misfolded or unfolded proteins, cell cycle control, and regulation of apoptosis. However, the function of proteasome subunits in viral immunity has not been well characterized. In this study, we identified PSMB1, a member of the proteasome β subunits (PSMB) family, as a negative regulator of innate immune responses during viral infection. Knockdown of PSMB1 enhanced the RNA virus-induced cytokine and chemokine production. Overexpression of PSMB1 abolished virus-induced activation of the interferon-stimulated response element (ISRE) and interferon beta (IFNβ) promoters. Mechanistically, PSMB1 inhibited the activation of RIG-I-like receptor (RLR) and Toll-like receptor 3 (TLR3) signaling pathways. PSMB1 was induced after viral infection and its interaction with IKK-ε promoted degradation of IKK-ε through the ubiquitin-proteasome system. Collectively, our study demonstrates PSMB1 is an important regulator of innate immune signaling.

scholarly journals Hepacivirus NS3/4A Proteases Interfere with MAVS Signaling in both Their Cognate Animal Hosts and Humans: Implications for Zoonotic Transmission

2016 ◽  
Vol 90 (23) ◽  
pp. 10670-10681 ◽  
Author(s):  
Anggakusuma ◽  
Richard J. P. Brown ◽  
Dominic H. Banda ◽  
Daniel Todt ◽  
Gabrielle Vieyres ◽  
...  
Keyword(s):  
Mammalian Species ◽  
Companion Animals ◽  
Adaptor Protein ◽  
Innate Immune ◽  
Zoonotic Transmission ◽  
Common Mechanism ◽  
Zoonotic Potential ◽  
Immune Signaling ◽  
Content Type ◽  
Innate Immune Signaling

ABSTRACTMultiple novel members of the genusHepacivirushave recently been discovered in diverse mammalian species. However, to date, their replication mechanisms and zoonotic potential have not been explored in detail. The NS3/4A serine protease of hepatitis C virus (HCV) is critical for cleavage of the viral polyprotein. It also cleaves the cellular innate immune adaptor MAVS, thus decreasing interferon (IFN) production and contributing to HCV persistence in the human host. To investigate the conservation of fundamental aspects of the hepaciviral life cycle, we explored if MAVS cleavage and suppression of innate immune signaling represent a common mechanism employed across different clades of the genusHepacivirusto enhance viral replication. To estimate the zoonotic potential of these nonhuman hepaciviruses, we assessed if their NS3/4A proteases were capable of cleaving human MAVS. NS3/4A proteases of viruses infecting colobus monkeys, rodents, horses, and cows cleaved the MAVS proteins of their cognate hosts and interfered with the ability of MAVS to induce the IFN-β promoter. All NS3/4A proteases from nonhuman viruses readily cleaved human MAVS. Thus, NS3/4A-dependent cleavage of MAVS is a conserved replication strategy across multiple clades within the genusHepacivirus. Human MAVS is susceptible to cleavage by these nonhuman viral proteases, indicating that it does not pose a barrier for zoonotic transmission of these viruses to humans.IMPORTANCEVirus infection is recognized by cellular sensor proteins triggering innate immune signaling and antiviral defenses. While viruses have evolved strategies to thwart these antiviral programs in their cognate host species, these evasion mechanisms are often ineffective in a novel host, thus limiting viral transmission across species. HCV, the best-characterized member of the genusHepaciviruswithin the familyFlaviviridae, uses its NS3/4A protease to disrupt innate immune signaling by cleaving the cellular adaptor protein MAVS. Recently, a large number of HCV-related viruses have been discovered in various animal species, including wild, livestock, and companion animals. We show that the NS3/4A proteases of these hepaciviruses from different animals and representing various clades of the genus cleave their cognate host MAVS proteins in addition to human MAVS. Therefore, cleavage of MAVS is a common strategy of hepaciviruses, and human MAVS is likely unable to limit replication of these nonhuman viruses upon zoonotic exposure.

scholarly journals Inhibition of Antiviral Innate Immunity by Avibirnavirus VP3 via Blocking TBK1-TRAF3 Complex Formation and IRF3 Activation

mSystems ◽  
2021 ◽  
Vol 6 (3) ◽  
Author(s):  
Tingjuan Deng ◽  
Boli Hu ◽  
Xingbo Wang ◽  
Lulu Lin ◽  
Jianwei Zhou ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immunity ◽  
Virus Infection ◽  
Complex Formation ◽  
Rna Virus ◽  
Critical Role ◽  
Type I ◽  
Antiviral Immune Response ◽  
Critical Residue ◽  
Irf3 Activation

ABSTRACT The host innate immune system develops various strategies to antagonize virus infection, and the pathogen subverts or evades host innate immunity for self-replication. In the present study, we discovered that Avibirnavirus infectious bursal disease virus (IBDV) VP3 protein significantly inhibits MDA5-induced beta interferon (IFN-β) expression by blocking IRF3 activation. Binding domain mapping showed that the CC1 domain of VP3 and the residue lysine-155 of tumor necrosis factor receptor-associated factor 3 (TRAF3) are essential for the interaction. Furthermore, we found that the CC1 domain was required for VP3 to downregulate MDA5-mediated IFN-β production. A ubiquitination assay showed that lysine-155 of TRAF3 was the critical residue for K33-linked polyubiquitination, which contributes to the formation of a TRAF3-TBK1 complex. Subsequently, we revealed that VP3 blocked TRAF3-TBK1 complex formation through reducing K33-linked polyubiquitination of lysine-155 on TRAF3. Taken together, our data reveal that VP3 inhibits MDA5-dependent IRF3-mediated signaling via blocking TRAF3-TBK1 complex formation, which improves our understanding of the interplay between RNA virus infection and the innate host antiviral immune response. IMPORTANCE Type I interferon plays a critical role in the host response against virus infection, including Avibirnavirus. However, many viruses have developed multiple strategies to antagonize the innate host antiviral immune response during coevolution with the host. In this study, we first identified that K33-linked polyubiquitination of lysine-155 of TRAF3 enhances the interaction with TBK1, which positively regulates the host IFN immune response. Meanwhile, we discovered that the interaction of the CC1 domain of the Avibirnavirus VP3 protein and the residue lysine-155 of TRAF3 reduced the K33-linked polyubiquitination of TRAF3 and blocked the formation of the TRAF3-TBK1 complex, which contributed to the downregulation of host IFN signaling, supporting viral replication.

scholarly journals MAVS Coordination of Antiviral Innate Immunity

2015 ◽  
Vol 89 (14) ◽  
pp. 6974-6977 ◽  
Author(s):  
Christine Vazquez ◽  
Stacy M. Horner
Keyword(s):  
Immune Response ◽  
Innate Immunity ◽  
Endoplasmic Reticulum ◽  
Retinoic Acid ◽  
Rna Virus ◽  
Adaptor Protein ◽  
Innate Immune ◽  
Antiviral Signaling ◽  
Antiviral Innate Immunity ◽  
Inducible Gene

RNA virus infection is sensed in the cytoplasm by the retinoic acid-inducible gene I (RIG-I)-like receptors. These proteins signal through the host adaptor protein MAVS to trigger the antiviral innate immune response. Here, we describe how MAVS subcellular localization impacts its function and the regulation underlying MAVS signaling. We propose a model to describe how the coordination of MAVS functions at the interface between the mitochondria and the mitochondrion-associated endoplasmic reticulum (ER) membrane programs antiviral signaling.

scholarly journals Pathogen-Associated Molecular Pattern Recognition of Hepatitis C Virus Transmitted/Founder Variants by RIG-I Is Dependent on U-Core Length

2015 ◽  
Vol 89 (21) ◽  
pp. 11056-11068 ◽  
Author(s):  
Alison Kell ◽  
Mark Stoddard ◽  
Hui Li ◽  
Joe Marcotrigiano ◽  
George M. Shaw ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Acute Infection ◽  
Innate Immune ◽  
Hcv Infection ◽  
Immune Signaling ◽  
Molecular Pattern ◽  
Innate Immune Signaling ◽  
Acute Hcv

ABSTRACTDespite the introduction of direct-acting antiviral (DAA) drugs against hepatitis C virus (HCV), infection remains a major public health concern because DAA therapeutics do not prevent reinfection and patients can still progress to chronic liver disease. Chronic HCV infection is supported by a variety of viral immune evasion strategies, but, remarkably, 20% to 30% of acute infections spontaneously clear prior to development of adaptive immune responses, thus implicating innate immunity in resolving acute HCV infection. However, the virus-host interactions regulating acute infection are unknown. Transmission of HCV involves one or a few transmitted/founder (T/F) variants. In infected hepatocytes, the retinoic acid-inducible gene I (RIG-I) protein recognizes 5′ triphosphate (5′ppp) of the HCV RNA and a pathogen-associated molecular pattern (PAMP) motif located within the 3′ untranslated region consisting of poly-U/UC. PAMP binding activates RIG-I to induce innate immune signaling and type 1 interferon antiviral defenses. HCV poly-U/UC sequences can differ in length and complexity, suggesting that PAMP diversity in T/F genomes could regulate innate immune control of acute HCV infection. Using 14 unique poly-U/UC sequences from HCV T/F genomes recovered from acute-infection patients, we tested whether RIG-I recognition and innate immune activation correlate with PAMP sequence characteristics. We show that T/F variants are recognized by RIG-I in a manner dependent on length of the U-core motif of the poly-U/UC PAMP and are recognized by RIG-I to induce innate immune responses that restrict acute infection. PAMP recognition of T/F HCV variants by RIG-I may therefore impart innate immune signaling and HCV restriction to impact acute-phase-to-chronic-phase transition.IMPORTANCERecognition of nonself molecular patterns such as those seen with viral nucleic acids is an essential step in triggering the immune response to virus infection. Innate immunity is induced by hepatitis C virus infection through the recognition of viral RNA by the cellular RIG-I protein, where RIG-I recognizes a poly-uridine/cytosine motif in the viral genome. Variation within this motif may provide an immune evasion strategy for transmitted/founder viruses during acute infection. Using 14 unique poly-U/UC sequences from HCV T/F genomes recovered from acutely infected HCV patients, we demonstrate that RIG-I binding and activation of innate immunity depend primarily on the length of the uridine core within this motif. T/F variants found in acute infection contained longer U cores within the motif and could activate RIG-I and induce innate immune signaling sufficient to restrict viral infection. Thus, recognition of T/F variants by RIG-I could significantly impact the transition from acute to chronic infection.

scholarly journals Interleukin-37 regulates innate immune signaling in human and mouse colonic organoids

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Joannie M. Allaire ◽  
Anita Poon ◽  
Shauna M. Crowley ◽  
Xiao Han ◽  
Zohreh Sharafian ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Individual Variability ◽  
Innate Immune ◽  
Negative Regulator ◽  
Intestinal Epithelial ◽  
Immune Signaling ◽  
Strong Expression ◽  
Innate Immune Signaling ◽  
Close Proximity ◽  
Species Specific

AbstractIntestinal epithelial cells (IEC) reside in close proximity to the gut microbiota and are hypo-responsive to bacterial products, likely to prevent maladaptive inflammatory responses. This is in part due to their strong expression of Single Ig IL-1 related receptor (SIGIRR), a negative regulator of interleukin (IL)-1 and toll-like receptor signaling. IL-37 is an anti-inflammatory cytokine that inhibits innate signaling in diverse cells by signaling through SIGIRR. Despite the strong expression of SIGIRR by IEC, few studies have examined whether IL-37 can suppress their innate immune signaling. We characterized innate immune responses of human and murine colonoids to bacteria (FliC, LPS) and host (IL-1β) products and the role of IL-37/SIGIRR in regulating these responses. We demonstrated that human colonoids responded only to FliC, but not to LPS or IL-1β. While colonoids derived from different donors displayed significant inter-individual variability in the magnitude of their innate responses to FliC stimulation, all colonoids released a variety of chemokines. Interestingly, IL-37 attenuated these responses through inhibition of p38 and NFκB signaling pathways. We determined that this suppression by IL-37 was SIGIRR dependent, in murine organoids. Along with species-specific differences in IEC innate responses, we show that IL-37 can promote IEC hypo-responsiveness by suppressing inflammatory signaling.

scholarly journals Interleukin-37 Regulates Innate Immune Signaling in Human and Mouse Colonic Organoids

2020 ◽  
Author(s):  
Joannie Allaire ◽  
Anita Poon ◽  
Shauna Crowley ◽  
Xiao Han ◽  
Navjit Moore ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Individual Variability ◽  
Innate Immune ◽  
Negative Regulator ◽  
Intestinal Epithelial ◽  
Immune Signaling ◽  
Strong Expression ◽  
Innate Immune Signaling ◽  
Close Proximity ◽  
Species Specific

Abstract Intestinal epithelial cells (IEC) reside in close proximity to the gut microbiota and are hypo-responsive to bacterial products, likely to prevent maladaptive inflammatory responses. This is in part due to their strong expression of Single Ig IL-1 related receptor (SIGIRR), a negative regulator of interleukin (IL)-1 and toll-like receptor signaling. IL-37, an anti-inflammatory cytokine that inhibits innate signaling in diverse cells by signaling through SIGIRR. Despite the strong expression of SIGIRR by IEC, few studies have examined whether IL-37 can suppress their innate immune signaling. We characterized innate immune responses of human and murine colonoids to bacteria (FliC, LPS) and host (IL-1β) products and the role of IL-37/SIGIRR in regulating these responses. We demonstrated that human colonoids responded only to FliC, but not to LPS or IL-1β. While colonoids derived from different donors displayed significant inter-individual variability in the magnitude of their innate responses to FliC stimulation, all colonoids released a variety of chemokines. Interestingly, IL-37 attenuated these responses through inhibition of p38 and NFκB signaling pathways. We determined that this suppression by IL-37 was SIGIRR dependent, in murine organoids. Along with species-specific differences in IEC innate responses, we show that IL-37 can promote IEC hypo-responsiveness by supressing inflammatory signaling.

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