scholarly journals RNA sensing via LGP2 is essential for the induction of a type I IFN response in ADAR1 deficiency

2021 ◽  
Author(s):  
Jorn E. Stok ◽  
Timo Oosenbrug ◽  
Laurens R. ter Haar ◽  
Dennis Gravekamp ◽  
Christian P. Bromley ◽  
...  
Keyword(s):  
Immune Responses ◽  
Tumor Cells ◽  
Tumor Therapy ◽  
Innate Immune ◽  
Type I ◽  
Type I Ifn ◽  
Innate Immune Responses ◽  
Canonical Function ◽  
Chemotherapy Drugs ◽  
Rare Mutations

RNA editing by the enzyme Adenosine Deaminase Acting on RNA 1 (ADAR1) is an important mechanism by which cells avoid innate immune responses to some endogenous RNAs. In ADAR1-deficient cells, unedited self RNAs can form base-paired structures that resemble viral RNAs and inadvertently activate antiviral innate immune pathways that lead to the induction of type I interferon (IFN). Rare mutations in ADAR1 cause Aicardi-Goutieres Syndrome (AGS), a severe childhood autoinflammatory syndrome that is characterized by chronic and excessive type I IFN production and developmental delay. Conversely, ADAR1 dysfunction and consequent type I IFN production helps restrict tumor growth and potentiates the activity of some chemotherapy drugs. Induction of type I IFN in ADAR1-deficient cells is thought to be due to triggering of the cytosolic RIG-I-like receptor (RLR), MDA5, by unedited self RNAs. Here, we show that another RLR, LGP2, also has an essential role. We demonstrate that ADAR1-deficient human cells fail to mount a type I IFN response in the absence of LGP2 and this involves the canonical function of LGP2 as an RNA sensor and facilitator of MDA5-dependent signaling. Further, we show that the sensitivity of tumor cells to ADAR1 loss requires the presence of LGP2. Finally, we find that type I IFN induction in tumor cells depleted of ADAR1 and treated with some chemotherapeutics is fully dependent on the expression of LGP2. These findings highlight a central role for LGP2 in self RNA sensing with important clinical implications for the treatment of AGS as well as for the potential application of ADAR1-directed anti-tumor therapy.

scholarly journals Disruption of MDA5-Mediated Innate Immune Responses by the 3C Proteins of Coxsackievirus A16, Coxsackievirus A6, and Enterovirus D68

2017 ◽  
Vol 91 (13) ◽  
Author(s):  
Yajuan Rui ◽  
Jiaming Su ◽  
Hong Wang ◽  
Junliang Chang ◽  
Shaohua Wang ◽  
...  
Keyword(s):  
Immune Responses ◽  
Respiratory Disease ◽  
Foot And Mouth Disease ◽  
Innate Immune ◽  
Type I ◽  
Type I Ifn ◽  
Innate Immune Responses ◽  
Key Factors ◽  
Coxsackievirus A16 ◽  
Enterovirus D68

ABSTRACT Coxsackievirus A16 (CV-A16), CV-A6, and enterovirus D68 (EV-D68) belong to the Picornaviridae family and are major causes of hand, foot, and mouth disease (HFMD) and pediatric respiratory disease worldwide. The biological characteristics of these viruses, especially their interplay with the host innate immune system, have not been well investigated. In this study, we discovered that the 3Cpro proteins from CV-A16, CV-A6, and EV-D68 bind melanoma differentiation-associated gene 5 (MDA5) and inhibit its interaction with MAVS. Consequently, MDA5-triggered type I interferon (IFN) signaling in the retinoic acid-inducible gene I-like receptor (RLR) pathway was blocked by the CV-A16, CV-A6, and EV-D68 3Cpro proteins. Furthermore, the CV-A16, CV-A6, and EV-D68 3Cpro proteins all cleave transforming growth factor β-activated kinase 1 (TAK1), resulting in the inhibition of NF-κB activation, a host response also critical for Toll-like receptor (TLR)-mediated signaling. Thus, our data demonstrate that circulating HFMD-associated CV-A16 and CV-A6, as well as severe respiratory disease-associated EV-D68, have developed novel mechanisms to subvert host innate immune responses by targeting key factors in the RLR and TLR pathways. Blocking the ability of 3Cpro proteins from diverse enteroviruses and coxsackieviruses to interfere with type I IFN induction should restore IFN antiviral function, offering a potential novel antiviral strategy. IMPORTANCE CV-A16, CV-A6, and EV-D68 are emerging pathogens associated with hand, foot, and mouth disease and pediatric respiratory disease worldwide. The pathogenic mechanisms of these viruses are largely unknown. Here we demonstrate that the CV-A16, CV-A6, and EV-D68 3Cpro proteins block MDA5-triggered type I IFN induction. The 3Cpro proteins of these viruses bind MDA5 and inhibit its interaction with MAVS. In addition, the CV-A16, CV-A6, and EV-D68 3Cpro proteins cleave TAK1 to inhibit the NF-κB response. Thus, our data demonstrate that circulating HFMD-associated CV-A16 and CV-A6, as well as severe respiratory disease-associated EV-D68, have developed a mechanism to subvert host innate immune responses by simultaneously targeting key factors in the RLR and TLR pathways. These findings indicate the potential merit of targeting the CV-A16, CV-A6, and EV-D68 3Cpro proteins as an antiviral strategy.

scholarly journals Innate immune responses elicited by Sin Nombre virus or type I IFN agonists protect hamsters from lethal Andes virus infections

2018 ◽  
Vol 99 (10) ◽  
pp. 1359-1366 ◽  
Author(s):  
Rebecca L. Brocato ◽  
Victoria Wahl ◽  
Christopher D. Hammerbeck ◽  
Matthew D. Josleyn ◽  
Anita K. McElroy ◽  
...  
Keyword(s):  
Immune Responses ◽  
Innate Immune ◽  
Sin Nombre Virus ◽  
Type I ◽  
Type I Ifn ◽  
Innate Immune Responses ◽  
Virus Infections ◽  
Andes Virus

scholarly journals pMGF505-7R determines pathogenicity of African swine fever virus infection by inhibiting IL-1β and type I IFN production

2021 ◽  
Vol 17 (7) ◽  
pp. e1009733
Author(s):  
Jiangnan Li ◽  
Jie Song ◽  
Li Kang ◽  
Li Huang ◽  
Shijun Zhou ◽  
...  
Keyword(s):  
Immune Responses ◽  
Inflammatory Responses ◽  
African Swine Fever Virus ◽  
African Swine Fever ◽  
Innate Immune ◽  
Fever Virus ◽  
Type I ◽  
Type I Ifn ◽  
Innate Immune Responses

Inflammatory factors and type I interferons (IFNs) are key components of host antiviral innate immune responses, which can be released from the pathogen-infected macrophages. African swine fever virus (ASFV) has developed various strategies to evade host antiviral innate immune responses, including alteration of inflammatory responses and IFNs production. However, the molecular mechanism underlying inhibition of inflammatory responses and IFNs production by ASFV-encoded proteins has not been fully understood. Here we report that ASFV infection only induced low levels of IL-1β and type I IFNs in porcine alveolar macrophages (PAMs), even in the presence of strong inducers such as LPS and poly(dA:dT). Through further exploration, we found that several members of the multigene family 360 (MGF360) and MGF505 strongly inhibited IL-1β maturation and IFN-β promoter activation. Among them, pMGF505-7R had the strongest inhibitory effect. To verify the function of pMGF505-7R in vivo, a recombinant ASFV with deletion of the MGF505-7R gene (ASFV-Δ7R) was constructed and assessed. As we expected, ASFV-Δ7R infection induced higher levels of IL-1β and IFN-β compared with its parental ASFV HLJ/18 strain. ASFV infection-induced IL-1β production was then found to be dependent on TLRs/NF-κB signaling pathway and NLRP3 inflammasome. Furthermore, we demonstrated that pMGF505-7R interacted with IKKα in the IKK complex to inhibit NF-κB activation and bound to NLRP3 to inhibit inflammasome formation, leading to decreased IL-1β production. Moreover, we found that pMGF505-7R interacted with and inhibited the nuclear translocation of IRF3 to block type I IFN production. Importantly, the virulence of ASFV-Δ7R is reduced in piglets compared with its parental ASFV HLJ/18 strain, which may due to induction of higher IL-1β and type I IFN production in vivo. Our findings provide a new clue to understand the functions of ASFV-encoded pMGF505-7R and its role in viral infection-induced pathogenesis, which might help design antiviral agents or live attenuated vaccines to control ASF.

scholarly journals Proteolytic Disassembly of Viral Outer Capsid Proteins Is Crucial for Reovirus-Mediated Type-I Interferon Induction in Both Reovirus-Susceptible and Reovirus-Refractory Tumor Cells

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Yuki Katayama ◽  
Yuichi Terasawa ◽  
Masashi Tachibana ◽  
Hiroyuki Mizuguchi ◽  
Fuminori Sakurai
Keyword(s):  
Immune Responses ◽  
Tumor Cells ◽  
Human Tumor ◽  
Innate Immune ◽  
Capsid Proteins ◽  
Type I ◽  
Innate Immune Responses ◽  
Outer Capsid ◽  
Proapoptotic Gene

Oncolytic reovirus induces innate immune responses, which contribute to the antitumor activity of reovirus, followingin vivoapplication. Reovirus-induced innate immune responses have been relatively well characterized in immune cells and mouse embryonic fibroblasts cells; however, the mechanisms and profiles of reovirus-induced innate immune responses in human tumor cells have not been well understood. In particular, differences in reovirus-induced innate immune responses between reovirus-susceptible and reovirus-refractory tumor cells remain unknown, although the intracellular trafficking of reovirus differs between these tumor cells. In this study, we examined reovirus-induced upregulation of interferon- (IFN-)βand of the proapoptotic gene, Noxa, in reovirus-susceptible and -refractory tumor cells. IFN-βand Noxa were significantly induced by reovirusviathe IFN-βpromoter stimulator-1 (IPS-1) signaling in both types of tumor cells. Inhibition of cathepsins B and L, which are important for disassembly of reovirus outer capsid proteins and escape into cytoplasm, largely suppressed reovirus-induced upregulation of IFN-βand Noxa expression in not only reovirus-susceptible but also reovirus-refractory tumor cells. These results indicated that in both reovirus-susceptible and reovirus-refractory tumor cells, disassembly of the outer capsid proteins by cathepsins and the escape into the cytoplasm were crucial steps for reovirus-induced innate immunity.

scholarly journals RIG-I-Like Receptor-Mediated Recognition of Viral Genomic RNA of Severe Acute Respiratory Syndrome Coronavirus-2 and Viral Escape From the Host Innate Immune Responses

2021 ◽  
Vol 12 ◽  
Author(s):  
Takahisa Kouwaki ◽  
Tasuku Nishimura ◽  
Guanming Wang ◽  
Hiroyuki Oshiumi
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Innate Immune Response ◽  
Cytokine Expression ◽  
Innate Immune ◽  
Viral Escape ◽  
Type I ◽  
Type I Ifn ◽  
Innate Immune Responses ◽  
Viral Genomic Rna

RIG-I-like receptors (RLR), RIG-I and MDA5, are cytoplasmic viral RNA sensors that recognize viral double-stranded RNAs and trigger signals to induce antiviral responses, including type I interferon production. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) caused the coronavirus disease 2019 pandemic. However, the RLR role in innate immune response to SARS-CoV-2 has not been fully elucidated. Here, we studied the roles of RLR in cytokine expression responding to SARS-CoV-2 and found that not only MDA5 but also RIG-I are involved in innate immune responses in some types of human cells. Transfection of total RNAs extracted from SARS-CoV-2-infected cells into epithelial cells induced IFN-β, IP-10, and Ccl5 mRNA expression. The cytokine expression was reduced by knockout of either RIG-I or MDA5, suggesting that both proteins are required for appropriate innate immune response to SARS-CoV-2. Two viral genomic RNA regions strongly induced type I IFN expression, and a 200-base fragment of viral RNA preferentially induced type I IFN in a RIG-I-dependent manner. In contrast, SARS-CoV-2 infectious particles hardly induced cytokine expression, suggesting viral escape from the host response. Viral 9b protein inhibited RIG-I and MAVS interaction, and viral 7a protein destabilized the TBK1 protein, leading to attenuated IRF-3 phosphorylation required for type I IFN expression. Our data elucidated the mechanism underlying RLR-mediated response to SARS-CoV-2 infection and viral escape from the host innate immune response.

scholarly journals Encephalomyocarditis virus 3C protease attenuates type I interferon production through disrupting the TANK–TBK1–IKKε–IRF3 complex

2017 ◽  
Vol 474 (12) ◽  
pp. 2051-2065 ◽  
Author(s):  
Li Huang ◽  
Tao Xiong ◽  
Huibin Yu ◽  
Quan Zhang ◽  
Kunli Zhang ◽  
...  
Keyword(s):  
Immune Responses ◽  
Sendai Virus ◽  
Innate Immune ◽  
Encephalomyocarditis Virus ◽  
Type I ◽  
Type I Ifn ◽  
Innate Immune Responses ◽  
3C Protease ◽  
Iκb Kinase ◽  
Novel Strategy

TRAF family member-associated NF-κB activator (TANK) is a scaffold protein that assembles into the interferon (IFN) regulator factor 3 (IRF3)-phosphorylating TANK-binding kinase 1 (TBK1)–(IκB) kinase ε (IKKε) complex, where it is involved in regulating phosphorylation of the IRF3 and IFN production. However, the functions of TANK in encephalomyocarditis virus (EMCV) infection-induced type I IFN production are not fully understood. Here, we demonstrated that, instead of stimulating type I IFN production, the EMCV-HB10 strain infection potently inhibited Sendai virus- and polyI:C-induced IRF3 phosphorylation and type I IFN production in HEK293T cells. Mechanistically, EMCV 3C protease (EMCV 3C) cleaved TANK and disrupted the TANK–TBK1–IKKε–IRF3 complex, which resulted in the reduction in IRF3 phosphorylation and type I IFN production. Taken together, our findings demonstrate that EMCV adopts a novel strategy to evade host innate immune responses through cleavage of TANK.

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