Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038362 (stomatitis)
 8,852 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activation of the interferon regulatory factors (IRFs) 3 and 7 transcription factors is essential for the induction of type I interferon (IFN) and development of the innate antiviral response. Retinoic acid-inducible gene I has been shown to contribute to virus-induced IFN production independent of the Toll-like receptor pathways in response to a variety of RNA viruses and double-stranded RNA. In the present study, we demonstrate that the NF-kappaB-inducible, anti-apoptotic protein A20 efficiently blocks RIG-I-mediated activation of NF-kappaB-, IRF-3-, and IRF-7-dependent promoters but only weakly interferes with TRIF-TLR-3-mediated IFN activation. Expression of A20 completely blocked CARD domain containing DeltaRIG-I-induced IRF-3 Ser-396 phosphorylation, homodimerization, and DNA binding. The level of A20 inhibition was upstream of the TBK1/IKKepsilon kinases that phosphorylate IRF3 and IRF7 and paradoxically, A20 selectively degraded the TRIF protein but not RIG-I. A20 possesses two ubiquitin-editing domains, an N-terminal deubiquitination domain and a C-terminal ubiquitin ligase domain consisting of seven zinc finger domains. Deletion of the N-terminal de-ubiquitination domain had no significant effect on the inhibitory effect of A20, whereas deletion or mutation of zinc finger motif 7 ablated the inhibitory function of A20 on IRF- or NF-kappaB-mediated gene expression. Furthermore, cells stably expressing the active form of RIG-I induced an antiviral state that interfered with replication of vesicular stomatitis virus, an effect that was reversed by stable co-expression of A20. These results suggest that the virus-inducible, NF-kappaB-dependent activation of A20 functions as a negative regulator of RIG-I-mediated induction of the antiviral state.
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PMID:Negative regulation of the retinoic acid-inducible gene I-induced antiviral state by the ubiquitin-editing protein A20. 1630 43

TLR3 and the cytoplasmic helicase family proteins (retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5)) serve as dsRNA pattern-recognition receptors. In response to poly(I:C), a representative of dsRNA, and viral infection, they have been shown to activate the transcription factor IFN regulatory factor (IRF)-3, which in turn induces activation of the IFN-beta promoter. RIG-I/MDA5 recognizes dsRNA in the cytoplasm, whereas TLR3 resides in the cell surface membrane or endosomes to engage in extracytoplasmic recognition of dsRNA. Recent reports suggest that TLR3 induces cellular responses in epithelial cells in response to respiratory syncytial virus (RSV). The modus for TLR3 activation by RSV, however, remains unresolved. By small interference RNA gene-silencing technology and human cell transfectants, we have revealed that knockdown of NAK-associated protein 1 (NAP1) leads to the down-regulation of IFN-beta promoter activation >24 h after poly(I:C) or virus (RSV and vesicular stomatitis virus) treatment. NAP1 is located downstream of the adapter Toll-IL-1R homology domain-containing adapter molecule (TICAM)-1 (Toll/IL-1R domain-containing adapter-inducing IFN-beta) in the TLR3 pathway, but TICAM-1 and TLR3 did not participate in the IRF-3 and IFN-beta promoter activation by RSV infection. Virus-mediated activation of the IFN-beta promoter was largely abrogated by the gene silencing of IFN-beta promoter stimulator-1 (mitochondria antiviral signaling (MAVS), VISA, Cardif), the adapter of the RIG-I/MDA5 dsRNA-recognition proteins. In both the TLR and virus-mediated IFN-inducing pathways, IkappaB kinase-related kinase epsilon and TANK-binding kinase 1 participated in IFN-beta induction. Thus, RSV as well as other viruses induces replication-mediated activation of the IFN-beta promoter, which is intracellularly initiated by the RIG-I/MDA5 but not the TLR3 pathway. Both the cytoplasmic and TLR3-mediated dsRNA recognition pathways converge upon NAP1 for the activation of the IRF-3 and IFN-beta promoter.
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PMID:NAK-associated protein 1 participates in both the TLR3 and the cytoplasmic pathways in type I IFN induction. 1714 68

The DExD/H box RNA helicase retinoic acid-inducible gene I (RIG-I) and the melanoma differentiation-associated gene 5 (MDA5) are key intracellular receptors that recognize virus infection to produce type I IFN. A third helicase gene, Lgp2, is homologous to Rig-I and Mda5 but lacks a caspase activation and recruitment domain. We generated Lgp2-deficient mice and report that the loss of this gene greatly sensitizes cells to cytosolic polyinosinic/polycytidylic acid-mediated induction of type I IFN. However, negative feedback inhibition of IFN-beta transcription was found to be normal in the absence of LGP2, indicating that LGP2 is not the primary negative regulator of type I IFN production. Our data further indicate that Lgp2-/- mice exhibited resistance to lethal vesicular stomatitis virus infection, a virus whose replicative RNA intermediates are recognized specifically by RIG-I rather than by MDA5 to trigger the production of type I IFN. However, mice lacking LGP2 were observed to exhibit a defect in type I IFN production in response to infection by the encephalomyocarditis virus, the replication of which activates MDA5-dependent innate immune responses. Collectively, our data indicate a disparate regulatory role for LGP2 in the triggering of innate immune signaling pathways following RNA virus infection.
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PMID:Loss of DExD/H box RNA helicase LGP2 manifests disparate antiviral responses. 1747 74

Autophagy is an essential process for physiological homeostasis, but its role in viral infection is only beginning to be elucidated. We show here that the Atg5-Atg12 conjugate, a key regulator of the autophagic process, plays an important role in innate antiviral immune responses. Atg5-deficient mouse embryonic fibroblasts (MEFs) were resistant to vesicular stomatitis virus replication, which was largely due to hyperproduction of type I interferons in response to immunostimulatory RNA (isRNA), such as virus-derived, double-stranded, or 5'-phosphorylated RNA. Similar hyperresponse to isRNA was also observed in Atg7-deficient MEFs, in which Atg5-Atg12 conjugation is impaired. Overexpression of Atg5 or Atg12 resulted in Atg5-Atg12 conjugate formation and suppression of isRNA-mediated signaling. Molecular interaction studies indicated that the Atg5-Atg12 conjugate negatively regulates the type I IFN production pathway by direct association with the retinoic acid-inducible gene I (RIG-I) and IFN-beta promoter stimulator 1 (IPS-1) through the caspase recruitment domains (CARDs). Thus, in contrast to its role in promoting the bactericidal process, a component of the autophagic machinery appears to block innate antiviral immune responses, thereby contributing to RNA virus replication in host cells.
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PMID:The Atg5 Atg12 conjugate associates with innate antiviral immune responses. 1770 47

Upon detection of viral RNA, the helicases RIG-I and/or MDA5 trigger, via their adaptor Cardif (also known as IPS-1, MAVS, or VISA), the activation of the transcription factors NF-kappaB and IRF3, which collaborate to induce an antiviral type I interferon (IFN) response. FADD and RIP1, known as mediators of death-receptor signaling, are implicated in this antiviral pathway; however, the link between death-receptor and antiviral signaling is not known. Here we showed that TRADD, a crucial adaptor of tumor necrosis factor receptor (TNFRI), was important in RIG-like helicase (RLH)-mediated signal transduction. TRADD is recruited to Cardif and orchestrated complex formation with the E3 ubiquitin ligase TRAF3 and TANK and with FADD and RIP1, leading to the activation of IRF3 and NF-kappaB. Loss of TRADD prevented Cardif-dependent activation of IFN-beta, reduced the production of IFN-beta in response to RNA viruses, and enhanced vesicular stomatitis virus replication. Thus, TRADD is not only an essential component of proinflammatory TNFRI signaling, but is also required for RLH-Cardif-dependent antiviral immune responses.
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PMID:TRADD protein is an essential component of the RIG-like helicase antiviral pathway. 1843 48

Viral infection activates Toll-like receptor and RIG-I (retinoic acid-inducible gene I) signaling pathways, leading to phosphorylation of IRF3 (interferon regulatory factor 3) and IRF7 and stimulation of type I interferon (IFN) transcription, a process important for innate immunity. We show that upon vesicular stomatitis virus infection, IRF3 and IRF7 are modified not only by phosphorylation but by the small ubiquitin-related modifiers SUMO1, SUMO2, and SUMO3. SUMOylation of IRF3 and IRF7 was dependent on the activation of Toll-like receptor and RIG-I pathways but not on the IFN-stimulated pathway. However, SUMOylation of IRF3 and IRF7 was not dependent on their phosphorylation, and vice versa. We identified Lys(152) of IRF3 and Lys(406) of IRF7 to be their sole small ubiquitin-related modifier (SUMO) conjugation site. IRF3 and IRF7 mutants defective in SUMOylation led to higher levels of IFN mRNA induction after viral infection, relative to the wild type IRFs, indicating a negative role for SUMOylation in IFN transcription. Together, SUMO modification is an integral part of IRF3 and IRF7 activity that contributes to postactivation attenuation of IFN production.
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PMID:Virus infection triggers SUMOylation of IRF3 and IRF7, leading to the negative regulation of type I interferon gene expression. 1863 38

The cellular innate immune system is essential for recognizing pathogen infection and for establishing effective host defence. But critical molecular determinants responsible for facilitating an appropriate immune response-following infection with DNA and RNA viruses, for example-remain to be identified. Here we report the identification, following expression cloning, of a molecule (STING; stimulator of interferon genes) that appears essential for effective innate immune signalling processes. It comprises five putative transmembrane regions, predominantly resides in the endoplasmic reticulum and is able to activate both NF-kappaB and IRF3 transcription pathways to induce expression of type I interferon (IFN-alpha and IFN-beta ) and exert a potent anti-viral state following expression. In contrast, loss of STING rendered murine embryonic fibroblasts extremely susceptible to negative-stranded virus infection, including vesicular stomatitis virus. Further, STING ablation abrogated the ability of intracellular B-form DNA, as well as members of the herpesvirus family, to induce IFN-beta, but did not significantly affect the Toll-like receptor (TLR) pathway. Yeast two-hybrid and co-immunoprecipitation studies indicated that STING interacts with RIG-I and with SSR2 (also known as TRAPbeta), which is a member of the translocon-associated protein (TRAP) complex required for protein translocation across the endoplasmic reticulum membrane following translation. Ablation by RNA interference of both TRAPbeta and translocon adaptor SEC61beta was subsequently found to inhibit STING's ability to stimulate expression of IFN-beta. Thus, as well as identifying a regulator of innate immune signalling, our results imply a potential role for the translocon in innate signalling pathways activated by select viruses as well as intracellular DNA.
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PMID:STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. 1872 57

FLN29 was identified as an interferon (IFN)-inducible gene, and it has been shown to suppress Toll-like receptor 4-mediated NF-kappaB activation by binding to TRAF6. To elucidate the physiological roles of FLN29, we generated FLN29-deficient mice. FLN29 deficiency resulted in hyper-response to LPS both in vivo and in vitro, demonstrating the negative regulatory role of FLN29 in TLR4 signaling. Furthermore, we found that FLN29(-/-) mice exhibited increased susceptibility to poly(I:C)-induced septic shock compared with WT mice. FLN29(-/-) fibroblasts were highly resistant to vesicular stomatitis virus infection, and these cells produced more IFN-beta than WT cells did in response to not only intracellular poly(I:C) but also overexpression of IPS-1. Forced expression of FLN29 inhibited the IPS-1-dependent activation of both NF-kappaB and IRF3. We also found that FLN29 could interact with TRIF, IPS-1, TRAF3, and TRAF6. Together, these results suggest that FLN29, in addition to playing a negative regulatory role in the TLR4 signaling pathway, negatively regulates the RIG-I-like helicase signaling pathway at the level of IPS-1/TRAF6 and IPS-1/TRAF3 complexes.
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PMID:FLN29 deficiency reveals its negative regulatory role in the Toll-like receptor (TLR) and retinoic acid-inducible gene I (RIG-I)-like helicase signaling pathway. 1884 41

Type I interferons (IFN-alpha/beta) are essential for immune defense against viruses and induced through the actions of the cytoplasmic helicases, RIG-I and MDA5, and their downstream adaptor molecule IPS-1. TRAF6 and the downstream kinase TAK1 have been shown to be essential for the production of proinflammatory cytokines through the TLR/MyD88/TRIF pathway. Although binding of TRAF6 with IPS-1 has been demonstrated, the role of the TRAF6 pathway in IFN-alpha/beta production has not been fully understood. Here, we demonstrate that TRAF6 is critical for IFN-alpha/beta induction in response to viral infection and intracellular double-stranded RNA, poly(I:C). Activation of NF-kappaB, JNK, and p38, but not IRF3, was impaired in TRAF6-deficient mouse embryo fibroblasts in response to vesicular stomatitis virus and poly(I:C). However, TAK1 was not required for IFN-beta induction in this process, since normal IFN-alpha/beta production was observed in TAK1-deficient mouse embryo fibroblasts. Instead, another MAP3K, MEKK1, was important for the activation of the IFN-beta promoter in response to poly(I:C). Forced expression of MEKK1 in combination with IRF3 was sufficient for the induction of IFN-beta, whereas suppression of MEKK1 expression by small interfering RNA inhibited the induction of IFN-beta by poly(I:C). These data suggest that IPS-1 requires TRAF6 and MEKK1 to activate NF-kappaB and mitogen-activated protein kinases that are critical for the optimal induction of type I interferons.
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PMID:TRAF6 and MEKK1 play a pivotal role in the RIG-I-like helicase antiviral pathway. 1898 93

RIG-I (retinoic acid-inducible gene-I), a cytoplasmic RNA helicase, interacts with IPS-1/MAVS/Cardif/VISA, a protein on the outer membrane of mitochondria, to signal the presence of virus-derived RNA and induce type I interferon production. Activation of RIG-I requires the ubiquitin ligase, TRIM25, which mediates lysine 63-linked polyubiquitination of the RIG-I N-terminal CARD-like region. However, how this modification proceeds for activation of IPS-1 by RIG-I remains unclear. Here we identify an alternative factor, Riplet/RNF135, that promotes RIG-I activation independent of TRIM25. The Riplet/RNF135 protein consists of an N-terminal RING finger domain, C-terminal SPRY and PRY motifs, and shows sequence similarity to TRIM25. Immunoprecipitation analyses demonstrated that the C-terminal helicase and repressor domains of RIG-I interact with the Riplet/RNF135 C-terminal region, whereas the CARD-like region of RIG-I is dispensable for this interaction. Riplet/RNF135 promotes lysine 63-linked polyubiquitination of the C-terminal region of RIG-I, modification of which differs from the N-terminal ubiquitination by TRIM25. Overexpression and knockdown analyses revealed that Riplet/RNF135 promotes RIG-I-mediated interferon-beta promoter activation and inhibits propagation of the negative-strand RNA virus, vesicular stomatitis virus. Our data suggest that Riplet/RNF135 is a novel factor of the RIG-I pathway that is involved in the evoking of human innate immunity against RNA virus infection, and activates RIG-I through ubiquitination of its C-terminal region. We infer that a variety of RIG-I-ubiquitinating molecular complexes sustain RIG-I activation to modulate RNA virus replication in the cytoplasm.
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PMID:Riplet/RNF135, a RING finger protein, ubiquitinates RIG-I to promote interferon-beta induction during the early phase of viral infection. 1901 31


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