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

Type I interferon (IFN) production is a critical component of the innate defence against viral infections. Viral products induce strong type I IFN responses through the activation of Toll-like receptors (TLRs) and intracellular cytoplasmic receptors such as protein kinase R (PKR). Here we demonstrate that cells lacking TRAF3, a member of the TNF receptor-associated factor family, are defective in type I IFN responses activated by several different TLRs. Furthermore, we show that TRAF3 associates with the TLR adaptors TRIF and IRAK1, as well as downstream IRF3/7 kinases TBK1 and IKK-epsilon, suggesting that TRAF3 serves as a critical link between TLR adaptors and downstream regulatory kinases important for IRF activation. In addition to TLR stimulation, we also show that TRAF3-deficient fibroblasts are defective in their type I IFN response to direct infection with vesicular stomatitis virus, indicating that TRAF3 is also an important component of TLR-independent viral recognition pathways. Our data demonstrate that TRAF3 is a major regulator of type I IFN production and the innate antiviral response.
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PMID:Critical role of TRAF3 in the Toll-like receptor-dependent and -independent antiviral response. 1630 36

Upon recognition of viral components by pattern recognition receptors, including TLRs and retinoic acid-inducible gene I (RIG-I)- like helicases, cells are activated to produce type I IFN and proinflammatory cytokines. These pathways are tightly regulated by host to prevent inappropriate cellular response, but viruses can down-regulate these pathways for their survival. Recently, identification of negative regulators for cytoplasmic RNA-mediated antiviral signaling, especially the RIG-I pathway, attract much attention. However, there is no report about negative regulation of RIG-I antiviral pathway by microRNAs (miRNA) to date. We found that vesicular stomatitis virus (VSV) infection up-regulated miR-146a expression in mouse macrophages in TLR-myeloid differentiation factor 88-independent but RIG-I-NF-kappaB-dependent manner. In turn, miR-146a negatively regulated VSV-triggered type I IFN production, thus promoting VSV replication in macrophages. In addition to two known miR-146a targets, TRAF6 and IRAK1, we proved that IRAK2 was another target of miR-146a, which also participated in VSV-induced type I IFN production. Furthermore, IRAK1 and IRAK2 participated in VSV-induced type I IFN production by associating with Fas-associated death domain protein, an important adaptor in RIG-I signaling, in a VSV infection-inducible manner. Therefore, we demonstrate that miR-146a, up-regulated during viral infection, is a negative regulator of the RIG-I-dependent antiviral pathway by targeting TRAF6, IRAK1, and IRAK2.
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PMID:MicroRNA-146a feedback inhibits RIG-I-dependent Type I IFN production in macrophages by targeting TRAF6, IRAK1, and IRAK2. 1959 90