Topic
MDA5
About: MDA5 is a research topic. Over the lifetime, 740 publications have been published within this topic receiving 80681 citations. The topic is also known as: DEAD/H (Asp-Glu-Ala-Asp/His) box polypeptide & MDA-5.
Papers published on a yearly basis
Papers
TL;DR: The identity of human immunogenic dsRNAs is revealed to fill the gap in the ADAR1-dsRNA-MDA5 axis and they were found to be highly enriched in mRNAs and depleted of introns, an expected indication of bona fide substrates of cytosolic MDA5.
Abstract: The innate immune system detects viral infection via pattern recognition receptors and induces defense reactions such as production of type I interferon1. One such receptor, MDA5, is activated upon the recognition of double-stranded RNAs (dsRNAs) that are often produced during viral replication2. Endogenous dsRNAs evade MDA5 activation through RNA editing by ADAR1, thus preventing autoimmunity3-5. Among the large number of endogenous dsRNAs, the key substrates whose editing is critical to evade MDA5 activation (termed as immunogenic dsRNAs) remain elusive. Here we reveal the identity of human immunogenic dsRNAs, a surprisingly small fraction of all cellular dsRNAs, to fill the gap in the ADAR1-dsRNA-MDA5 axis. We found that, in contrast to previous findings6,7, the immunogenic dsRNAs were highly enriched in mRNAs and depleted of introns, an expected indication of bona fide substrates of cytosolic MDA5. The immunogenic dsRNAs, in contrast to non-immunogenic dsRNAs, tended to have shorter loop between the stems, which may facilitate dsRNA formation. They also tended to be enriched at the GWAS signals of common inflammatory diseases, implying that they are truly immunogenic. We validated the MDA5-dependent immunogenicity of the dsRNAs, which was dampened following ADAR1-mediated RNA editing. We anticipate that a focused analysis of immunogenic dsRNAs will greatly facilitate the understanding and treatment of cancer and inflammatory diseases in which the important roles of dsRNA editing and sensing continue to be revealed8-13.
19 citations
TL;DR: Investigation of the role of FLIP in cellular response to cytoplasmic polyinosinic:polycytidylic acid, poly(I:C), a synthetic analog of dsRNA provides evidence for a crucial dual role for FLip in antiviral responses to cytopsized ds RNA: it protects from cytopLasmic dsRNAs-mediated cell death while down-regulating IRF3-and NF-κB-mediated gene expression.
Abstract: Background
Cytoplasmic viral double-stranded RNA (dsRNA) is detected by a class of ubiquitous cytoplasmic RNA helicases, retinoic acid inducible gene-I (RIG-I) and melanoma differentiation antigen-5 (MDA5), which initiate a signaling cascade via their common adaptor called interferon-β (IFN-β) promoter stimulator-1 (IPS-1). This leads to the production of proinflammatory and antiviral cytokines, the type I Interferons, via mainly nuclear factor kappa B (NF-κB) and interferon response factor-3 (IRF3) transcription factors. Fas-associated death domain (FADD) protein, receptor-interacting protein (RIP1), caspase-8 and tumor necrosis factor receptor (TNFR)-associated death domain (TRADD) protein, all traditionally associated with death receptor signaling, are also involved in RIG-I/MDA5 signaling pathway. We previously showed that FLIP (Flice-like inhibitory protein), also designated as cflar (CASP8 and FADD-like apoptosis regulator), negatively regulates lipopolysaccharide (LPS)-induced toll-like receptor 4 (TLR4) signaling in endothelial cells and mouse embryonic fibroblasts (MEFs) and protected against TLR4-mediated apoptosis.
19 citations
TL;DR: Several signaling adaptors that are reported to participate in the regulation of IFN gene activation are summarized, based on knowledge of the virus or RNA pathogen specificity as well as the function-structure relationship of RNA sensing.
Abstract: Viral infections trigger the innate immune system, serving as the first line of defense, and are characterized by the production of type I interferon (IFN). Type I IFN is expressed in a broad spectrum of cells and tissues in the host and includes various subtypes (IFN-α, IFN-β, IFN-δ, IFN-e, IFN-κ, IFN-τ, IFN-ω, IFN-ν, and IFN-ζ). Since the discovery of type I IFN, our knowledge of the biology of type I IFN has accumulated immensely, and we now have a substantial amount of information on the molecular mechanisms of the response and induction of type I IFN, as well as the strategies utilized by viruses to evade the type I IFN response. Foot-and-mouth disease virus (FMDV) can selectively alter cellular pathways to promote viral replication and evade antiviral immune activation of type I IFN. RNA molecules generated by FMDV are sensed by the cellular receptor for pathogen-associated molecular patterns (PAMPs). FMDV preferentially activates different sensor molecules and various signal transduction pathways. Based on knowledge of the virus or RNA pathogen specificity as well as the function-structure relationship of RNA sensing, it is necessary to summarize numerous signaling adaptors that are reported to participate in the regulation of IFN gene activation.
19 citations
TL;DR: This paper showed transformation-promoting spontaneous DNA damage and MDA5-driven, but cGAS/STING-dependent, chronic type I interferon production in SAMHD1-deficient mice.
Abstract: Loss of the dNTPase and DNA repair enzyme SAMHD1 is associated with cancer and causes systemic autoimmunity. We show transformation-promoting spontaneous DNA damage and MDA5-driven, but cGAS/STING-dependent, chronic type I interferon production in SAMHD1-deficient mice.
19 citations
TL;DR: It is suggested that RNF123 functions as a novel inhibitor of innate antiviral signaling mediated by RIG‐I and MDA5, a function that does not depend on its E3 ligase activity.
Abstract: Retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) are cytoplasmic sensors crucial for recognizing different species of viral RNAs, which triggers the production of type I interferons (IFNs) and inflammatory cytokines. Here, we identify RING finger protein 123 (RNF123) as a negative regulator of RIG-I and MDA5. Overexpression of RNF123 inhibits IFN-β production triggered by Sendai virus (SeV) and encephalomyocarditis picornavirus (EMCV). Knockdown or knockout of endogenous RNF123 potentiates IFN-β production triggered by SeV and EMCV, but not by the sensor of DNA viruses cGAS RNF123 associates with RIG-I and MDA5 in both endogenous and exogenous cases in a viral infection-inducible manner. The SPRY and coiled-coil, but not the RING, domains of RNF123 are required for the inhibitory function. RNF123 interacts with the N-terminal CARD domains of RIG-I/MDA5 and competes with the downstream adaptor VISA/MAVS/IPS-1/Cardif for RIG-I/MDA5 CARD binding. These findings suggest that RNF123 functions as a novel inhibitor of innate antiviral signaling mediated by RIG-I and MDA5, a function that does not depend on its E3 ligase activity.
19 citations
Related Topics (5)
Performance Metrics
| Year | Papers |
|---|---|
| 2025 | 44 |
| 2024 | 75 |
| 2023 | 80 |
| 2022 | 127 |
| 2021 | 55 |
| 2020 | 53 |