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MDA5 (melanoma differentiation-associated protein 5) is a RIG-I-like receptor dsRNA helicase enzyme that is encoded by the IFIH1 gene in humans. [5] MDA5 is part of the RIG-I-like receptor (RLR) family, which also includes RIG-I and LGP2 , and functions as a pattern recognition receptor capable of detecting viruses .
At a resting state for the cell, a protein called mitofusin 2 (MFN2) is known to interact with MAVS, preventing MAVS from binding to the cytosolic proteins, such as RIG-I and MDA5. [ 7 ] [ 8 ] Upon recognition of the virus in the cytosol, mitochondria-associated ER membranes (MAM) and mitochondria will become physically tethered by MFN2 and RIG ...
RIG-I domain architecture. (A) Schematic representation of full-length RIG-I. (B) X-ray crystal structure of RNA-bound RIG-I ( ), excluding the CARD domains.The RLR receptors are members of the DEAD-box (SF2) helicase family (despite containing a DExD/H motif, rather than the DEAD motif characteristic of the family) and share a common domain architecture.
In order to evade pattern recognition, other viruses such as Enterovirus have evolved multi-functional proteins that not only help in viral protein processing but also cleave cytoplasmic recognition proteins MDA5 and RIG-I, further demonstrating the extent to which viruses can reduce Interferon Signaling through various pathways.
MDA5, an RNA helicase, is known to be activated by complex high molecular weight dsRNA transcribed from the viral genome. [13] [14] In a cell with RNase L, MDA5 activity may be further enhanced. [13] When active, RNase L cleaves and identifies viral RNA and feeds it into MDA5 activation sites, enhancing the production of IFN-β.
RIG-I and Mda5-mediated signalling pathway. Three RLR helicases have so far been described: RIG-I and MDA5 (recognizing 5'triphosphate-RNA and dsRNA, respectively), which activate antiviral signaling, and LGP2, which appears to act as a dominant-negative inhibitor. RLRs initiate the release of inflammatory cytokines and type I interferon (IFN I).
80861 Ensembl ENSG00000108771 ENSMUSG00000017830 UniProt Q96C10 Q99J87 RefSeq (mRNA) NM_024119 NM_030150 RefSeq (protein) NP_077024 NP_084426 Location (UCSC) Chr 17: 42.1 – 42.11 Mb Chr 11: 100.59 – 100.6 Mb PubMed search Wikidata View/Edit Human View/Edit Mouse Probable ATP-dependent RNA helicase DHX58 also known as RIG-I-like receptor 3 (RLR-3) or RIG-I-like receptor LGP2 (RLR) is a RIG ...
There is very little known about the mechanism of action of these drugs. However, it was shown in 2015 that a possible mechanism of action of these drugs in colorectal cancer-initiating cells is through activating dsRNA expression which leads to the activation of the MDA5/MAVS RNA recognition pathway inducing some sort of viral mimicry inside the cell.