MDA5

Abstract: Many interferon (IFN)-stimulated genes are also induced by double-stranded RNA (dsRNA), a component closely associated with the IFN system in the context of virus-host interactions. Recently, we demonstrated that the IFN-induced 3' --> 5' exonuclease ISG20 possesses antiviral activities against RNA viruses. Here we show that ISG20 induction by synthetic dsRNA (pIpC) is stronger and faster than its induction by IFN. Two families of transcription factors are implicated in the transcriptional activation of ISG20 by dsRNA. Initially, the NF-kappaB factors p50 and p65 bind and activate the kappaB element of the Isg20 promoter. This is followed by IRF1 binding to the ISRE. As pIpC often induces protein movements in the cells, we questioned whether it could influence ISG20 localization. Interestingly and contrary to IFN, dsRNA induces a nuclear matrix enrichment of the ISG20 protein. dsRNA induction of ISG20 via NF-kappaB and its antiviral activity led us to suggest that ISG20 could participate in the cellular response to virus infection.

Abstract: Anti-MDA5 (Melanoma differentiation-associated protein 5) myositis is a rare subtype of dermatomyositis (DM) characterized by distinct ulcerative, erythematous cutaneous lesions and a high risk of rapidly progressive interstitial lung disease (RP-ILD). It has been shown that SARS-CoV-2 (COVID-19) replicates rapidly in lung and skin epithelial cells, which is sensed by the cytosolic RNA-sensor MDA5. MDA5 then triggers type 1 interferon (IFN) production, and thus downstream inflammatory mediators (EMBO J 40(15):e107826, 2021); (J Virol, 2021, https://doi.org/10.1128/JVI.00862-21 ); (Cell Rep 34(2):108628, 2021); (Sci Rep 11(1):13638, 2021); (Trends Microbiol 27(1):75–85, 2019). It has also been shown that MDA5 is triggered by the mRNA COVID-19 vaccine with resultant activated dendritic cells (Nat Rev Immunol 21(4):195–197, 2021). Our literature review identified one reported case of MDA5-DM from the COVID-19 vaccine (Chest J, 2021, https://doi.org/10.1016/j.chest.2021.07.646 ). We present six additional cases of MDA5-DM that developed shortly after the administration of different kinds of COVID-19 vaccines. A review of other similar cases of myositis developing from the COVID-19 vaccine was also done. We aim to explore and discuss the evidence around recent speculations of a possible relation of MDA5-DM to COVID-19 infection and vaccine. The importance of vaccination during a worldwide pandemic should be maintained and our findings are not intended to discourage individuals from receiving the COVID-19 vaccine.

Abstract: Retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), such as RIG-I, melanoma differentiation-associated gene 5 (MDA5), and virus-induced signaling adaptor (VISA), are intracellular molecules that sense diverse viral RNAs and trigger immune responses In this study, we demonstrate that the ankyrin repeat protein ankrd17 interacts with RIG-I, MDA5, and VISA and upregulates RLR-mediated immune signaling Overexpression of ankrd17 enhances RLR-mediated activation of IRF-3 and NF-κB and upregulates the transcription of IFN-β It also promotes RLR signaling in response to poly (I:C), influenza virus RNA, and Sendai virus Consistently, knockdown of ankrd17 impairs RLR signaling Furthermore, we demonstrate that ankrd17 enhances the interaction of RIG-I and MDA5 with VISA; the ankyrin repeat domain of ankrd17 is required for its interaction with RIG-I as well as for its function in regulating the RLR pathway Taken together, our results indicate that ankrd17 is a positive regulator of the RLR signaling pathway