Nov 2, 2023 · We demonstrate that discrete functions of ADAR1p150 determine MDA5 or PKR engagement: A-to-I editing of endogenous dsRNA specifically prevents MDA5 activation, whereas PKR activation is prevented by editing-independent, competitive dsRNA binding in the cytoplasm.

Mar 3, 2016 · While PKR may be capable of functioning independently from MDA5 when activated in an RNA-independent manner (Fig 7B, 8 h), its ability to signal to MAVS during viral infection is augmented in an MDA5-dependent manner, suggesting that PKR acts ‘downstream’ of MDA5 and ‘upstream’ of MAVS.

Feb 8, 2018 · Remarkably, ADAR1 knockout neuronal progenitor cells exhibited MDA5 (dsRNA sensor)-dependent spontaneous interferon production, PKR activation, and cell death. Thus, human ADAR1 regulates sensing of self versus nonself RNA, allowing pathogen detection while avoiding autoinflammation.

Mar 3, 2016 · Sensing invading pathogens early in infection is critical for establishing host defense. Two cytosolic RIG-like RNA helicases, RIG-I and MDA5, are key to type I interferon (IFN) induction in response to viral infection. Mounting evidence suggests that another viral RNA sensor, protein kinase R (PKR) …

Here, Hu and Heraud-Farlow et al. 1 describe an RNA-editing-independent mechanism of ADAR1 that suppresses activation of another cytosolic dsRNA-sensing PRR protein kinase R (PKR) that, along with MDA5, causes fatal inflammation in mice (Figure 1).

Dec 17, 2018 · MDA5 and PKR therefore mediate distinct mechanisms of increased susceptibility to anti-tumour immunity in Adar1 -null tumours (Fig. 4h).

Mar 13, 2025 · We manipulated the stable ADAR1 KD cells to differentially express MDA5, RIG-I, or PKR (supplemental Figure 9). Notably, the depletion of MDA5 significantly rescued the growth inhibitory effects of ADAR1 KD, restoring cell growth to levels comparable with (RPMI-8226) or even exceeding (OCI-MY5) those observed in ADAR1-WT cells.

We now demonstrate that the loss of ADAR1-mediated RNA editing specifically activates MDA5, whereas loss of the cytoplasmic ADAR1p150 isoform or its dsRNA-binding activity enabled PKR activation.

5 days ago · However, the exact mechanism by which MDA5 senses dsRNA is not yet fully understood. In the case of OAS1/2/3 and PKR, the presence of the RNA duplex seems to be the only requirement to classify the transcripts as a potential threat to the host cell (15, 26, 27).

Aug 27, 2024 · ADAR1 protein inhibition of PKR activation requires a predicted direct protein interaction between ADAR1 and the PKR kinase domain. Inhibition also requires ADAR1 dsRNA binding; the mechanism reveals a new level of antiviral innate immune sensor regulation.