Year: 2024
Type: dissertation
Abstract: Recent progress in human and mouse genetics has transformed our understanding of the molecular mechanisms by which recognition of self double-stranded RNA (self-dsRNA) causes immunopathology.Novel mouse models recapitulate loss-of-function mutations in the RNA editing enzyme ADAR1 that are found in patients with Aicardi-Goutières syndrome (AGS) -a monogenic inflammatory disease associated with increased levels of type I interferon.Extensive analyses of the genotype-phenotype relationships in these mice have now firmly established a causal relationship between increased intracellular concentrations of endogenous immunostimulatory dsRNA and type I interferon-driven immunopathology.Activation of the dsRNA-specific immune sensor MDA5 perpetuates the overproduction of type I interferons, and chronic engagement of the interferon-inducible innate immune receptors PKR and ZBP1 by dsRNA drives immunopathology by activating an integrated stress response or by inducing excessive cell death.Biochemical and genetic data support a role for the p150 isoform of ADAR1 in the cytosol in suppressing the spontaneous, pathological response to self-dsRNA.
Author: de Reuver, Richard
Language: English
Topic: RNA regulation and disease
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: G2023642260, Factors that determine RIPK1-dependent necroptosis, Investigating the role of ferroptosis in acute liver injury and multiple sclerosis with newly developed chemical tool compounds, G5843063039, G649776571, G7724930489, Unraveling the in vivo role of RIPK1: Physiological and pathological consequences of kinase-dependent and kinase-independent functions , G8980775851
OpenAlex ID: W7007941331