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. Author manuscript; available in PMC: 2023 Mar 1.
Published in final edited form as: J Allergy Clin Immunol. 2021 Dec 8;149(3):819–832. doi: 10.1016/j.jaci.2021.10.027

FIG 3. Interferon mediated/amplified diseases are caused by dysregulation of interferon production and signaling.

FIG 3.

Viral replication in the cell leads to aberrant accumulation of cytosolic nucleic acids, which are sensed by the host and trigger type I/III interferon production. Cytosolic DNAs are sensed by cGAS, which produces 2’3’cGAMP, a ligand for the adaptor STING. Cytosolic RNAs are sensed by RIG-I or MDA5, which activates the adaptor MAVS. Adaptor activation leads to TBK1 phosphorylation, which phosphorylates the transcription factor IRF3 and triggers the Type I/III interferon production. Cytosolic nucleic acids are also generated in cell homeostatic processes such as DNA replication, and are degraded/reduced by various enzymes including nucleases. Mitochondrial RNAs are degraded by RNases including PNPT1. Type I and II interferons bind to their respective receptors and mediate the transcription of interferon response genes. Interferon signaling is tightly controlled by signaling suppressors including USP18, ISG15, SOCS family proteins, and STAT2, which bind to the signaling complexes for proteasome degradation. Mutations in proteasome components also lead to IFN production by yet unknown mechanisms. Disease-causing mutations in ACP5 are associated with enhanced interferon signaling, possibly via Osteopontin and IRF7. Due to space limitations, two AGS associated genes, LSM11, RNU7–1, are not shown in the figure.