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. 2021 Mar 31;9:631329. doi: 10.3389/fped.2021.631329

Figure 1.

Figure 1

Type I IFN signaling: the intracytoplasmatic accumulation of viral (or endogenous due to loss of function of the enzymes responsible for degradation) nucleic acids is sensed by two systems: (1) the cytoplasmic DNA receptors cyclic GMP-AMP synthase cGAS: intracellular dsDNA activate cGAS, leading to the production of cGAMP. cGAMP binds and activates STING in ER, which translocates into the Golgi apparatus. Here, the STING C-terminal tail recruits TBK1. TBK1 induces the coupling and the phosphorylation of IFR3 and, consequently, IFR7. (2) The cytosolic RNA helicases RIG-I–MDA5 system: intracellular dsRNA activates MDA5 and RIG I, which bind and activate MAVS in the mitochondrial membrane, forming the MAVS signaling complex. MAVS triggers downstream TBK1, than activating IRF3 and IRF7. Finally, IRF3 and IRF7 translocate to the nucleus and induce the transcription of IFN-β and IFN-α, respectively. Type I IFNs, through autocrine and paracrine action, bind to IFN receptors. The IFNR dimerization recruits JAK1 and TyK2 proteins. This activation promotes the STAT1–STAT2 dimerization and the binding of IRF9 to assemble the heterotrimeric transcription complex ISGF3. In the nucleus, ISGF3 binds to IFN-stimulated response elements (ISRE), promoting the expression of interferon-stimulated genes (ISGs). At the same time, IFN signaling is regulated by a negative feedback mechanism by the USP18–ISG15 system. The USP18 binds the IFNAR2 subunit, decoupling it from JAK1 and inhibiting the propagation of the next signal. ISG15 prevents the degradation of UBS18 by SPK2. TREX1, DNA 3′–repair exonuclease 1; RNASEH2, ribonuclease H2; POLA1, polymerase-α; cGAS, GMP-AMP synthase; cGAMP, 2′3′GMP-AMP; STING, STimulator of INterferon Genes; TBK1, TANK-binding kinase 1; MAVS, mitochondrial antiviral-signaling protein; IRF3, IFN regulatory factors 3; IRF7, IFN regulatory factors; RIG-I, retinoic acid-inducible gene-I; MDA5, melanoma differentiation-associated gene 5; JAK1, Janus kinase 1; TyK2, tyrosine kinase 2; IRF9, IFN regulatory factors 9; ISGF3, interferon-stimulated gene factor 3; USP18, ubiquitin-specific peptidase 18; ISG15, interferon-stimulated gene 15; SPK2, S-phase kinase-associated protein 2.