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. 2017 May;37(5):207-213.
doi: 10.1089/jir.2016.0095.

RIG-I-Like Receptors and Type I Interferonopathies

Free PMC article

RIG-I-Like Receptors and Type I Interferonopathies

Hiroki Kato et al. J Interferon Cytokine Res. .
Free PMC article


Type I interferon (IFN) production by the proper activation of nucleic acid sensors is essential for hosts to eliminate invading viruses. Among these sensors, RIG-I-like receptors (RLRs) are well-known viral RNA sensors in the cytoplasm that recognize the nonself signatures of viral RNAs to trigger IFN responses. Recent accumulating evidence has clarified that some specific and atypical self-RNAs also cause activation of RLRs independently of virus infection. Importantly, when RLR-activation by these RNAs or a conformational change via missense mutations is sustained, the resulting continuous production of type I IFN will lead to autoimmune disorders. We, herein, focus on autoimmune diseases caused by chronic activation of RLRs and discuss possible mechanisms of their onset.

Keywords: RIG-I-like receptors (RLRs); autoimmune diseases; interferon (IFN).

Conflict of interest statement

No competing financial interests exist.


<b>FIG. 1.</b>
FIG. 1.
IFN production and signaling upon viral infection. Viral infection causes cytoplasmic exposure of viral nucleic acids. RIG-I and MDA5 are RNA helicases that directly bind to viral dsRNA species to trigger a downstream signal cascade (black arrows). Ubiquitin ligases, Riplet and TRIM25, mediate K63-linked polyubiquitination of RIG-I and facilitate its activation and self-oligomerization. MDA5 is activated by forming filamentous structure around dsRNA in an ubiquitin-independent manner. MAVS, a mitochondrial adaptor protein, associates with activated RIG-I/MDA5 with accompanying prion-like aggregation on the mitochondrial outer membrane, and further activates downstream molecules, including TRAF3/TANK, TRAF6, TBK1/IKKɛ, and IKKα/β/γ. IRF3/7 and NF-κB (p65 + p50) transcription factors are then translocated into the nucleus and undertaken IFN gene expression. Secreted IFNs bind to cognate IFN receptor (IFNR) expressed on neighboring cells and elicit JAK-STAT signal cascade to induce expression of hundreds of ISGs. OAS is an ISG-encoded antiviral enzyme that processes viral dsRNA into 2′,5′-linked oligoadenylate (2-5A) (blue arrows). This unique RNA is subsequently cleaved by RNase L into small product, which potentially activates RIG-I for secondary IFN induction. AT-rich viral dsDNA is a latent template of a DNA-dependent RNA polymerase, Pol III, to produce immunostimulatory 5′ppp-dsRNA (purple arrows). cGAS also binds to viral dsDNA and catalyzes cyclic GMP-AMP (cGAMP) synthesis (green arrows). This second messenger activates ER-associated STING for the IFN induction.
<b>FIG. 2.</b>
FIG. 2.
Type I interferonopathy caused by dysfunction of regulatory proteins. A cytoplasmic exonuclease TREX1 degrades extranuclear ss/dsDNA accumulated within intrinsic DNA metabolism. A dGTP-dependent triphosphohydrolase SAMHD1 and a heterotrimeric ribonuclease complex RNase H2 (RNase H2A, B, and C) also function as DNA metabolizing enzymes. Mutations in their respective genes (TREX1, SAMHD1, and RNASEH2A/B/C) abrogate their enzymatic activities and cause redundant accumulation of self-DNA in the cytoplasm. This abnormal DNA pool potentially stimulates cGAS-STING signaling axis (blue arrows). ADAR1, which is encoded by ADAR1, is an RNA-editing enzyme that binds to dsRNA and converts adenosine bases to inosines to prevent MDA5 from sensing endogenous dsRNA as nonself. Mutations in ADAR1 result in constant activation of MDA5 (red arrows). Gain-of-function mutation in IFIH1, which encodes MDA5, is also identified. All these mutations lead to constitutive activation of IFN and are strongly associated with Aicardi–Goutières syndrome (AGS), a genetic disorder referred to as type I interferonopathy.

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