Introns encode dsRNAs undetected by RIG-I/MDA5/interferons and sensed via RNase L

Abstract

Double-stranded RNA (dsRNA), a hallmark viral material that activates antiviral interferon (IFN) responses, can appear in human cells also in the absence of viruses. We identify phosphorothioate DNAs (PS DNAs) as triggers of such endogenous dsRNA (endo-dsRNA). PS DNAs inhibit decay of nuclear RNAs and induce endo-dsRNA via accumulation of high levels of intronic and intergenic inverted retroelements (IIIR). IIIRs activate endo-dsRNA responses distinct from antiviral defense programs. IIIRs do not turn on transcriptional RIG-I/MDA5/IFN signaling, but they trigger the dsRNA-sensing pathways of OAS3/RNase L and PKR. Thus, nuclear RNA decay and nuclear-cytosolic RNA sorting actively protect from these innate immune responses to self. Our data suggest that the OAS3/RNase L and PKR arms of innate immunity diverge from antiviral IFN responses and monitor nuclear RNA decay by sensing cytosolic escape of IIIRs. OAS3 provides a receptor for IIIRs, whereas RNase L cleaves IIIR-carrying introns and intergenic RNAs.

Changes in ADAR1 activity duringPlasmodiuminfection contribute to protection from malaria

“…Particularly, the classical role of ADAR1 is to prevent 'self'-dsRNAs from activating immune sensors that detect viral and other 'non-self'-dsRNAs in the cytoplasm. Such innate immune sensors include the RIG-I like receptors (RLRs) (3)(4)(5), protein kinase R (PKR) (6)(7)(8)(9)(10)(11)(12), oligoadenylate synthetase (OAS)-ribonuclease (RNase) L (13)(14)(15)(16), and Z-D/RNA binding protein 1 (ZBP1) (17)(18)(19)(20)(21)(22). When activated by dsRNAs, these pathways drive antiviral innate immune responses, including expression of Type-I interferons (IFNs) and proinflammatory cytokines, inhibition of translation, cleavage of cellular RNAs, and/or activation of cell death pathways (23)(24)(25) (Fig.…”

Activation of cytosolic RNA sensors by endogenous ligands: roles in disease pathogenesis

“…Endogenous nuclear-derived dsRNA can accumulate and activate PKR and its downstream targets in response to different stressors and conditions. Two recently published examples are ADAR1 dysfunction and exposure to phosphorothioate-modified antisense oligos (ASOs), which induce PKR-dependent eIF2α phosphorylation ( 84 – 86 ). The postnatally lethal phenotype and ISR and ISG expression signature of Adar1 P195A/p150- mice, which lack the catalytically active, IFN-inducible Adar1 isoform p150, has previously been described as MDA5-dependent ( 30 ).…”

“…2-5A acts as a second messenger molecule that activate RNase L, a ribonuclease that dimerizes and indiscriminately degrades both viral and cellular single-stranded RNA, and induces apoptosis ( 98 ). Cleavage and decay of viral RNA limits virus replication, while degradation of cellular RNA limits translation and promotes expression of innate immune response genes ( 84 , 99 – 101 ).…”

“…OAS1 has been reported to have a binding preference for shorter dsRNA (≥17 bp), while OAS2 appears to require a minimum of 35 bp duplex structures and its target affinity increases with increasing dsRNA length ( 102 ). OAS3 on the other hand has a high affinity for RNA duplex structures longer than 50 bp, but its affinity for larger dsRNA sequences decreases, such as for a recently published 112 bp structure generated by in vitro transcription that resembles viral dsRNA ( 84 , 97 , 103 , 104 ). These studies were largely conducted with recombinant proteins in vitro , thus precise delineation of OAS ligands in cells is still lacking.…”

“…Similar to the previously discussed dsRNA sensors, OAS overactivation or dysfunction is associated with autoinflammatory diseases, such as Alzheimer’s disease and AGS, as well as a higher risk of development of severe disease outcomes like COVID-19 ( 105 , 106 ). Recent findings show activation of OAS family members by endogenous dsRNA in response to different stressors in the absence of viral infection ( 84 , 105 ). Small molecule inhibitors of DNA methyltransferases induced hypomethylation of DNA and increased expression of EREs in both directions.…”