The Unusual Role of Ribonuclease L in Innate Immunity

Figures

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  FIGURE 1. dsRNA activates RNase L and it then cleaves most species of RNA. dsRNA is generated in the cytoplasm due to viral infection or it can also be produced endogenously. OAS enzymes recognize dsRNA and, as a result, produce 2′‐5′ linked oligoadenylates (2–5A) from ATP. 2–5A binds the monomer RNase L, causing it to dimerize and activate its endonucleolytic activity. RNase L cleaves most RNAs in the cell, including viral and host RNAs (mRNA, tRNA and rRNA as part of the ribosome (grey) are depicted here).

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  FIGURE 2. Recent studies have revealed novel roles for RNase L. Active RNase L cleaves host mRNAs into fragments that can be translated (1). This RNA fragment translation can induce ribosome stalling and/or collisions and recognition by a ribosome collision sensor, ZAKα, leads to an inflammatory response and apoptosis (2). The overall loss of mRNA in the cell increases the amount of free RNA binding proteins and results in their translocation to the nucleus (3). This is thought to be responsible of other observed effects of RNase L activation, such as effects on alternative splicing (4) and nuclear mRNA retention (5). Inactive RNase L was also shown to be recruited to the cytoskeleton to promote formation of Zika virus replication factories (6). Viral and host RNA cleavage results in formation of RNase‐L dependent bodies (7).

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  FIGURE 3. The OAS‐RNase L pathway contributes to and further amplifies the effects of activation of other dsRNA pathways, such as MDA5/RIG‐I and PKR. In particular, RNase L enhances apoptosis, promotes new transcription, and, on average, reduces the overall level of gene expression.

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  FIGURE 4. The role of OAS‐RNase L pathway in recently characterized human diseases or disease therapies.