The Hunt for Enemy RNA

How our cells tell foreign RNA from friendly RNA, in a truly baroque process.

RNA is hot these days. It is the active ingredient of the leading and innovative coronavirus vaccines, it appears to be the primordial molecule at the origin of life, and it keeps cropping up in new permutations in molecular biology, with every year bringing new acronyms for novel roles it plays in our cells. Half of viruses use RNA for their genomes, making it an important target of the immune system as well. We have several mechanisms that sense viral RNAs, and likewise several mechanisms to differentiate self-RNA from foreign RNA. It is evident that an arms race of military intelligence has been taking place over the evolutionary eons. 

Among the common ways we have to tell friendly RNA from foe are special "caps" chemically attached to the front end of message RNAs, further methylation modifications of the front end of RNAs, and the existence of double-stranded RNA, which is generally rare in our cells. Most RNA viruses have single-standed genomes, but they usually have a double-stranded RNA intermediate in their replication process. Eukaryotic cells focus intently on recognizing that double-stranded RNA, doing so with proteins named RIG1 and MDA5. RIG1 is an RNA helicase that binds and recognizes double-stranded RNA, and then triggers the production of interferons, the primary signaling molecules telling cells that there is a viral infection, and which induce production of a wide range of other antiviral proteins.

But with our own RNA all over the place, it naturally happens that some double-stranded RNA forms accidentally, from our own sequences. What to do about that? One mechanism is RNA editing, where selected "A" residues are chemically switched to "I" or inosine, which base pairs differently from A, and destabilizes double-stranded RNA. This editing is performed by an enzyme called ADAR1. For coding mRNAs, these edits can alter their meaning, so it is also called RNA recoding, and  routinely affects the sequences of several important proteins. 

ADAR gene products and isoforms (left) all perform RNA editing of A (adenine) to I (inosine) in double-standed RNA regions of self-RNAs, (right), to prevent them from causing false alarms of our internal antiviral surveillance systems.

Another mechanism to protect friendly RNA is the attachment of methyl groups to A residues, (m6A), which also shields them directly from RIG1 surveillance. The m6A modifications are applied by enzymes METTL3 and METTL14, and are detected by YTHDF1, which binds them and can increase their expression by speeding up translation, or destabilize them, or have other effects on their expression. The logic of the various proteins that recognize m6A modifications is diverse and remains rather unclear, actually, though the general trend is one of increasing expression of recognized messages. 

One has to suppose that these editing and modification systems are relatively slow, so that incoming viral RNAs can be recognized before they themselves are modified and turned into invisible infiltrators. So there must be some very careful tuning involved, and great incentives for viruses to encode such modification systems for themselves. For example, coronaviruses encode in their tiny genomes several proteins that put "friendly" chemical caps on the front ends of their own RNAs.

Getting back to the editing and m6A systems, genetic mutations generating defective ADAR1 cause severe auto-immune disorders, where the anti-viral interferon system is over-activated. What recent researchers found curious, however, was that defects in YTHDF1 cause similar effects, over-activating antiviral immune systems, even though YTHDF1 is not inherently part of the core systems of protecting self-RNA from recognition by all these antiviral detectors. It turns out that YTHDF1's effect is mediated by just one of its gene targets- ADAR1. Translation of the ADAR1 mRNA is enhanced by YTHDF1 after it binds to m6A modifications on that mRNA. This in turn promotes the ADAR1- catalyzed edits of other cellular RNAs, especially double-stranded ones, preventing them from getting caught up in the RIG1-activated red alert system of interferons and viral response.

In this way, one system of self-identification and protection is tied into another system, for reasons that are truly hard to fathom, and are only a tiny part of a far more elaborate system. I think it is an example of evolution run amok, developing one bureaucracy on top of other ones, on top of yet other ones, in a gerry-rigged system that has had billions of years to accumulate. Yes, it is all very finely tuned, thanks to the necessities of natural selection and the struggle against predation by invaders. But it is the farthest thing from being designed.

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