RNA Editing as an Apparently Paradoxical Molecular Immune Defense with a Role in Autoimmunity

I do f'ng love science!

I love science because we never stop learning. I'm teaching the full-semester course Biology of Immunology online next semester at IPAK-EDU, and have started to accumulate some really interesting, emerging knowledge.

Making proteins from the information in our genome is complex. The one-gene-one-enzyme Central Dogma of molecular biology died long ago, with knowledge that intervening processes like alternative splicing, post-transcriptional modification, and post-translational modification can all create differences in the final protein encoded by protein-coding genes in our genome. Such a dynamic ecosystem of molecular processes is of course subject to natural selection; dynamics that work well will persist, and variations on those processes that lead to harm will tend to not persist.

Each time a pathogen enters our bodies, they are faced with a gauntlet of molecular defenses that do not involve antibody responses (our adaptive immune response). This goes way, way back in the tree of life: Immune defenses in bacteria involve incorporation of viral and bacteriophage sequences into the bacterial genome specifically so the bacterial lineage knows which segment of foreign nucleotide sequences to destroy. This is a well-characterized form of molecular immune defense that was adapted by scientists to create the famous (or infamous) CRISPR/CAS9 gene editing laboratory procedure.

Part of our innate immune system, which uses ions, nitroxides, oxides and other chemicals is another form of molecular immune defense. RNA editing seems to provide another layer of defense: when a virus hijacks our cells and they start making RNAs that are translated into viral proteins, there is a molecular gauntlet that the RNAs themselves have to pass through. This gauntlet is normal part of RNA processes - it's just that our genes that encode proteins don't actually encode the proteins predicted by the genetic code. Instead, the codons that are found in the transcript product read off the genome are modified - changed - so the nucleotides themselves can be changed.

There are various forms of RNA editing. Some examples include site-specific deamination (cytidine deaminase) which changes cytidine to uridine), guide-dependent U insertion, and (A)-to-inosine (I) RNA editing, catalyzed by adenosine deaminases acting on RNA. In (A) to (I) editing, there is some evidence that the substitution of I from A leads to a recoded "guanine" signal during translation. Adenosine-to-inosine RNA editing of Alu retroelements is a primate-specific type of RNA editing that is controlled by adenosine deaminases acting on RNA (ADARs).

A review article in Nature in 2018 from Eisenberg and Levanon, "A-to-I RNA editing — immune protector and transcriptome diversifier" points out that many of the recoded sites are conserved within lineages, meaning they likely serve a useful function, in particular, they might serve to protect our proteins from being seen as self-antigens. This would be a way to reduce molecular mimicry, for example, because even though the DNA-RNA-protein transcription/translational direct read might predict high protein sequence similarity, in an environment with pathogens throwing their proteins against our adaptive immune system, individuals who edited their RNA such that it was less similar to immunogenic antigens would be expected to have a survival and reproductive advantage.

As in all things in molecular biology, there are variations on themes, so not all potentially RNA editable sites are, in fact, edited. But there are over 100 million potentially editable sites, primarily in Alu repetitive elements that preferentially form a double-stranded RNA (dsRNA) structure (Nakahama and Kawahara, 2020). There is evidence of RNA editing in tRNAs, rRNAs, mRNAs and miRNA molecules in eukaryotes (fungi, plants, animals), and their viruses (See Su and Randau).

When it comes things going wrong leading to disease, RNA editing might be playing a role in autoimmunity and cancer. A review published in 2020 by Nakahama and Kawahara "Adenosine-to-inosine RNA editing in the immune system: friend or foe?" presents evidence that RNA editing as a regulator of the immune system in both autoimmune diseases and cancer. And an article in the Journal of Autoimmunity in 2020 (Increased adenosine-to-inosine RNA editing in rheumatoid arthritis) reported evidence that a key enzyme involved in RNA editing, ADAR1 is over-expressed in synovium (membrane tissue in joints) in people with Rheumatoid arthritis. However, ADAR1 might also be a response to oddly folded proteins (see "ADAR1-Dependent RNA Editing Promotes MET and iPSC Reprogramming by Alleviating ER Stress", and ADAR1 serves to balance immune activation and self-tolerance in the thymus (see: ADAR1-mediated RNA editing is required for thymic self-tolerance and inhibition of autoimmunity, EMBO Rep).

The multifactorial nature of autoimmune disease leads to an apparent paradox of the balancing act: why would we have a system capable of making us ill while at the same time help us fight pathogens? It is important to note that RNA editing gone awry is not an alternative to other known mechanisms of autoimmunity; in fact, all of the proteins involved in RNA editing themselves are subject to the requirement of healthy demethylation, transcription, translation and protein-folding. Thus, any environmental factors that impede any of these processes, such as aluminum hydroxide and other compounds that cause endoplasmic reticulum stress (ER-stress) and any genetic source of ER-stress, are critical factors that can interact with or in fact initiate problems with normal RNA editing.