Arc – How an ancient virus helps us learn

The year 2018 is about to end and it was yet another extremely eventful year for molecular biology and biomedicine. CRISPR has captured the headlines around the globe. But not every piece of research that has caused a sensation and astonishment this year has been directly related to CRISPR. As early as January 2018, two articles were published in the same issue of the journal Cell, which was jaw-dropping for several members of our working group, including myself.

Back then – due to an acute lack of time – I did not manage to explain why these two articles had such an effect. Anyway, here finally is the long overdue article on the ARC gene and the question about whether an evolutionarily ancient virus(!), could be responsible for us being able to remember things so well.

Mechanisms of cell-cell communication

To understand why the publication of these articles had such an effect back then, we first need to look at what kinds of information transfer between cells can occur according to the common textbook knowledge. It has long been known that the cells in our body exchange information by means of signaling molecules, e.g. hormones. In the brain – as most people in biology classes have learned – information exchange takes place via neurotransmitters. Those are packaged by a nerve cell in vesicles and released on a synapse when this nerve cell is excited, that is, when a so-called action potential is created. Then they act on the receptors of the nerve cell onto which it signals. These receptors can be roughly divided into two classes. Ionotropic receptors directly alter the ion concentration in the cell and thus the probability that this cell also produces an action potential in response. Metabotropic receptors act more slowly: they activate signal transporters within the cell, which then regulate the activity of different genes. 

Depending on the exact question, you would probably get many to all points with such an answer in a test for molecular genetics. By contrast, with the following answer, one would probably not provoke anything except red pencil and a deep sigh from the lecturer: “The cell then grabs a bit of this RNA, puts it in a package and throws it outside; it lands in another cell and then the RNA is read.” Well, this is absurd. The student did not understand and / or read anything, one would think.

It would have been much better if, for example, the examinee had demonstrated something of his knowledge of “immediate early genes”. Because these are exactly those genes whose protein products are formed immediately after the excitation of the cell. And ARC is one of these immediate early genes, as was published in 1995. In the same year, another research group showed that the ARC protein mainly sits at synapses. Both that this gene is regulated by neuronal activity and that the protein is located at the synapses made ARC a highly interesting research object. An early hypothesis was that ARC might have something to do with synaptic plasticity and therefore learning and indeed, about ten years later, in 2006, it was shown that mice without ARC have long-term memory problems.

“Junk-DNA”

It is not uncommon in genetics that first of a certain function of a gene product is described (eg: mice without a functioning copy of the ARC gene do not learn well anymore) and only much later will the mechanism of action be elucidated. An extreme example of a similar process is our assessment of the approximately 98.5% of our genome, which consists of sequences that do not directly code for the construction of a protein. Fortunately, these days nobody talks about “junk DNA” any more; instead, we started sorting these areas into different groups.

It has been noticed that nearly half of our genome (about 45%) consists of so-called transposable elements (these would be LINEs, SINEs, LTRs and DNA transposons). As the name implies, these areas are derived from sequences that are in principle capable of changing their position within the genome, even though most have lost that ability over time. One particular class of these ” jumping genes ” are the so-called LTR transposons, which essentially look like endogenous retroviruses. And retroviruses are not only important for understanding the ARC gene, but are so cool for so many more reasons that I simply have to explain how they work.

How do retroviruses work?

Perhaps some have wondered before that the “structure” of a retrovirus is sometimes portrayed as a uniform polygon or similar body, but sometimes simply as a section of DNA. This is because even an active retrovirus spends part of its time as a piece of DNA. If you look at the virus as an organism (which is by the way what the majority of biologists do not!), you could say that being a piece of DNA is a certain “part of the life cycle” of the retrovirus. In simple terms, this piece of DNA consists of three sections: gag, pol, and env, flanked by long terminal repeats (LTRs). gag and env encode envelope proteins. pol encodes a protein that is later cleaved into three enzymes: a reverse transcriptase (which – contrary to the usual flow of information in the cell – can create DNA transcripts of RNA templates), an integrase (which can insert DNA sections which are flanked by LTRs into genomes) and a protease (which aids in the maturation of the other two enzymes). The mode of action of such a retrovirus is ingenious: when an RNA copy of this entire DNA is made, all those proteins are constructed and then the RNA transcript is packed into the envelope protein along with the three enzymes. When this virus then infects a cell, the reverse transcriptase causes the RNA transcript to be rewritten into DNA, and the integrase then re-integrates this DNA into the genome of the infected cell. This way, the virus jumped from one genome to another genome.

ARC is a specialized retrovirus!

When the exact structure of the ARC gene product was published in 2015, US research group leader Jason Shepherd, who said in an interview that after about 25 years he almost lost interest in ARC, suddenly wakes up wide awake. The ARC protein just looked so much like the capsid of probably the most famous retrovirus, HIV. This has rekindled research at ARC and led to the completely crazy observation that was described in these two seminal articles in Cell: ARC is essentially a rudimentary retrovirus! In response to the excitement of a nerve cell, ARC is activated and its components assemble into capsid-like particles that contain RNA. Even though these ARC particles like to pack their own RNA ten times as much, it is quite possible that they also pack other RNAs. The whole package, so a kind of virus, is then removed from the cell and taken from adjacent cells. Thus RNA is passed from one nerve cell to another nerve cell in an activity-dependent manner. Now the race to clarify so many subsequent questions has been opened: which RNAs are selected by the ARC protein for packaging and how? How widespread is this novel mechanism of cell-cell communication? Furthermore, the possibility of using ARC for gene therapy opens up: in order to introduce healthy copies of certain genes into cells that carry defective copies of these genes, one often uses retroviruses. However, a huge problem with retroviruses is that they usually trigger an immune response. When using ARC particles, this immune response will probably not occur because it is an endogenous protein. In any case, research on ARC should continue to be a source of wonder in the coming years.

And now, a happy new year 2019 to all readers!