Tag Archives: syncytin1

Thank your inner retrovirus for your existence

When the human genome project was first rolled out 20 years ago it came as a shock to find out that 8% of our 3,200,000 nucleotide genome was made of retrovirus relics.  They are the perfect example of selfish DNA — they don’t do anything other than insure their transmission to the next generation.   They are the perfect parasite infecting the host without killing it.  Since they don’t have to do anything, mutations rapidly accumulate in them and none of them can make a functioning virus.

As most know, retroviruses have genomes made of RNA, which is reverse transcribed into by an enzyme they contain into a DNA copy (cDNA) which then is inserted into the genome of the host.  HIV1, the virus of AIDs is one such retrovirus.   Fortunately HIV1 hasn’t entered the genome of eggs or sperm, so it hasn’t become an endogenous retrovirus, but it is all over the DNA or immune cells of those infected.

What is even more interesting (and totally unexpected) is that the host can repurpose these retroviral relics to do something useful.

In fact they’ve become so useful that we couldn’t reproduce without them.  The syncytiotrophoblast layer of the placenta is at the maternal fetal interface.  It is a continuous structure, one cell deep formed by fusion of the constituent trophoblast cells.  The layer has microvillar surfaces which facilitate exchanges of nutrients and waste products between mother and fetus.

Syncytin1 is a protein expressed here.  It is produced from the env gene, of a Human Endogenous RetroVirus (HERV) called HERV-W.  Adding the protein to culture systems leads to syncytium formation.  Mice in which the gene has been knocked out die in utero, due to failure of trophoblast cells to fuse.

Well that’s pretty spectacular and not much commented on although it’s been known for 20 years.

It shows that the envelope protein from another retrovirus (HERV-K subtype HML-2 is expressed at high levels on human pluripotent stem cells.  Not only that it keeps them from differentiating — something important for our longevity — so we always have a few pluripotent stem cells around.

As a neurologist I find it fascinating that knocking down the env protein causes the stem cells to differentiate into neurons.  Don’t get too excited that we’ve found the fount of neuronal youth, as forced expression of the env protein in terminally differentiated neurons kills them.

Why drug development is hard #31: retroviruses at the synapse

What if I told you that a very important neuronal synaptic protein Arc (Arg3.1) is acting like like a virus, sending copies of itself (and its messenger RNA) across the synapse?  Would a team of shrinks, who’ve never examined me, tell you that I was crazy and unfit to blog?  Well there is very good evidence that exactly this occurs in one situation and probably many more [ Cell vol. 172 pp. 8 – 10, 262 – 274, 275 – 288 ’18] — http://www.cell.com/cell/fulltext/S0092-8674(17)31509-X.

Arc stands for Activity Regulated Cytoskeleton associated protein.  It’s messenger RNA (mRNA) is transcribed from the gene in response to neuronal activity.  More importantly, the mRNA for  Arc is rapidly distributed to active synapses through the cell body and dendrites, where it is translated into protein. It is locally and rapidly stimulated during the induction of long term depression and plays a critical role in removing a class of glutamic acid receptors (AMPA receptors) from the synapse.  To whet the interest of drug developers, Arc regulates the activity dependent cleavage of the Amyloid Precursor Protein (APP) and beta amyloid production by its interaction with presenilin

Several posts could easily be filled with what Arc does, but that’s not what is so amazing about these papers.  Parts of the Arc protein arose from one of the many transcriptionally dead retroviruses found in our genome.  Our species literally wouldn’t exist without other retroviral gifts.  For instance syncytin1 is a protein expressed a high levels in the placenta.  It is produced from the envelope gene of an endogenous retrovirus (HERV-W) which has undergon inactivating mutations in its other major genes (gag and pol).  Mutant mice in which the gene has been knocked out die in utero due to failure of placenta formation.

Part of the arc gene arose from the Gag gene (Group specific antigen gene) of a retrovirus.  Recall most viruses have proteins coating their genetic material when they’re on the move (e. g. a capsid).  In the case of retroviruses, the genetic material is RNA rather than DNA.  Well the gag elements of the Arc protein form a capsid containing the mRNA for Arc (just like a virus).  In some way or other the capsid containing mRNA gets outside the neuron at the nerve muscle junction and gets into muscle.  The evidence is good that this happens, but in a system somewhat removed from us — the fruitfly (Drosophila).  Fruitfly neuromuscular junctions lacking this mechanism are weaker.

Well that’s pretty far from us.  However one of the papers (275 – 288) showed that the Arc protein and its mRNA was found in extracellular vesicles released from mouse neurons cultured from their cerebral cortex.  Could viral-like particles be crossing the synapses in our brains (which are already pretty chockfull of stuff — see https://luysii.wordpress.com/2017/11/15/the-bouillabaisse-of-the-synaptic-cleft/).  It’s very early times (in fact the Cell issue came out 3 days ago) but people are sure to look.  There are at least 100 Gag derived genes in the human genome (Campillos, M., Doerks, T., Shah, P.K., and Bork, P. (2006). Computational characterization of multiple Gag-like human proteins. Trends Genet. 22, 585–589.).

Remarkable.  Remember CRISPR was hiding in plain sight for half a century.  We have a lot to learn.  No wonder drugs have unexpected side effects.