Tuesday, February 2, 2010

Trim5a- Guardian of the Genome:

As you can see from the title, the first factor I am going to blog about in the series on host restriction factors is Trim5a (T5a). Before I jump right into it, I want to give a little background I forgot to give in my introductory post, specifically what do viruses do? Viruses can’t do a whole lot, they are just balls of protein, nucleic acid (DNA or RNA), and maybe lipid and some sugars. They need a cell and it’s machinery for every step of its life cycle. The life cycle starts when I virus is floating around and finds something that makes it stick to a cell. If the virus binds to a specific receptor the virus can enter that cell, if the receptor is not there the virus cannot get in. This is the first block to infection. Next all viruses enter the cell and the genetic material must got to the right place. At this point the virus makes viral proteins and copies its genome. Once all the components to assemble new viruses are present, progeny viruses are mande and these new viruses leave the cell to infect others. You may be able think of many steps in this process where a cell can try to defend itself. I am going to focus on proteins that block entry, freeing of genetic material, leaving the cell, and infecting the next cell in this series.

Trim proteins are named for their tripartite motif comprised of a RING, B-Box and coiled-coil domains. A RING domain is a domain that similar to those of E3 ubiquitin ligases. These enzymes help add ubiquitin (a protein) to a target protein. Ubiquitin is most commonly a tag that makes a protein for degradation. The coiled-coil domain mediates the multimerization of proteins. The B box is thought to enhance both of the previously mentioned functions. An additional domain, SPRY/B30.2 is added through alternative splicing to generate Trim5a, the antiviral form of the protein. Conceptually this protein consists of two parts, the TRIM and SPRY. The TRIM domain gives it its effector function while the SPRY domain gives it its specificity. Evidence suggests that the SPRY domain recognizes features on the N-Terminal domain of the capsid protein (shell around the viral RNA/DNA). Although the precise mechanism behind T5a mediated restriction is unknown, evidence suggests that restriction occurs through two processes: destabilization of the capsid core before the completion of reverse transcription and degradation of the core-T5a complex. Retroviruses have an additional step in their life cycle, they copy their RNA into DNA. For viruses like HIV this takes place after it enters the cell. This requires that the capsid (shell) stays mostly intact. Its almost like making a hard boiled egg, if you boil an egg in its shell you get breakfast, if you break the egg in boiling water you get mush. T5a does exactly that, turns retroviruses into mush. T5α has a short half-life in the cell possibly due to autoubiquitination from theTrim motif. Rapid turnover targets the core-T5a complex for degradation. In a nutshell, T5a breaks the virus open too soon and takes out the trash. Understanding how these two processes work individually or in concert is the subject of intense investigation.

With that background done, I am going to talk about why these proteins are cool and what they teach us about evolution and selection pressure. Of all the factors on the list only Trim5a (T5a) acts as a post entry, preintegration block to initial infection of retroviruses. It can render viruses 10-100 (possibly more) less infectious. Considering this crucial function, the great diversity among homologs and orthologs at the T5a locus is to be expected. For example every species of primate tested has a unique T5a. They are not different all over. Instead the diversity is mostly limited to the specific amino acids that allow T5a to recognize a viral capsid (see figure from Newman et al. 2006). These hot spots of mutations highlight the idea of the Red Queen. Whenever a T5a protein that can block a specific virus is selected for, the virus must evolve around this block. Now getting around one T5a

is difficult enough, but in some species like rhesus macaques there are anywhere from 6-11 T5a alleles circulating in the population (as a spoiler, yes retroviruses get around all of them). So what about us? As it turns out there is actually very little variation in humans. The only really different one we have found is broken. There are a number of possibilities for why we are so homogeneous, we are a young species, we have gone through many bottlenecks and our radiation out of Africa is has resulted in founder effects. We know humans get retroviruses, HIV-1, HIV-2, SIVmac, HTLV-1 and 2, XMRV, and Foamy virus, so our T5a can’t be the most amazing block ever conceived. Could it be possible that one virus nearly wiped us out. We have come close to the brink of extinction on a number of occasions in the past. Did this one T5a allele win the Red Queen arms race? We can only speculate, but you can be sure that in some ways the T5a in every one of your cells has been shaped from battles with ancient or maybe not so ancient retroviruses.

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