Remote-Url: https://blogs.sciencemag.org/pipeline/archives/2021/08/06/viral-knots
Retrieved-at: 2021-08-15 11:33:32.112188+00:00

The current pandemic has made everyone think a lot more about viruses than they ever had any desire to, but they’re a constant background to our lives – and to the lives of pretty much every living creature. Humans have their viruses, other mammals have theirs (with occasional catastrophic overlaps), and birds, reptiles, and fish all have their own as well. Worms, ocean sponges, mollusks, insects – they all have their suite of viruses that infect them, all the way down to the phages that attack bacteria. Plants of all kinds have their own viral load as well. This is what things look like after a couple of billion years of evolutionary competition; viruses are too successful at what they do to not be everywhere.We’ve also all had to learn a lot more than we ever wanted to about our defense mechanisms against these things, and I wanted to highlight an odd feature of one of those today, as seen inthis paper. When you’re infected with an RNA virus, one of the common counterattacks is through RNAse enzymes, which attempt to break down the foreign sequences. They break down a lot of our own RNA molecules as well, of course – many types of RNA have a rather short half-life in the cell, and if you need them to last longer, you have to work in some special features.Viruses have long since stumbled onto those sorts of trick as well, of course: an RNA virus whose genetic material isn’t degraded so quickly by host defenses has an obvious advantage. One of the things that dodges RNAse activity is for the RNA molecule itself to be oddly shaped and knotted. These sequences (exoribonuclease-resistant RNAs, or xrRNAs) have been elaborated over the years to the point that some viruses use them both as protection and as a means to have host RNAse enzymes directed to places where the RNA needs to be cut anyway! Viruses travel light. Any work that can be offloaded onto the host cell generally is.The flaviviruses were the first family seen to be taking advantage of these effects (although they’ve since been noticed in other types of viruses as well). That one’s pretty high-profile, though: yellow fever, Zika, chikungunya and dengue are all caused by pathogens in this group. Zika, for example, has an interesting knotted structure in one region of its RNA that causes a whole range of incompletely broken-down RNA species to form when the host cell RNAses try to digest it. These things pile up inside the cell and start disrupting all sorts of other cellular processes in turn (such as the ones that respond to viral attack!) making for a more successful infection.You always have to guard your thinking about these things, of course. Our brains have a bias towards imputing agency to things – it’s how we model behavior of threats like animals (including other humans), and it’s a valuable heuristic indeed. But it also makes us think that Zeus or whoever is trying to zap us with lightning bolts, that hurricanes steer into godless dens of sinners that deserved it anyway, and that the reason the NMR sample changer dropped three hours worth of tubes onto the floor last night is because the robot hates you and wants your experiments to fail. Viruses are not planning out their strategies. They mutate and wander and stumble and putz around randomly until something works a bit better to make Moar Virus, and then that Moar Virus change, whatever the hell it was, gradually becomes more common in the population. We’re seeing the end result of who knows how many epochs of such mutations, all done under the pressure of host organism counterattacks, so it looks pretty impressive by now. The fact that we don’t see the untold, unknowable number of misfires also helps. It’s the same strategy that astrologers and fortunetellers use on purpose: make the most out of your successes and sweep all the failures out of sight. If at first you don’t succeed, destroy all evidence that you even tried. Virus success is obvious and rises quickly to the top; virus failures vanish.The paper linked above looks at one of the knots in Zika viruses, by the high-tech means of attaching chemical handles to each end of the knot and capturing those in optical traps. This allows you to pull on the ends in a very controlled fashion and to get a profile of the unraveling as it takes place on a single RNA molecule. Here’s what they find:By measuring the extension of the xrRNA as its structure changed, we identified intermediates in the folding and deduced their structures. We found that the core of the native fold was very resistant to mechanical unfolding, but achieving this extreme resistance required a specific sequence of steps in the folding: formation first of a three-helix junction, then threading of the 5′ end into a cleft in this junction and stabilization by tertiary contacts, before closure of the ring around the threaded 5′ end by a PK.So when we say that there’s a knot in the RNA, that is exactly what’s going on, and these knots – like the ones you’d tie with rope – have a particular topology and a particular series of steps to get them tied correctly. The structure of this one is shown in schematic at right, and you can see that 5′ end stuck back in through that cleft. The RNAse enzymes obviously don’t quite know what to make of this, since many of them start digesting from the 5′ end and run smack into the knot. What this paper found, though, is that all knots are not created equal. It appears that just forming any old knot is insufficient by itself to fight off the RNAses, but this Zika one has much high mechanical resistance to being pulled apart than usual, and that’s the key feature. The authors are planning to test this idea with RNA knots from other viruses. Perhaps in another few million years an RNAse will show up that will be able to deal with these things, and things will move on.If I had to pick one thing about cell biology from my undergraduate education – heck, my graduate education – that has utterly changed over the years, it would be the wild functional and structural variety of RNA molecules that have been uncovered. RNAs in general can form a bewildering number of structures, and only a fool would think that we’ve come to the end of them. And there are surely useful things that we could make that nature has never quite gotten around to finding a use for, either!