I last wrote about intracellular condensates here, but the topic has come up several times over the last few years. Now here’s a paper (preprint and final version) that has some thoughts on them that I hadn’t seen before, with help from everyone’s favorite unkillable animal, the tardigrade.
Those are tiny beasts (under a millimeter long) that live among mosses and lichens. They have eight legs, and wander around slowly sucking the contents out of plant cells and even smaller invertebrates. They have chitinaceous armor, and it seems to work pretty well, because these critters have been shown to put up with conditions that would kill most other creatures. Various tardigrade species have survived being frozen in liquid helium, heated to 150C, and exposed to pressures several times greater than those found in deep ocean trenches (with rapid pressurization and decompression as well) and to ionizing radiation at hundreds of times the human lethal dose. One species even had some survival after ten days of direct exposure to outer space conditions in low earth orbit. Of all of those, the heating is their most conspicuous weakness, although they can certainly put up with a lot more than most creatures.
They get away with these feats because they are able to almost completely stop their metabolism (down to far below one-thousandth of normal) and to lose 99% of their water mass. They have been documented to wait in this dessicated state for years or even decades, only to rehydrate and carry on as before – moving, foraging, and even reproducing as if nothing had happened. So it’s safe to say that there are some odd things about their cellular biology, and they’re certainly worth studying.
There are several mechanisms that kick in. Many dessication-tolerant creatures produce the sugar trehalose as sort of a “water replacement” in their cytosol, and it’s also used to keep ice crystals from forming inside the cells. On the protein side, there are a number of intrinsically disordered proteins that seem to be important, perhaps by helping to form a glass-like noncrystalline state, and there’s also the possibility that these pitch in by forming condensate droplets that sequester vulnerable proteins and other species inside them. One of the more well-studied condensate classes is the “stress granules“, which could well be doing the same thing. There’s evidence that these things are acting through some kinds of nonselective general physical mechanisms, because expressing such tardigrade proteins in human cell lines improves their response to stress as well, and it’s safe to say that humans (most humans) and tardigrades branched off evolutionarily some time ago.
The current paper takes that work further, looking at over 100 proteins from extreme-tolerant (ExTol) critters like tardigrades, and the team went on to design several hundred new proteins based on these (such as fusions with known human proteins). They’re especially looking at conferring resistance to apoptosis under stress conditions – most mammalian cells would indeed activate that fall-on-your-cellular-sword response in such cases. But adding in ExTol proteins and some of the engineered ones made them more hardy. Some (but not all) of these seem to be working through condensate formation, especially in the cases of human proteins (such as ApoE) that are already prone to that behavior. One of their new proteins (DHR81), for example, forms condensates that seem to sequester activated caspase-7, known to be a major player in apoptosis signaling, and this suggests that there might be at least two mechanisms working: sequestering vulnerable proteins and sequestering ones that would otherwise trigger cell death.
But the authors are careful to note that the physical changes in the cytosol during condensate formation, such as increased viscosity, could also be a big factor. There are probably other mechanisms at work as well, but the overall protective effect of condensate formation (well, the right condensates) seems to be a solid result. The results on the human ApoE protein are quite interesting in that regard. Overexpression of that lipoprotein inside cells, or even just its domain that is predicted to drive condensate formation, were both useful in staving off apoptosis. The paper is willing to make the leap that this might tie in to ApoE’s known protective effect in the development of Alzheimer’s, and they might be right (although that needs shoring up). It would seem that we could learn from our tardigrade brethern. Radiation, extreme cold, high pressures and vacuum conditions – those are all pretty stressful, but so is aging. Isn’t it?
