Some time ago, I wrote about how mislocalised proteins get binned immediately. Otherwise they might form dangerous clusters, such as those that cause the human form of mad cow disease. It turns out that this process – protein aggregation – might actually play an important role in our bodies and help protect us against viruses.
Faulty prion proteins are deadly not because their localisation and shape is incorrect, but because they cause deformation of other proteins which were normal to that point. Then, the newly distorted protein deforms another one and so on. This chain reaction on one hand partially depletes the cell of normally shaped and functional proteins and on the other, causes aggregation of the misfolded ones, which you might think of as a big pile of sticky rubbish. When a neuron cell is overwhelmed by such a pile, it can no longer function normally and decides to die. Such a decision, a cell suicide, by scientists called ‘apoptosis’, is nothing unusual and happens to many cells in every healthy person’s body. Normally, a suicide cell partially digests itself from the inside and the “corpse” is removed by other cells. But the problem with a prion aggregates from a dead cell is that they are very resistant to digestion. They persist and can come in contact with normal proteins on surrounding cells, causing them to misfold. This process is similar to a viral infection: a virus, after killing one cell, in which it copied itself thousands of times – infects further cells. And similarly, a misfolded prion protein – after forcing other proteins to misfold and killing the cell it originated in – moves on to other cells and causes more damage.
All of the above makes it seem like the progressive aggregation of proteins is something dangerous and deadly. But scientists in Texas found that there is another protein that behaves in a very prion-like way, but actually does it to protect us (1). The protein is called MAVS and it was known for quite a while that it responds to viral infections: when a virus enters a cell, the MAVS protein is able to pick it up and instruct the cell to activate an anti-viral programme. Fajian Hou and colleagues showed that what viral infection actually does, is aggregation of the MAVS protein, and only in this clustered form can it start the virus defence. They also found that even MAVS aggregates made synthetically (and not by viral infection) are able to activate the anti-viral programme. And these aggregates, just like prions, after enzymatic digestion don’t get destroyed and are still functional. Another similarity to prions came from the observation that pre-made MAVS clusters can enforce aggregation of natural MAVS proteins. And all this happens to help our cells fight the viral invaders.
From all of the above it appears that MAVS can very much behave like a prion protein – it aggregates, it doesn’t get digested easily and it can make other MAVS proteins aggregate too. But instead of making us worse – this actually helps to make us better. It is not clear however, what happens next. Since the aggregates are so resistant to digestion – how are they cleared? Is there another yet-unknown enzyme that actually can digest or untangle them? Do they de-aggregate spontaneously? Hopefully, one day these questions will find answers and the answers will help fight diseases caused by the evil prions.
1. MAVS Forms Functional Prion-like Aggregates to Activate and Propagate Antiviral Innate Immune Response
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