Prions by activation not amyloid

If conformational change can cause an infection—as appears to be the case with the amyloid-inducing prions—then perhaps the same is true for other protein modifications. B. Tibor Roberts and Reed Wickner (NIH, Bethesda, MD) now claim to have found an example of this latter case, and they suggest that the discovery of more cases is a matter of time.

Wickner says he knew “for 10 years” about work from Beth Jones (Carnegie Mellon University, Pittsburgh, PA), in which yeast cells lacking the upstream activator protease A (PrA) suffered a gradual disappearance of protease B (PrB) activity. This slow decline was always blamed on gradual dilution (even 10⁶-fold dilution) of PrA and PrB mRNAs and proteins, and inefficient autoactivation by PrB.

But now Roberts and Wickner show that PrB activity can be maintained indefinitely in the absence of PrA, presumably based on PrB autoactivation. That process fails, however, when PrB expression is temporarily extinguished and then restored. The newly expressed PrB cannot activate itself, apparently because only the activated form of PrB can carry out this function. This rule also holds true between cells: the inactive PrB can be rescued via an “infection” with cytoplasm from cells with activated PrB.

This may seem like an oddity of one particular yeast mutant. But, says Wickner, “there are undoubtedly a lot of other examples, because there are so many proteins that have the ability to modify themselves. You just need the situation where you need the modified form to do the modification.” Transfer of these proteins in carriers such as exosomes could even spread such an infection to distant cell types. ▪

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