"Drips" -- Susan S. Roberts
“Drips” (Susan S. Roberts. 2007)

Fred Goldberg has just published a paper that may have interesting implications for Jon Yewdell’s DRiPs theory.

Over a decade ago,1 Yewdell proposed that, first, protein translation sucks in terms of accuracy, so that many defective proteins are produced; second, that these defective proteins are rapidly degraded, which was why they hadn’t been identified before; and third, that these defective proteins are the dominant source of T cell (MHC class I) epitopes. It had long been known, of course, that MHC class I epitopes are produced as a byproduct of protein degradation; Yewdell’s suggestion was that because defective proteins are the most abundant class of degraded proteins, they are also the dominant source of MHC class I epitopes.

Lots of people were uncomfortable with the concept of sloppy translation, since I think it was generally believed (perhaps without much evidence) that translation is a very accurate process. That particular issue never bothered me very much, for reasons I’ve discussed earlier.  (And there seems to be support for this concept, too; see the paper I quoted from a couple of weeks ago, that concluded that some 20% of newly-synthesized proteins are defective.)

However, it did bother me very much that there were quite a few examples of MHC class I epitope production that was clearly not linked to degradation of newly synthesized, defective proteins. As we interpreted Yewdell at the time, he wanted to propose that the vast majority of MHC class I epitopes came from DRiPs (“Defective Ribosomal Products“, a terrific acronym that has probably helped contribute to the success of the theory). Either he has subsequently softened his stance, or we overinterpreted his proposal, or — most likely — both; I think I’m fairly comfortable, now, with the current model that a significant fraction of epitopes come from DRiPs, and a significant fraction do not. What exactly a “significant fraction” is, remains to be determined.

One prediction Yewdell has made from his DRiPs theory is the presence of “immunoribosomes”. He reasons that if sloppy translation by ribosomes is a major source of MHC class I epitopes, then in the presence of inflammation (i.e. when there is the potential for infection, when you’d want to increase T cell surveillance) you would expect translation to become even sloppier, generating even more epitopes. (This, like the “immunoribosome” name, is an argument based on proteasomes and immunoproteasomes, which conceptually do something very similar.) This, I think, has been a much less successful prediction.

Fred Goldberg’s paper offers a bit of weak support to the concept,2 though it is far from vindication. The paper is

Medicherla, B., Goldberg, A.L. (2008). Heat shock and oxygen radicals stimulate ubiquitin-dependent degradation mainly of newly synthesized proteins. The Journal of Cell Biology, 182(4), 663-673. DOI: 10.1083/jcb.200803022


Because this work is done in yeast, which of course lack anything like MHC-based immunity, there’s no reason to expect immunoribosomes here. What Medicherla and Goldberg did find, though, is that cellular stress leads to differential degradation of proteins, with newly-synthesized proteins being particularly targeted for destruction. (There are a lot of other interesting things about this paper, including the evidence that these rapidly-degraded proteins require ubiquitination, which has been a little controversial.  But I’m just going to talk about the one aspect of the work here.)  

“Cellular stress” in this case was due to things like heat shock and toxins like paraquat, but mammalian cells undergo cell stress when they’re infected with viruses, among other things, so this might be something that could be adapted to immune responses. Their suggestion is that “many cytosolic proteins proceed through a prolonged “fragile period” during which they are sensitive to degradation induced by superoxide radicals or increased temperatures” and that this fragile period is because many proteins need to interact with binding partners or whatever before they become resistant to misfolding and degradation.

Because it is unlikely that the folding of many proteins would require 30-60 min, this “fragile period” presumably represents the time necessary for postsynthetic modifications, proper multimer formation, and localization, which together contribute to thermal resistance.

This fragile period apparently lasts an hour or so, longer than Yewdell had described for his DRiPs,3 and Goldberg seems to hint that such fragile, incompletely assembled proteins may be a more plausible source of rapidly-degraded proteins than DRiPs.

This fragile population, in Medicherla and Goldberg’s hands, represents a rather small fraction:

 In yeast growing at 20 or 30°C, such rapidly degraded components comprise 3-4% of newly synthesized proteins, but the short-lived fraction reached 13% after shift to 38 or 42°C, and 10-13% of the proteins synthesized in the presence of cadmium or paraquat at 30°C. These treatments accelerated the degradation of 10% of proteins that would otherwise be long lived so that they behaved like short-lived components.

(My emphasis.) Nevertheless, it represents a 4-fold increase in degradation, and potentially (if these findings can be extended to cells with an MHC class I system) a 4-fold increase in antigen presentation. What’s more, if the cellular stress was triggered by a viral infection, the targeted proteins would probably be disproportionately biased toward viral over cellular proteins. All in all, this sounds more like the concept Yewdell was pushing toward with his immunoribosomes: Shoud we call it “Immunostress”?

  1. Yewdell, J. W., Aton, L. C., and Benink, J. R. (1996). Defective ribosomal products (DRiPs): A major source of antigenic peptides for MHC class I molecules? J. Immunol. 157, 1823-1826[]
  2. Probably much to Fred’s dismay, since I think he is at best unenthusiastic about the whole DRiPs thing[]
  3. though the half-life of DRiPs as defined in this model seems to have increased over the years[]