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Unfolding the Unfolded Protein Response.

When you look closely at cellular biochemistry, what you see are a lot of amazing processes that are surrounded by amazing amounts of redundancy, backups, patches, and accumulated tweaks and fixes. That’s evolution for you; these things have been piling up for a billion years or two, and we’re all the descendants of the critters whose systems were a little more resilient or efficient. The “unfolded protein response” is a case in point.

Here, the amazing part is the maturation of proteins. Protein synthesis itself is awe-inspiring, of course, but it doesn’t spit out fully formed proteins ready for action. They first go to finishing school (the endoplasmic reticulum and often then the Golgi apparatus) before they report for their jobs. That’s why you see the ribosomes doing all that protein synthesis piled up on the outside of the ER (the “rough” ER since it’s covered with them), because it’s the next stop, and one of the first things that happens is some protein folding and quality control thereof. The ER has a whole suite of chaperones, isomerases, and such that bend common protein structural motifs into shape, but like any other system in the cell, this can get overloaded. Various kinds of stress (low oxygen, trouble with calcium levels – the ER has a ton of calcium in it, metabolic problems, infection and more) can cause misfolded proteins to start piling up at the ER. That’s a real problem, because the ER has a lot of other protein activity of its own (involved in extremely nontrivial stuff like lipid and glucose synthesis and mitochondrial regulation), so anything that stresses that system has a good chance of eventually killing the cell.

Enter the Unfolded Protein Response. That has evolved as a way of rescuing ER function under stress conditions, and one of its main functions is to turn down protein synthesis itself to give things a chance to recover. That process has three mostly separate systems, working though the IRE family (inositol-required enzyme), PERK (PKR-like endoplasmic reticulum kinase), and the ATF6 family (activating transcription factor), and these work in a bewildering variety of ways, all the way down to transcription and up to ribosomal activity. They’re also ready, should the stress not start going down, to throw up their proteinaceous hands and hit the self-destruct switch by setting off apoptotic pathways. All of these functions are (as you can imagine) interlaced with numerous checks and balances and regulators; by the time you count up all the proteins involved in the greater unfolded protein response you’re heading way down the page. Every system that is wired to apoptosis has such things, since being too quick on the fall-on-your-cellular-sword option isn’t a good long-term strategy, either. And definitely don’t let me give you the idea that all this is figured out. We’re still not even sure how the whole process gets activated – for example, do misfolded proteins bind directly to some of those enzymes just mentioned and send them into their activated state? Or is there an inactivating protein (or set of them) that they’re normally bound to that is taken away by its own binding to the misfolded species, releasing the UPR proteins to do their things? Or both, or something else?

Here’s a recent review in Nature Chemical Biology of the UPR as it relates to drug discovery. There are a number of diseases of protein misfolding (such as the neurodegeneration ones that I blogged about yesterday) that overload the UPR and lead to long-term repression of protein production, which isn’t the right idea, either. And other conditions (some cancers, immunological diseases, and more) have been shown to have a UPR connection as well, where mitigating its overactivity could be beneficial. As that review shows, there are a number of proteins in this area that have been targeted by small-molecule inhibitors, and these compounds in turn have led to more understanding of UPR function, but it’s clearly a tricky area. As the paper says, “. . .distinct signaling components of the pathway have specific, and sometimes even opposite effects on the disease pathophysiology depending on the disease context, the cell type affected and the stage of progression“. So that’s going to require some care.

The range of disease processes modified by such compounds is impressive (a result that’s simultaneously encouraging and worrying!) None of them (as far as I’m aware) have reported any human data yet, and there are a lot of toxicology questions that still have to be answered before we get any. Most of these are going to have to be dealt with in long-term studies in primates; there’s probably no other way. There also appear to be signaling differences in the acute UPR versus chronic activation, so potential therapies will have to be tailored towards those (although not all the animal models that have been used thus far are appropriate for that purpose). And there’s the bigger question of what happens to the rest of your cells if you start inhibiting the UPR. Secretory cells and others could be particularly sensitive to that sort of thing, and there are normal neuronal functions that are impacted as well, so it’s going to be a balance between desirable and undesirable effects (more toxicology). It may be that such mechanisms will only be appropriate for relatively brief chemotherapy applications or life-threatening diseases of protein misfolding, but no one knows. . .

9 comments on “Unfolding the Unfolded Protein Response.”

  1. Barry says:

    When a whole-cell screen first turned up geldanomycin, it was assumed to be a kinase inhibitor. Only after ruling out a bunch of potential kinase targets did anyone immobilize it on a column and fish a target out of cell lysates. Turned out to hit Hsp90. Why such a chaperone blockade should kill cancer cells in vitro wasn’t clear. Only years later would “unfolded protein response” enter our conversations.

  2. kk says:

    is there any drug that turns off UPR ?

    1. Barry says:

      Maybe I’m being dense. Why would you want to block the UPR? A cell that’s not competent to fold its own proteins deserves to apoptose. Hsp90 blockers tip them (and not healthy wt cells) to apoptose.

      1. c says:

        One hypothesis in the literature is that certain cells can be “over eager” to trigger apoptosis via acute ER stress. This can lead to a loss of cells that could otherwise recover. One example of this might be Type 1 Diabetes. In some cases, if the UPR can be blunted long enough for the acute stressor to pass, the cells can ultimately recover and preserve functionality.

        1. Barry says:

          The etiology of type 1 diabetes is well-explained by T-cell mediated auto-immune attack. There is no need to invoke a UPR fifth column

          https://www.jci.org/articles/view/94549

    2. c says:

      https://www.ncbi.nlm.nih.gov/pubmed/25018104

      Here is some work on a set of compounds that modulates the UPR and can “turn it off”, so to speak

  3. Nat says:

    It’s stories like this that make me, a non-biologist, think: evolution by natural selection seems pretty believable and understandable once you have functioning cells, but, wow, getting to the complexity of functioning cells…pretty amazing!

    1. Chris Phoenix says:

      That complexity evolved a bit at a time. Early cells weren’t so optimized.

  4. Belgian PhD student says:

    Spotted an embarrassing mistake in figure 1… Tradozone should be trazodone!

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