How the ER deals with stress

OK today I'll talk about yet another paper from Jonathan Weissman's group at UCSF ... but I'll write it up in two parts. This post will be generally background about the ER and its ability to degrade proteins.

When many scientists think about "cellular functions", diagrams of the central dogma of biology (DNA=>RNA=>protein) pop into their head. But sorting out the good stuff (properly processed mRNA, well folded proteins) from the bad stuff (misprocessed mRNA, misfolded protein) is equally important.

Proteins can be divided into two classes, those that have to cross a membrane (membrane proteins, secreted proteins, organellar proteins) and those that don't. Proteins can cross the membrane while they are being synthesized by ribosomes (see the blue blobs in the cartoon at the bottom of the entry). Basically the ribosome pumps the newly made protein through a pore (the translocon, the purple membrane protein in the cartoon) which is situated on the membrane of the endoplasmic reticulum (ER). The process of pumping newly made proteins into the ER is called translocation.

For quite a while, one mystery of cell biology was how the cell sorted ER targeted proteins and how misfolded proteins within the ER are degraded.

Eventually it was found that unfolded proteins were simply pumped right back out of the ER and then destroyed by the cytoplasmic degredation machinery. The act of pumping the protein out of the ER is referred to as retrotranslocation, and the entire act of pumping proteins out of the ER and degrading them is called ERAD (ER associated degredation). Now proteins that are pumped into the ER are folded with the help of a class of proteins called chaperones. If cells are faced with conditions that result in an increase in protein unfolding (or denaturation), such that the ER machinery is overwhelmed, a second cellular activity (besides ERAD) is activated, the Unfolded Protein Response (UPR).

What is UPR?

Basically the cell wants to turn off the synthesis of most ER targeted proteins while increasing the synthesis of chaperones and other ER proteins that function to fold and/or degrade excess denatured proteins.

So how is UPR turned on? Well it's a weird story. It all starts off with IRE1, a protein that resides in the ER's membrane. IRE1 is thought to sense the presence of unfolded proteins within the lumen of the ER. At this point, the cytosolic part of IRE1 clips an mRNA that encodes XBP1 (X-box binding protein 1). The clipped mRNA then endergoes an unconventional splicing reaction and then gets transcribed into XBP1 protein. XBP1 enters the nucleus and activates the transcription of UPR induced genes, such as chaperones and ERAD components.

OK a summary is in order now.
- the ER is an organelle devoted to synthesizing and folding translocated proteins.
- If a newly synthesized protein can't fold, it is pumped out of the ER and degraded by the cytosolic protein degredation machinery. This process is called ERAD.
- If too many unfolded proteins accumulate, IRE1 senses the excess denatured proteins and clips XBP1 mRNA. XBP1 protein is then made and activates the expression of genes involved in protein folding and ERAD. This process is called UPR.

But wait, when UPR is activated it must turn off the translation of mRNAs present on the ER surface, or else more and more protein will be pumped into a stressed out ER. How is that done?

Well a second sensor besides IRE1 exists, and its name is PERK (protein kinase R-like ER kinase). When the level of unfolded proteins within the ER increases, PERK phosphorylates (covalently adds a phosphate) to eIF2alpha, a factor that is required to initiate mRNA translation. The result: ribosomes can't reinitiate a new round or translation. In the new paper by the Weissman group, a second UPR mediated mechanism to turn off protein synthesis at the ER membrane was discovered. The bottom line, IRE1 cleaves mRNAs that sit on the surface of the ER ... but the implied mechanism is a bit surprising (I'll explain in the next post). I ripped off a nice diagram of the whole UPR process, from a David Ron review in a recent issue of Science (actually talking about the same Weissman paper).

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I'll have a full description of the Weissman paper either later today or tomorrow.

More like this

It reminds me of a seminar given by Peter Walter on UPR that I attended about a year ago. It was fascinating for its clarity, the logic behind each experiment, surprising findings, and above all his enthusiasm. It was probably one of the best seminars I've ever attended, even though the topic was unfamiliar to me and I had wrongly thought it a boring topic.

I'm looking forward to reading your description of the Weissman paper.

Thanks.

I must sat that I omitted QUITE a bit ... for example, what does PERK and IRE sense? Some say that the chaperone BiP inactivates them under normal conditions, and is "too busy" to inhibit them under stress. Others say that these proteins can bind dirrectly to excess unfolded proteins.

Another point that I should have mentioned, is that there is a third branch of the UPR pathway regulated by ATF6. Like PERK and IRE1, ATF6 can "sense" unfolded proteins. When it does, BiP lets go of ATF6, and allows ATF6 to be transported to the Golgi where it is cleaved. The free cytosolic domain can then enter the nucleus and upregulate UPR transcription.

I'll try to post something on the Weissman paper this weekend.

Thanks Alex.Your comments are a big help to me. I am from Argentina, and want to writte a paper about ER, for Argentinian physicians, "non ER-aficionados"!!!
Thanks, thanks a lot.

By MarÃa Marta Aranda (not verified) on 23 Aug 2009 #permalink