"Ya stressed out. Depressed out ya brain." - Baatin

I've been meaning to write about the Costa-Mattioli et al paper in the early April issue of Cell. It's got some very cool findings, but there is a lot of background to get on board. So maybe we can take a running start by covering some of their references and some basic biology. The basic idea is that some proteins are counterintuitively upregulated while the protein synthesis machinery is globally inhibited. The mechanism is pretty clever and it may be used in a relatively large number of eukaryotic mRNAs.

First off, just a little bit about the mechanism of translation. Of course you know the central dogma of genetics. DNA --transcription-> mRNA --translation-> protein. The mRNA is supposed to act an intermediary between the nucleus and the cytoplasm so the two worlds can communicate. An mRNA contains a nucleotide 'recipe' that is decoded by translation machines called ribosomes and a special type of RNAs called transfer RNAs (tRNAs). Numerous cofactors help the process of translation along at its various stages: initiation, elongation, termination, and release/recycling. In eukaryotes, these factors are named in a semi-organized system indicating which stage they have been implicated in. For instance, initiation factors are named eIFsomething for eukaryotic Initiation Factor X. You can't always trust nomenclature systems based on function though, because new knowledge renders the naming system inaccurate. For instance, new studies indicate a role for eEF1a in initiation of translation. I apologize for all the nomenclature, but the names are the names and we all have to live with it.

So I want to talk about a particular initiation factor, eIF2. There are three eIf2 subunits: alpha, beta, and gamma. We are going to pretend gamma doesn't exist. Alpha is crucial to the assembly of ribosomes on an mRNA. In its GTP-bound form, it is responsible for bringing the first amino acid for any given protein (which is always methionine) to the ribosome. As initiation actually occurs, the Guanidine TRI - phosphate is converted to Guanidine DI - phosphate (GDP) releasing energy and allowing the machine to change shapes in the necessary ways to start scootching down the mRNA reading codons. You have to have eIF2alpha-GTP to start synthesizing a new protein, and it is a resource that must be replenished with every round of translation initiation. The job of exchanging the GDP falls to eIF2beta.

All of that is the normal process carried out by cells day-to-day. Under a range of circumstances, cells will want to regulate the amount of new proteins being synthesized on a more-or-less global level. For instance, during viral infection it may be to the cell's advantage to reduce synthesis of new proteins and go into a more protective, stressed-out state. Also, if something in the protein folding process starts going haywire, the cell may want to slow down on creating new proteins until they can get the post-translational processing sorted out. These cellular stress states are communicated to the translation machinery by way of a group of enzymes called eIF2alpha kinases. They are capable of phosphorylating eIF2alpha. I'm not sure how many times I've explained what phosphorylation is, but you can think of it in basic terms as adding a reactive group to a protein to change its shape and electronegative characteristics. It is a very common way of 'throwing a switch' to activate or deactivate a given protein. A kinase, by definition, is an enzyme that phosphorylates other proteins.

EIF2alpha that has been phosphorylated becomes a qualitatively different protein. Rather than promoting translation initiation, it now acts as an inhibitor. It is still bound by eIF2beta, but eIF2beta can no longer load it up with a new GTP. Instead alpha sticks in its craw and ruins it even for other unphosphorylated alphas. The net effect is to reduce the amount of eIF2-GTP and thus the amount of ready-to-roll translation machines. The pathway to remember here is this:

Cellular Stressor -> Cellular Stress Response -> eIF2alpha Kinases -> eIF2alpha phosphorylation > eIF2beta inhibition -> reduced eIF2alpha-GTP -> globally reduced translation initiation.

This is a lot of names and a lot of pathways to get up on. In coming posts I hope to build on this knowledge to examine a specific type of mRNA that can circumvent this global translation reduction. In fact, certain mRNAs gain an advantage during cellular stress states. Generally these mRNAs code for proteins that are important for dealing with the stressor. Once we have the mechanism on board we will be at the very starting point for understanding the Costa-Mattioli paper I mentioned at the beginning. By the way, for our Spanish speaking audience, I think I found an interview with Costa-Mattioli en espanol. Three classes later I still don't know any spanish science terminology, so if anyone listens to it and I am entirely mistaken about the content, lemme know.

Labels: RNA, translation