Category Archives: alzheimers disease

Don’t Stress – Just ASK!: New Role Found for Stress-Activated Molecule in Preventing Cellular Dustbins from Degrading Waste

The stress-activated molecule, ASK, prevents cellular dustbins from degrading waste proteins and may offer a new target for treating various diseases including cancer, AIDs and neurodegenerative diseases, according to a study in the Journal of Biological Chemistry this month.

It happens to us all, you’ve got a ridiculously tight deadline, an exam tomorrow, or something else that really stresses you out, and your heart starts beating a little bit faster, your palms get sweaty, and you feel sick. These responses are some of the direct results of stress on the human body. Similarly, just as the body as a whole can react to stress, so can individual cells.

ASK1 is triggered when a cell is exposed to stressful stimuli including oxidative stress (when toxic free radicals are produced within the cell which can cause serious damage to DNA) or endoplasmic reticulum stress (accumulation of unwanted proteins within the endoplasmic reticulum [the area of the cell responsible for protein production]). When triggered, ASK1 translates the stimuli of stress to within the cell, activating various intracellular processes linked to cell death and normal cell function. However, recent research by Um and Im in the November issue of the Journal of Biological Chemistry have found an additional role for ASK1 in that it inhibits the actions of cellular dustbins, or ‘proteasomes’, which eat up unwanted proteins in cells, a process which is vital for normal cell function.

Proteasomes break down unwanted proteins by a process called proteolysis to smaller components called amino acids, which are then re-used to make more new proteins. These unwanted proteins are tagged by a small protein called ubiquitin. Once tagged, these proteins are doomed as the cell is alerted to add additional ubiquitin molecules, and degrade the tagged protein. Well, that’s the norm, but as with most diseases sometimes something goes wrong and proteasomes  can malfunction. As a result, some proteins essential for normal cell function, are lost or accumulated depending on whether protein degradation is increased or decreased. This can lead to diseases such as cancer, AIDS, and neurodegenerative diseases .

In a series of elaborate and very thorough experiments, Um and Im investigated the link between ASK1 and proteasome function (these guys were meticulous; in fact Tefalhead reckons the whole set of experiments took 2 to 3 years!).

They specifically chose to work on the 26S proteasome, the most common proteasome in human cells, which is composed of two 19S ‘lids’ where the proteins are tagged for destruction and the 20S hollow core where proteins are mashed up (Figure 1). Hey, like I said earlier, this thing really is a cellular dustbin!

Figure 1. Parts of the 26S proteasome- a cellular dustin

They found that ASK1 interacts with the 19S lids of the 26S proteasome, the parts responsible for tagging unwanted proteins and transferring them to the core to be mashed up. Specifically ASK1 seems to inhibit an enzyme in the 19S lid called ATPase Rpt5, which is  critical for normal 26 S proteasome activity.

The authors go on to hypothesise that ASK1’s ability to inhibit 26S proteasome activity through blocking ATPase Rpt5 may account for the reduction of 26S proteasome activity in stressful conditions in the cell, which can eventually lead to disease. If scientists can develop inhibitors of ASK1 to stabilize proteasome activity, and if any beneficial effects are translated from the bench into the clinic, they may provide much needed treatments for cancer, AIDs, and neurodegenerative diseases.

Lots of ‘ifs’, but only time will tell whether ASK1 is a new target for the future

Ref: http://www.jbc.org/content/285/47/36434.abstract

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