Since its initial discovery as labelling proteins for the bin we have discovered many new roles for polyubiquitination within the cell. Depending upon which lysine residue within the ubiquitin sequence is used to extend the polyubiquitin chain it may serve different functions from DNA repair, cellular trafficking and activation of transcription factors.
A study published in Nature Structural & Molecular Biology has uncovered a novel role for ubiquitination in the cell’s defence against stress.
A team of biologists from NYU and Harvard used the yeast Sacchromyces cerevisiae to analyse the effect of oxidative stress on the cells. Oxidative species are a common by-product of cellular metabolism and additional challenges can arise through environmental factors such as cigarette smoke, pollution and radiotherapy.
Following exposure to peroxide the cells showed increases in both K48 and K63 polyubiquitin chains. While the increase in K48 polyubquitination persisted for over four hours following the treatment, indicative of labelled proteins being degraded via the proteasome, the spike in K63 polyubiquitin chains rapidly diminished.
Investigating the mechanism and function of this K63 spike, the researchers found that this occurred only under oxidative stress conditions, with other forms of stress failing to elicit the cellular response in both yeast cells and a murine neuronal cell line. The presence of peroxide inactivated the deubiquitinase Ubp2, which led to the sudden increase in K63 ubiquitination within the cells.
The researchers isolated the K63 polyubiquitin tagged proteins and analysed them via mass spec to find that the ribosomal 40S and 20S subunits were major targets of this modification. K63 mutants gave an insight into this, as their ribosomes and polysomes were unstable and protein production was hugely diminished.
The addition of K63 polyubiquitin chains appears to function to stabilise the ribosome under conditions of oxidative stress and allow protein production of a number of important stress-response proteins, such as folding chaperones and antioxidant enzymes, to promote cell survival.
Ubiquitination has emerged as a key player linking the traditionally opposing processes in protein expression: the translation machinery responsible for synthesis of proteins and the proteasome system involved in their degradation and more is continuously being learnt about the role of this modification in the cell.