Ubiquitin–proteasome pathway and cellular responses to oxidative stress

Abstract

The ubiquitin-proteasome pathway (UPP) is the primary cytosolic proteolytic machinery for the selective degradation of various forms of damaged proteins. Thus, the UPP is an important protein quality control mechanism. In the canonical UPP, both ubiquitin and the 26S proteasome are involved. Substrate proteins of the canonical UPP are first tagged by multiple ubiquitin molecules and then degraded by the 26S proteasome. However, in non-canonical UPP, proteins can be degraded by the 26S or the 20S proteasome without being ubiquitinated. It is clear that a proteasome is responsible for selective degradation of oxidized proteins, but the extent to which ubiquitination is involved in this process remains a subject of debate. While many publications suggest that the 20S proteasome degrades oxidized proteins independent of ubiquitin, there is also solid evidence indicating that ubiquitin and ubiquitination are involved in degradation of some forms of oxidized proteins. A fully functional UPP is required for cells to cope with oxidative stress and the activity of the UPP is also modulated by cellular redox status. Mild or transient oxidative stress up-regulates the ubiquitination system and proteasome activity in cells and tissues and transiently enhances intracellular proteolysis. Severe or sustained oxidative stress impairs the function of the UPP and decreases intracellular proteolysis. Both the ubiquitin conjugation enzymes and the proteasome can be inactivated by sustained oxidative stress, especially the 26S proteasome. Differential susceptibilities of the ubiquitin conjugation enzymes and the 26S proteasome to oxidative damage lead to an accumulation of ubiquitin conjugates in cells in response to mild oxidative stress. Thus, increased levels of ubiquitin conjugates in cells appear to be an indicator of mild oxidative stress.

Upregulated autophagy protects cardiomyocytes from oxidative stress-induced toxicity

“…The accumulation of high molecular weight ubiquitinated proteins has been observed in conditions of increased oxidative stress and can originate from an inefficient clearance of damaged proteins through the proteasomal system. 41,42 Under these conditions, autophagy induction can mediate the removal of accumulated proteins, averting potential proteotoxicity. We found that AMA induced the accumulation Inhibition of autophagy blocks the cytoprotective effects of rapamycin against AMA.…”

“…67,68 Damaged cellular components are marked by ubiquitination, to be subsequently removed by the ubiquitin-proteasome system (UPS). 41 Growing evidence suggests that under conditions of increased oxidative burden, accumulation of high molecular weight ubiquitinated proteins is frequently observed, owing to their inefficient removal through the UPS system. 41,42,69 Autophagy induction under these circumstances has been shown to mediate the removal of such accumulated proteins.…”

“…41 Growing evidence suggests that under conditions of increased oxidative burden, accumulation of high molecular weight ubiquitinated proteins is frequently observed, owing to their inefficient removal through the UPS system. 41,42,69 Autophagy induction under these circumstances has been shown to mediate the removal of such accumulated proteins. In our studies, rapamycin-induced autophagy attenuated the accumulation of ubiquitinated proteins that resulted from AMA-induced exposure.…”

HDAC4 preserves skeletal muscle structure following long-term denervation by mediating distinct cellular responses

“…To cope with OS, organisms have developed multiple defense mechanisms to alleviate oxidative damage, including antioxidants enzymes, molecular chaperones, and proteolytic systems. Indeed, both autophagy and UPS are activated in response to OS to remove damaged proteins [25,26].…”

Heat shock proteins (HSPs) in coeliac disease

“…Cells are equipped with an efficient surveillance system to selectively eliminate abnormally folded, damaged proteins (Mishra et al, 2009). First with the help of molecular chaperones the cell tries to refold the unfolded proteins (Bukau et al, 2006), but if the refolding is no more possible, the misfolded or irreversibly aggregated proteins will be degraded by the ubiquitin proteasome system (Shang & Taylor, 2011). In the second class of proteins belong the components of the ubiquitin-proteasome pathway, which is the primary cytosolic proteolytic machinery for the selective degradation of various forms of damaged proteins, so it is an important protein quality control mechanism (Dantuma & Lindsten, 2010).…”