The Discovery of p62-dependent Processing Bodies

The cellular degradation process autophagy can be a selective process during which, cellular <br/>components, such as excess proteins, can be marked for degradation by the post <br/>translational modification ubiquitination. Proteins that act as selective autophagy receptors <br/>can recognise the ubiquitinated substrates and target them to the selective autophagy <br/>pathway, facilitating their degradation and thereby mediating cellular homeostasis. The <br/>selective autophagy receptor Sequestome 1 (p62) undergoes liquid-liquid phase separation <br/>(LLPS) to form p62 bodies to mediate the autophagic degradation of ubiquitinated proteins. <br/>At the time of this research, it was unknown whether p62 could exist in a differential droplet <br/>form to p62 bodies. Ribonucleoprotein (RNP) granules such as stress granules and <br/>processing-bodies (PBs) also form through LLPS. Persistent RNP granules have been <br/>associated with neurodegenerative diseases, in particular amyotrophic lateral sclerosis and <br/>frontotemporal lobar degeneration. This research found that during proteotoxic, endotoxic <br/>or oxidative stress, p62 bodies can transform into PBs through the sequential movement of <br/>RNA binding proteins into basal p62 bodies, thus identifying a novel droplet form of p62. <br/>The presence of p62 was therefore found to be required for the formation of these <br/>structures, hence these structures represented a novel form of RNP granule and were <br/>termed p62-dependent PBs (pd-PBs). This research also found that pd-PBs were able to <br/>recruit essential components of the NLRP3 inflammasome and therefore facilitate NLRP3 <br/>inflammasome formation and activation. This novel route to NLRP3 inflammasome <br/>activation through pd-PBs, which are formed during proteotoxic stress such as experienced <br/>11<br/>in NDDs, provides a novel mechanism of proteotoxicity-induced neuroinflammation in <br/>NDDs. Previously, p62 had been reported to negatively regulate the NLRP3 inflammasome <br/>and therefore, this study has suggested a novel role of p62 in the positive regulation of the <br/>NLRP3 inflammasome, through the formation of pd-PBs. This dual role of p62 could act to <br/>regulate the NLRP3 inflammasome to maintain cellular homeostasis.

Author dc:creator

• Barrow, Elizabeth

Contributors dc:contributor

• Shouqing Luo, Konstantin Glebov, Claire Adams

Language dc:language

eng

Repository record dc:identifier

https://pearl.plymouth.ac.uk/pms-theses/61

OAI identifier oai:identifier

oai:pearl.plymouth.ac.uk:pms-theses-1060