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