Abstract
The cellular degradation process autophagy can be a selective process during which, cellularcomponents, 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
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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.
| Date of Award | 2025 |
|---|---|
| Original language | English |
| Awarding Institution |
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| Supervisor | Shouqing Luo (Director of Studies (First Supervisor)), Konstantin Glebov (Other Supervisor) & Claire Adams (Other Supervisor) |