During autophagy ubiquitinated cargo or substrates are engulfed in a double-membrane autophagosome and transported to the lysosome for degradation. This process is important for maintaining cellular homeostasis and for degrading damaged organelles or misfolded protein aggregates. p62, also known as sequestosome 1 (SQSTM1), is an autophagy receptor that recognizes and recruits cargo to the autophagosome through its interaction with Atg8. Atg8, known as LC3 in mammals, is a ubiquitin-like protein that is conjugated to the lipid phosphatidylethanolamine which anchors it into the double-membrane phagopore structure. Atg8/LC3 is essential for binding to and recruiting the core autophagy machinery through an Atg8 interacting motif (AIM) or through the LC3-Interacting region (LIR). AIM/LIR containing autophagy receptors, including p62/SQSTM1, recognize ubiquitinated proteins and target them to the autophagosome for destruction. Autophagy is essential for the removal of misfolded protein aggregates that are detected in neurodegenerative diseases. p62/SQSTM1 is found in ubiquitinated protein aggregates found in Alzheimer disease, Parkinson disease, and Huntington disease. Mutation or reduced expression of p62/SQSTM1 may disturb the normal autophagic process and contribute to these pathologies.
The Meisler group from the University of Michigan published research identifying a role for PI(3,5)P2 in regulating autophagy in neuronal cells (1). Mutations in the PI(3,5)P2 regulatory complex that cause neurodegeneration also led to the accumulation of p62 in neurons of the affected regions of the brain as shown through immunofluorescence with the p62/SQSTM1 antibody. Accumulation of p62 indicated a defect in the proper maturation of the autophagosome. Wu et al. detailed the effect of PI3K inhibitors on the induction or inhibition of autophagy (2). They used the p62/SQSTM1 antibody to monitor p62 levels. p62 was used as a marker for autophagic flux because it is quickly degraded by the lysosome following induction of autophagy. While p62 typically recognizes ubiquitinated cargo, the Zhu group from the University of Kentucky identified a ubiquitin-independent mechanism for the degradation of mutant SOD1 protein (3). They used the p62/SQSTM1 antibody in immunoprecipitation experiments to identify and characterize the ubiquitin independent interaction of p62 and SOD1 mutants commonly found in amyotrophic lateral sclerosis. The McLaurin group used a mouse model of Alzheimer disease to test the benefits of scyllo-Inositol (SI), an endogenous inositol stereoisomer that inhibits amyloid-beta aggregation. Through immunoblotting with the p62/SQSTM1 antibody researchers showed SI treatment helped alleviate the impairment of autophagy and prevent the accumulation of autophagosomes. In a Nature Communications article Pyo et al. shared their interesting research regarding autophagy and aging (5). They showed overexpression of Atg5 increased levels of autophagy and extended life span in mice by nearly 20%. Immunoblotting with the p62/SQSTM1 antibody showed accelerated turnover of p62 and ubiquitinated cargo and demonstrated increased autophagy as a result of Atg5 overexpression.
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