Abstract
BackgroundExtensive research on p62 has established its role in oxidative stress, protein degradation and in several diseases such as Paget’s disease of the bone, frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Importantly, previous studies showed that p62 binds directly to Keap1, which is a ubiquitin E3 ligase responsible for degrading Nrf2. Indeed, colocalisation of p62 and Keap1 occurs in tumorigenesis and neurodegeneration. A serine (S) residue in the Keap1-interacting region of p62 is phosphorylated in hepatocellular carcinoma, and this phosphorylation contributes to tumour growth through the higher affinity of p62 to Keap1. However, it remains largely unknown whether p62 is phosphorylated in the Keap1-interacting region under neurodegenerative conditions.ResultsTo answer this question, we generated an antibody against phosphorylated S349 (P-S349) of p62 and showed that S349 is phosphorylated following disruption of protein degradation. In particular, the ratio of P-S349 to total p62 levels was significantly increased in the brains with Alzheimer’s disease (AD) compared with controls. We also compared the reactivity of the P-S349 antibody with P-S403 of p62 and showed that these two phosphorylated sites on p62 cause different responses with proteasome inhibition and show distinct localisation patterns in AD brains. In addition to disruption of protein degradation systems, activation of oxidative stress can induce P-S349.ConclusionThese results support the hypothesis that disruption of protein degradation systems and sustained activation of the Keap1-Nrf2 system occur in the brains with AD.Electronic supplementary materialThe online version of this article (doi:10.1186/2051-5960-2-50) contains supplementary material, which is available to authorized users.
Highlights
Accumulation of misfolded or abnormally modified proteins is a major characteristic of many neurodegenerative diseases and is largely attributed to aging, oxidative stress, and genetic and environmental factors
Specificity of antibodies against p62 phosphorylated at serine 349 Recent papers reported that p62 binds to Keap1 through residues 344–356, called the Keap1-interacting region (KIR) (Figure 1a)
A recent study demonstrated that S403 of p62 can be phosphorylated and that this phosphorylation strengthens the affinity with polyubiquitin and ubiquitinated molecules [22]
Summary
Accumulation of misfolded or abnormally modified proteins is a major characteristic of many neurodegenerative diseases and is largely attributed to aging, oxidative stress, and genetic and environmental factors. Two major systems for protein degradation exist in mammals, the autophagy-lysosome system and the ubiquitin-proteasome system. Both systems cooperatively play an important role in intracellular p62/SQSTM1/sequestosome 1 (referred to as p62) is a multifunctional protein that is highly involved in protein degradation. A serine (S) residue in the Keap1-interacting region of p62 is phosphorylated in hepatocellular carcinoma, and this phosphorylation contributes to tumour growth through the higher affinity of p62 to Keap. A serine (S) residue in the Keap1-interacting region of p62 is phosphorylated in hepatocellular carcinoma, and this phosphorylation contributes to tumour growth through the higher affinity of p62 to Keap1 It remains largely unknown whether p62 is phosphorylated in the Keap1-interacting region under neurodegenerative conditions
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
