p62/SQSTM1 Protein
Overview
p62, also known as sequestosome-1 (SQSTM1), is a 62-kilodalton multifunctional adaptor protein that serves as a critical hub in cellular protein quality control systems. Encoded by the SQSTM1 gene located on chromosome 5q35.3, p62 functions as a ubiquitin-binding scaffold protein that coordinates autophagy, proteasomal degradation, and signal transduction pathways. The protein is expressed ubiquitously across tissues with particularly high levels in the brain, liver, and muscle. Due to its central role in clearing misfolded proteins and maintaining cellular homeostasis, p62 dysfunction is strongly implicated in multiple neurodegenerative diseases, making it both a molecular biomarker and therapeutic target in neurodegeneration research.
Function and Biology
...p62/SQSTM1 Protein
Overview
p62, also known as sequestosome-1 (SQSTM1), is a 62-kilodalton multifunctional adaptor protein that serves as a critical hub in cellular protein quality control systems. Encoded by the SQSTM1 gene located on chromosome 5q35.3, p62 functions as a ubiquitin-binding scaffold protein that coordinates autophagy, proteasomal degradation, and signal transduction pathways. The protein is expressed ubiquitously across tissues with particularly high levels in the brain, liver, and muscle. Due to its central role in clearing misfolded proteins and maintaining cellular homeostasis, p62 dysfunction is strongly implicated in multiple neurodegenerative diseases, making it both a molecular biomarker and therapeutic target in neurodegeneration research.
Function and Biology
p62 is a modular protein containing several functionally distinct domains that facilitate multiple protein-protein interactions. The N-terminal Phox and Bem1p (PB1) domain mediates homotypic interactions and binding to other PB1-containing proteins, allowing p62 to form oligomeric complexes. The ubiquitin-associated (UBA) domain at the C-terminus directly binds polyubiquitin chains on target proteins, particularly those marked with lysine-48 (K48)- and lysine-63 (K63)-linked ubiquitin modifications. The central region contains a zinc finger domain and an LC3-interacting region (LIR), which enables direct binding to the autophagy-associated protein microtubule-associated protein light chain 3 (LC3). Additionally, p62 possesses a Kelch-like ECH-associated protein 1 (KEAP1)-binding domain that regulates nuclear factor erythroid 2-related factor 2 (Nrf2) signaling.
In healthy cells, p62 primarily functions as an autophagy receptor that recognizes ubiquitinated protein aggregates and delivers them to autophagosomes for degradation through its dual LC3-binding and ubiquitin-binding capabilities. This "eat me" signal allows the selective autophagy machinery to identify and engulf accumulated misfolded proteins. p62 also participates in proteasomal degradation pathways by recruiting ubiquitinated substrates to the 26S proteasome. Beyond protein degradation, p62 regulates inflammatory signaling through interactions with protein kinase C (PKC), tumor necrosis factor receptor-associated factor 6 (TRAF6), and receptor interacting serine/threonine-protein kinase 1 (RIPK1), influencing nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation. Through KEAP1 interaction, p62 stabilizes Nrf2, promoting antioxidant response element (ARE)-driven transcription of cytoprotective genes.
Role in Neurodegeneration
p62 accumulation is a hallmark pathological feature across multiple neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). In these conditions, p62-positive inclusions are frequently observed in affected neurons, indicating impaired autophagy flux and protein quality control failure. In AD, p62 localizes to amyloid-beta plaques and phosphorylated tau tangles, suggesting its involvement in attempting to clear these pathogenic protein aggregates. In PD, p62-positive Lewy bodies reflect dystrophic autophagy in neurons affected by alpha-synuclein pathology. In ALS, p62 inclusions containing TDP-43 and FUS proteins mark neurons undergoing selective degeneration. Mutations in SQSTM1 itself cause Paget's disease of bone and frontotemporal dementia with ubiquitinated inclusions (FTDU), directly linking p62 dysfunction to neurodegeneration.
Molecular Mechanisms
Impaired autophagy flux represents the primary mechanism linking p62 dysfunction to neurodegeneration. When autophagic capacity is compromised—whether through lysosomal dysfunction, reduced autophagosome formation, or blocked autophagosome-lysosome fusion—p62-ubiquitin conjugates accumulate since they cannot be efficiently degraded. This accumulation triggers several pathogenic cascades: aggregated p62 stabilizes Nrf2 constitutively, leading to chronic oxidative stress responses; p62 oligomers activate NF-κB persistently, promoting neuroinflammation; and p62-containing inclusions sequester other proteins, creating toxic aggregation hubs. Additionally, excessive p62 can impair mTORC1 signaling regulation, further suppressing autophagy initiation.
Clinical and Research Significance
p62 levels and phosphorylation state serve as quantifiable biomarkers for autophagy dysfunction in neurodegeneration. Elevated cerebrospinal fluid and neuronal p62 correlate with disease progression in AD and ALS. Pharmacological approaches targeting p62 through autophagy enhancers, proteasome activators, or direct KEAP1-