Sqstm1 P62 is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
SQSTM1 (Sequestosome 1), also known as p62, is a multifunctional scaffold and signaling adaptor protein that serves as a central hub connecting protein-aggregation, selective autophagymechanisms/autophagy), the ubiquitin-proteasome-system, and cellular stress response pathways [1]. As a selective autophagy receptor, p62 recognizes ubiquitinated cargo — including misfolded proteins, damaged mitochondrial-dynamics, and intracellular pathogens — and targets them for lysosomal degradation via interaction with LC3/GABARAP on autophagic membranes. [2]
Mutations in SQSTM1 are causally linked to Paget disease of bone and have been identified as genetic risk factors for als and ftd [2:1]. Beyond its role as a cargo receptor, p62 is a critical signaling node that integrates the nf-kb inflammatory pathway, the Keap1-NRF2 antioxidant response, and mTORC1 nutrient sensing, making it a key determinant of neuronal survival and vulnerability. [3]
p62 is a 440-amino-acid protein organized into multiple functional domains, each mediating distinct protein-protein interactions [3:1]: [4]
The N-terminal PB1 domain mediates: [5]
The LIR motif (consensus: W/Y-X-X-L/I/V) directly binds to Atg8-family proteins (LC3A/B/C, GABARAP, GABARAPL1/2) on autophagosomal membranes: [6]
The C-terminal UBA domain: [7]
p62 is the prototypical selective autophagy receptor, mediating multiple forms of selective autophagy [8].
p62 activates the NRF2 antioxidant defense system through a non-canonical mechanism [3:2]: [9]
This pathway is disrupted in multiple [neurodegenerative diseases, where impaired autophagy leads to p62 accumulation, chronic NRF2 activation, and eventual exhaustion of antioxidant defenses. [10]
p62 promotes mTORC1 activation on lysosomal membranes: [11]
p62 modulates nf-kb signaling at multiple levels: [12]
p62 forms cellular punctate structures known as p62 bodies, which have properties of liquid-liquid phase-separated condensates [4:2]:
SQSTM1 mutations are established genetic risk factors for both als and ftd, supporting the concept of an ALS-FTD disease continuum [2:2]:
p62 dysfunction contributes to AD pathology:
p62 intersects with key PD pathways:
Biallelic loss-of-function mutations in SQSTM1 cause a severe childhood-onset neurodegenerative syndrome characterized by progressive ataxia, dystonia, supranuclear gaze palsy, and cognitive decline, demonstrating that complete p62 loss is incompatible with normal neuronal function [6:1].
p62 immunostaining is used diagnostically in neuropathology:
Strategies to enhance p62-mediated selective autophagy include:
The study of Sqstm1 P62 has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
Deng Z, Purtell K, Bhatt S, et al. (2020). SQSTM1/p62: A potential target for neurodegenerative disease. ACS Chemical Neuroscience, 11(18), 2849–2858. DOI). 2020. ↩︎
Sánchez-Martín P, Komatsu M. (2018). p62/SQSTM1 – steering the cell through health and disease. Journal of Cell Science, 131(21), jcs222836. DOI). 2018. ↩︎ ↩︎ ↩︎
Ciuffa R, Lamark T, Taber M, et al. (2020). Structural basis of p62/SQSTM1 helical filaments and their role in cellular cargo uptake. Nature Communications, 11, 440. DOI). 2020. ↩︎ ↩︎ ↩︎
Liu WJ, Ye L, Huang WF, et al. (2022). Selective autophagy receptor p62/SQSTM1, a pivotal player in stress and aging. Frontiers in Cell and Developmental Biology, 9, 793328. DOI). 2022. ↩︎
Haack TB, Ignatius E, Calber J, et al. (2016). Absence of the autophagy adaptor SQSTM1/p62 causes childhood-onset neurodegeneration with ataxia, dystonia, and gaze palsy. American Journal of Human Genetics, 99(3), 735–743. DOI). 2016. ↩︎ ↩︎
Berkamp S, Mostova A, Badurek S. (2021). Structure and function of p62/SQSTM1 in the emerging framework of phase separation. The FEBS Journal, 288(21), 6327–6345. DOI). 2021. ↩︎
Pankiv S, Clausen TH, Lamark T, et al. (2007). p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. Journal of Biological Chemistry, 282(33), 24131–24145. DOI. 2007. ↩︎
Komatsu M, Kurokawa H, Waguri S, et al. (2010). The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nature Cell Biology, 12(3), 213–223. DOI. 2010. ↩︎
Turco E, Witt M, Abert C, et al. (2019). FIP200 claw domain binding to p62 promotes autophagosome formation at ubiquitin condensates. Molecular Cell, 74(2), 330–346. DOI. 2019. ↩︎
Rubino E, Rainero I, Chiò A, et al. (2012). SQSTM1 mutations in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Neurology, 79(15), 1556–1562. DOI. 2012. ↩︎
Zatloukal K, Stumptner C, Fuchsbichler A, et al. [(2002). p62 is a common component of cytoplasmic inclusions in protein aggregation diseases. American Journal of Pathology, 160(1), 255–263. DOI](https://doi.org/10.1016/S0002-9440(10). 2002. ↩︎