p62/SQSTM1 (Sequestosome-1)

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p62/SQSTM1 (Sequestosome-1)

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Introduction

P62 Sqstm1 (Sequestosome 1) is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Overview

p62, also known as Sequestosome-1 (SQSTM1), is a multifunctional scaffold protein that serves as the classical selective [autophagy](/mechanisms/autophagy-lysosome-neurodegeneration) receptor in mammalian cells. It plays a central role at the intersection of the [ubiquitin-proteasome system](/mechanisms/ubiquitin-proteasome-system), selective [autophagy](/entities/autophagy), and multiple cell signaling pathways including [NF-κB](/entities/nf-kb), [mTOR](/mechanisms/mtor-neurodegeneration), and [Nrf2](/proteins/nrf2) oxidative stress response. p62 is encoded by the SQSTM1 gene on chromosome 5q35.[@moscat2009] [@fecto2011]

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Introduction

P62 Sqstm1 (Sequestosome 1) is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Overview

p62, also known as Sequestosome-1 (SQSTM1), is a multifunctional scaffold protein that serves as the classical selective [autophagy](/mechanisms/autophagy-lysosome-neurodegeneration) receptor in mammalian cells. It plays a central role at the intersection of the [ubiquitin-proteasome system](/mechanisms/ubiquitin-proteasome-system), selective [autophagy](/entities/autophagy), and multiple cell signaling pathways including [NF-κB](/entities/nf-kb), [mTOR](/mechanisms/mtor-neurodegeneration), and [Nrf2](/proteins/nrf2) oxidative stress response. p62 is encoded by the SQSTM1 gene on chromosome 5q35.[@moscat2009] [@fecto2011]

In [neurodegenerative diseases](/diseases), p62 has emerged as a pivotal player due to its dual role: (1) as a cargo receptor that tags and delivers ubiquitinated protein aggregates for autophagic degradation, and (2) as a component of the protein inclusions that characterize virtually all major neurodegenerative conditions. p62-positive inclusions are found in the neurofibrillary tangles of [Alzheimer's disease](/diseases/alzheimers-disease), [Lewy bodies](/mechanisms/alpha-synuclein) of [Parkinson's disease](/diseases/parkinsons-disease), and ubiquitinated inclusions of [ALS](/diseases/amyotrophic-lateral-sclerosis)/[FTD](/diseases/frontotemporal-dementia). Mutations in SQSTM1 are directly linked to familial [ALS](/diseases/amyotrophic-lateral-sclerosis) and [frontotemporal dementia](/diseases/frontotemporal-dementia), establishing p62 as both a pathological marker and a causal factor in neurodegeneration.[@fecto2011] [@komatsu2007]

Structure and Domains

p62 is a 440-amino acid protein with a modular domain architecture that enables its diverse functions: [@zaffagnini2018]

Key Functional Domains

PB1 (Phox and Bem1) domain (residues 1–102): Mediates oligomerization and interactions with atypical protein kinases C (aPKCs) and other PB1-containing proteins. Self-oligomerization via PB1 is essential for forming p62 bodies — phase-separated condensates that concentrate cargo for autophagy

ZZ-type zinc finger (residues 128–163): Binds RIP1 kinase, mediating [NF-κB](/entities/nf-kb) signaling activation

TRAF6-binding domain (TBS, residues 225–250): Interacts with TRAF6, an E3 ubiquitin ligase critical for [NF-κB](/entities/nf-kb) activation and neuroinflammatory signaling

LIR (LC3-interacting region) (residues 335–341): The critical motif for autophagy receptor function — binds [LC3](/proteins/lc3)/GABARAP proteins on the autophagosome membrane, tethering ubiquitinated cargo to the autophagic machinery

KIR (Keap1-interacting region) (residues 349–361): Binds Keap1, releasing Nrf2 for nuclear translocation and activation of antioxidant and cytoprotective gene expression

UBA (ubiquitin-associated) domain (residues 386–440): Binds K48- and K63-linked polyubiquitin chains on cargo proteins destined for degradation[@komatsu2007]

Structural Organization for Cargo Recognition

The spatial arrangement of the LIR and UBA domains allows p62 to simultaneously bind ubiquitinated substrates (via UBA) and autophagosome membranes (via LIR), functioning as a molecular bridge between cargo and the autophagic machinery. Self-oligomerization via the PB1 domain creates large p62 condensates that concentrate cargo, enhancing the efficiency of selective autophagy.[@zaffagnini2018] [@snchezmartn2019]

Functions in the Nervous System

Selective Autophagy Receptor

p62 is the prototypical receptor for aggrephagy — the selective autophagic degradation of protein aggregates. In [neurons](/entities/neurons), which are post-mitotic and cannot dilute toxic aggregates through cell division, this function is critically important. p62 recognizes and binds: [@geisler2010]

Ubiquitinated misfolded proteins (via UBA domain)
[Tau](/proteins/tau)(/proteins/tau) aggregates in [Alzheimer's disease](/diseases/alzheimers-disease)
[alpha-synuclein](/proteins/alpha-synuclein) aggregates in [Parkinson's disease](/diseases/parkinsons-disease)
[TDP-43](/proteins/tdp-43) and [FUS](/proteins/fus-protein) aggregates in [ALS](/diseases/amyotrophic-lateral-sclerosis)/[FTD](/diseases/frontotemporal-dementia)
[Huntingtin](/proteins/huntingtin) polyglutamine aggregates in [Huntington's disease](/mechanisms/huntington-pathway)[@snchezmartn2019]

Mitophagy

p62 participates in [PINK1](/proteins/pink1-protein)/[Parkin](/proteins/parkin)-dependent [mitophagy](/mechanisms/mitophagy) — the selective degradation of damaged mitochondria. When [PINK1](/proteins/pink1-protein) accumulates on depolarized mitochondria and recruits [Parkin](/proteins/parkin), the E3 ubiquitin ligase activity of Parkin ubiquitinates outer mitochondrial membrane proteins. p62 recognizes these ubiquitinated mitochondrial substrates and facilitates their engulfment by autophagosomes. Impaired mitophagy due to p62 dysfunction contributes to [mitochondrial dysfunction](/mechanisms/mitochondrial-dysfunction) in neurodegeneration.[@geisler2010] [@sanz2000]

NF-κB Signaling

Through its ZZ and TBS domains, p62 activates the [NF-κB](/entities/nf-kb) inflammatory pathway. In [microglia](/entities/microglia) and potentially harmful (via [neuroinflammation) — makes p62 a complex therapeutic target.[@sanz2000] [@komatsu2010]

Nrf2-Keap1 Oxidative Stress Response

When p62 accumulates (e.g., due to autophagy impairment), it sequesters Keap1 via its KIR domain, releasing Nrf2 to translocate to the nucleus and activate antioxidant response element (ARE)-driven genes. This p62-Keap1-Nrf2 axis provides a feedback loop linking autophagy status to the [oxidative stress](/mechanisms/oxidative-stress) response — a mechanism particularly relevant in [neurons](/entities/neurons) under proteotoxic stress.[@komatsu2010] [@du2012]

Role in Neurodegenerative Diseases

Alzheimer's Disease

In [Alzheimer's disease](/diseases/alzheimers-disease), p62 expression is reduced in affected brain regions, particularly the frontal [cortex](/brain-regions/cortex) and [hippocampus](/brain-regions/hippocampus), beginning early in the disease process. This reduction correlates with impaired autophagic clearance of both tau](/proteins/tau) tangles and [Amyloid-Beta](/proteins/amyloid-beta) aggregates. p62 co-localizes with neurofibrillary tangles and is believed to participate in tau](/proteins/tau) degradation via selective autophagy. p62 also modulates [APP](/entities/app-protein) processing: loss of p62 function shifts [APP](/entities/app-protein) processing toward the amyloidogenic pathway, increasing [Aβ](/proteins/amyloid-beta-protein) production.[@du2012] [@yilmaz2022]

CSF p62 concentrations are significantly elevated in AD patients compared to controls, suggesting that neuronal release of p62 (from dying neurons or exosomal secretion) may serve as a biomarker of autophagic dysfunction.[@yilmaz2022] [@haack2016]

ALS and Frontotemporal Dementia

Mutations in SQSTM1 are directly causative of familial [ALS](/diseases/amyotrophic-lateral-sclerosis) and [FTD](/diseases/frontotemporal-dementia). Over 25 pathogenic variants have been identified, most affecting the UBA domain and impairing ubiquitin binding. Key mutations include: [@bhatt2022]

P392L — the most common mutation, originally identified in Paget disease of bone and subsequently linked to ALS
L341V, P348L — affect the LIR domain, disrupting LC3 binding
K238E, D337E — impair [NF-κB](/entities/nf-kb) signaling or autophagy flux

p62-positive, [TDP-43](/proteins/tdp-43)-positive inclusions are the hallmark pathology of sporadic [ALS](/diseases/amyotrophic-lateral-sclerosis) and [C9orf72](/proteins/c9orf72-protein)-linked ALS/FTD, indicating that p62-mediated aggregate clearance is overwhelmed in these conditions.[@fecto2011]

Parkinson's Disease and Lewy Body Dementia

p62 is a consistent component of [Lewy bodies](/mechanisms/alpha-synuclein), where it co-localizes with ubiquitinated [alpha-synuclein](/proteins/alpha-synuclein). In models of [Parkinson's disease](/diseases/parkinsons-disease), overexpression of p62 enhances [alpha-synuclein](/proteins/alpha-synuclein) clearance, while p62 knockdown accelerates aggregate accumulation and neuronal death. The connection between p62 and [PINK1](/proteins/pink1-protein)/[Parkin](/proteins/parkin)-mediated [mitophagy](/mechanisms/mitophagy) further links p62 to PD pathogenesis.[@snchezmartn2019]

Huntington's Disease

p62 recognizes polyglutamine-expanded [huntingtin](/proteins/huntingtin) aggregates for autophagic clearance. In [Huntington's disease](/mechanisms/huntington-pathway) models, enhancing p62 expression or activity promotes aggregate clearance and improves neuronal survival.[@snchezmartn2019]

Childhood-Onset Neurodegeneration

Biallelic loss-of-function mutations in SQSTM1 cause a severe childhood-onset neurodegenerative syndrome characterized by progressive cerebellar ataxia, dystonia, and supranuclear gaze palsy, demonstrating that complete loss of p62 function is incompatible with normal neuronal maintenance.[@haack2016]

Therapeutic Implications

p62 as a Drug Target

Several strategies are being explored to modulate p62 function therapeutically:

Enhancing p62 expression: Small molecules and gene therapy approaches to increase p62 levels and boost selective autophagy
Stabilizing p62-LC3 interaction: Compounds that enhance the LIR-LC3 binding to improve autophagy flux
p62-based degraders: Using p62's UBA domain as a targeting module in chimeric degrader molecules (autophagy-targeting chimeras, AUTACs)
Nrf2 activation: Leveraging the p62-Keap1-Nrf2 axis for antioxidant neuroprotection[@bhatt2022]

Biomarker Applications

CSF and blood levels of p62 are being investigated as biomarkers for:

Autophagic dysfunction in [Alzheimer's disease](/diseases/alzheimers-disease) and [ALS](/diseases/amyotrophic-lateral-sclerosis)
Disease progression and treatment response in clinical trials targeting the [autophagy-lysosomal pathway](/mechanisms/autophagy-lysosomal-pathway)
Genetic risk assessment in ALS/FTD families[@yilmaz2022]

External Links

[UniProt — SQSTM1 Human](https://www.uniprot.org/uniprot/Q13501)
[OMIM — SQSTM1](https://www.omim.org/entry/601530)
[NCBI Gene — SQSTM1](https://www.ncbi.nlm.nih.gov/gene/8878)

Brain Atlas Resources

Allen Human Brain Atlas: [p62/SQSTM1 expression search](https://human.brain-map.org/microarray/search/show?search_term=p62%2FSQSTM1)
Allen Mouse Brain Atlas: [p62/SQSTM1 search](https://mouse.brain-map.org/search/index.html?query=p62%2FSQSTM1)
Allen Cell Type Atlas: [Transcriptomic cell type reference](https://portal.brain-map.org/atlases-and-data/rnaseq)
BrainSpan Developmental Transcriptome: [p62/SQSTM1 developmental expression](https://www.brainspan.org/rnaseq/search/index.html?search_term=p62%2FSQSTM1)

Background

The study of P62 Sqstm1 (Sequestosome 1) 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.

References

[Unknown, Moscat & Diaz-Meco, p62 at the Crossroads of Autophagy, Apoptosis, and Cancer, Cell 2009 (2009)](https://doi.org/10.1016/j.cell.2009.05.023)

[Fecto et al., SQSTM1 Mutations in Familial and Sporadic ALS, Archives of Neurology 2011 (2011)](https://doi.org/10.1001/archneurol.2011.250)

[Komatsu et al., Homeostatic Levels of p62 Control Cytoplasmic Inclusion Body Formation, J Cell Biol 2007 (2007)](https://doi.org/10.1083/jcb.200702050)

[Zaffagnini et al., p62 Filaments Capture and Present Ubiquitinated Cargos for Autophagy, EMBO J 2018 (2018)](https://doi.org/10.15252/embj.201798تار8)

[Unknown, Sánchez-Martín & Bhatt, SQSTM1/p62: A Potential Target for Neurodegenerative Disease, ACS Chemical Neuroscience 2019 (2019)](https://doi.org/10.1021/acschemneuro.8b00516)

[Geisler et al., PINK1/Parkin-Mediated Mitophagy Is Dependent on VDAC1 and p62/SQSTM1, Nature Cell Biology 2010 (2010)](https://doi.org/10.1038/ncb2012)

[Sanz et al., The Atypical PKC-Interacting Protein p62 Channels NF-κB Activation by the IL-1–TRAF6 Pathway, EMBO J 2000 (2000)](https://doi.org/10.1093/emboj/19.7.1576)

[Komatsu et al., The Selective Autophagy Substrate p62 Activates the Stress Responsive Transcription Factor Nrf2, Nature Cell Biology 2010 (2010)](https://doi.org/10.1038/ncb2021)

[Du et al., Emerging Role of p62/Sequestosome-1 in the Pathogenesis of Alzheimer's Disease, Progress in Neurobiology 2012 (2012)](https://doi.org/10.1016/j.pneurobio.2011.11.004)

Yilmaz et al., Investigating p62 Concentrations in CSF of Patients with Dementia, Brain Sciences 2022 (2022)

[Haack et al., Absence of the Autophagy Adaptor SQSTM1/p62 Causes Childhood-Onset Neurodegeneration, Am J Hum Genet 2016 (2016)](https://doi.org/10.1016/j.ajhg.2016.06.026)

[Unknown, Ma & Bhatt, Selective Autophagy Receptor p62/SQSTM1, a Pivotal Player in Stress and Aging, Frontiers in Cell and Developmental Biology 2022 (2022)](https://doi.org/10.3389/fcell.2022.793328)

Pathway Diagram

Mermaid diagram (expand to render)

Pathway Diagram

The following diagram shows the key molecular relationships involving p62/SQSTM1 (Sequestosome-1) discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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📊 Evidence Profile Foundational

Evidence Balance

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Certainty

60%

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Outgoing

40

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📗 Cite This Artifact

p62/SQSTM1 (Sequestosome-1)

Introduction

Overview

Introduction

Overview

Structure and Domains

Key Functional Domains

Structural Organization for Cargo Recognition

Functions in the Nervous System

Selective Autophagy Receptor

Mitophagy

NF-κB Signaling

Nrf2-Keap1 Oxidative Stress Response

Role in Neurodegenerative Diseases

Alzheimer's Disease

ALS and Frontotemporal Dementia

Parkinson's Disease and Lewy Body Dementia

Huntington's Disease

Childhood-Onset Neurodegeneration

Therapeutic Implications

p62 as a Drug Target

Biomarker Applications

See Also

External Links

Brain Atlas Resources

Background

References

Pathway Diagram

Pathway Diagram

💬 Discussion