p62/SQSTM1

p62/SQSTM1

Introduction

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">p62/SQSTM1</th>
</tr>
<tr>
<td class="label">Gene</td>
<td>[sqstm1](/genes/sqstm1)</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>[Q13501](https://www.uniprot.org/uniprot/Q13501)</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~62 kDa</td>
</tr>
<tr>
<td class="label">Amino Acids</td>
<td>440</td>
</tr>
<tr>
<td class="label">Subcellular Localization</td>
<td>Cytoplasm, autophagosomes, protein aggregates, nucleus</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>Selective autophagy receptors (SARs)</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">ALZHEIMER</a>, <a href="/wiki/alzheimer's-disease" style="color:#ef9a9a">ALZHEIMER'S DISEASE</a>, <a href="/wiki/amyotrophic-lateral-sclerosis" style="color:#ef9a9a">AMYOTROPHIC LATERAL SCLEROSIS</a>, <a href="/wiki/ataxia" style="color:#ef9a9a">ATAXIA</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">2336 edges</a></td>
</tr>
</table>

P62 Sqstm1 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/SQSTM1

Introduction

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">p62/SQSTM1</th>
</tr>
<tr>
<td class="label">Gene</td>
<td>[sqstm1](/genes/sqstm1)</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>[Q13501](https://www.uniprot.org/uniprot/Q13501)</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~62 kDa</td>
</tr>
<tr>
<td class="label">Amino Acids</td>
<td>440</td>
</tr>
<tr>
<td class="label">Subcellular Localization</td>
<td>Cytoplasm, autophagosomes, protein aggregates, nucleus</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>Selective autophagy receptors (SARs)</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">ALZHEIMER</a>, <a href="/wiki/alzheimer's-disease" style="color:#ef9a9a">ALZHEIMER'S DISEASE</a>, <a href="/wiki/amyotrophic-lateral-sclerosis" style="color:#ef9a9a">AMYOTROPHIC LATERAL SCLEROSIS</a>, <a href="/wiki/ataxia" style="color:#ef9a9a">ATAXIA</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">2336 edges</a></td>
</tr>
</table>

P62 Sqstm1 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, encoded by the [sqstm1](/genes/sqstm1) gene (sequestosome 1), is a multifunctional scaffold protein and the prototypical selective [autophagy](/mechanisms/autophagy-lysosome-neurodegeneration) receptor. It plays a central role in targeting ubiquitinated protein aggregates, damaged [mitochondrial-dynamics](/entities/mitochondrial-dynamics), and invading pathogens for autophagic degradation ([Pankiv et al., 2007](https://pubmed.ncbi.nlm.nih.gov/17580304/)). p62 is a critical component of the cellular protein quality control machinery and serves as a signaling hub connecting the [ubiquitin-proteasome-system](/mechanisms/ubiquitin-proteasome-system), selective [autophagy](/entities/autophagy), [nf-kb](/entities/nf-kb) signaling, and the Keap1-Nrf2 antioxidant response ([Komatsu et al., 2010](https://pubmed.ncbi.nlm.nih.gov/20404107/)). Mutations in SQSTM1 cause familial [als](/diseases/amyotrophic-lateral-sclerosis), [ftd](/diseases/frontotemporal-dementia), and Paget's disease of bone, while p62-positive inclusions are a ubiquitous pathological hallmark found in nearly all major neurodegenerative diseases, including [alzheimers](/diseases/alzheimers-disease), [parkinsons](/diseases/parkinsons-disease), [huntington-pathway](/mechanisms/huntington-pathway), and ALS-FTD ([Kuusisto et al., 2001](https://pubmed.ncbi.nlm.nih.gov/11739574/)). [@refa]

Structure and Domains

p62 is a 440-amino acid, 62 kDa protein with a modular multi-domain architecture that enables its diverse functions ([Lamark et al., 2017](https://pubmed.ncbi.nlm.nih.gov/28404599/)): [@refb]

Key Functional Domains

• PB1 (Phox and Bem1) domain (residues 3-102): Mediates self-oligomerization into helical filaments and hetero-oligomerization with other PB1 domain-containing proteins (atypical PKCs, NBR1, MEK5). PB1-mediated polymerization is essential for p62 body formation and efficient cargo sequestration
• ZZ (zinc finger) domain (residues 122-167): Binds N-end rule substrates and RIP1 kinase, connecting p62 to [nf-kb](/entities/nf-kb) inflammatory signaling
• TB (TRAF6-binding) domain (residues 225-250): Recruits TRAF6 E3 ligase, activating [nf-kb](/entities/nf-kb) signaling in response to inflammatory stimuli
• LIR (LC3-interacting region) motif (residues 335-341): A short WXXL motif (DDDWTHL in human p62) that directly binds LC3/GABARAP proteins on the autophagosome membrane, tethering cargo to the autophagy machinery. Phosphorylation at Ser349 (human) by [TBK1[/proteins/[TBK1](/proteins/TBK1) enhances LIR-LC3 binding affinity
• KIR (Keap1-interacting region) (residues 346-359): Competes with Nrf2 for Keap1 binding, activating the Nrf2 [oxidative-stress](/mechanisms/oxidative-stress) response when p62 accumulates
• UBA (ubiquitin-associated) domain (residues 386-440): Binds mono- and polyubiquitin chains (K48 and K63-linked), recognizing ubiquitinated cargo destined for degradation

Normal Function

Selective Autophagy Receptor

p62's primary function in the nervous system is as a selective autophagy receptor — a molecular bridge between ubiquitinated cargo and the autophagosome ([Johansen & Lamark, 2011](https://pubmed.ncbi.nlm.nih.gov/21258367/)):

Signaling Hub Functions

Beyond autophagy, p62 integrates multiple signaling pathways:

• [nf-kb](/entities/nf-kb) activation: Through TRAF6 and RIP1 recruitment, p62 activates pro-inflammatory [nf-kb](/entities/nf-kb) signaling in response to IL-1, TNF-alpha, and NGF
• Nrf2 antioxidant response: Accumulated p62 sequesters Keap1, releasing [nrf2](/proteins/nrf2) to translocate to the nucleus and activate antioxidant gene expression ([Komatsu et al., 2010](https://pubmed.ncbi.nlm.nih.gov/20404107/))
• mTORC1 regulation: p62 recruits mTORC1 to lysosomal membranes via Raptor binding, promoting [mtor-neurodegeneration](/mechanisms/mtor-neurodegeneration) activation and anabolic signaling
• [apoptosis](/mechanisms/apoptosis) modulation: Through interactions with caspase-8 and polyubiquitinated proteins

Aggrephagy and Mitophagy

p62 is critical for two forms of selective autophagy particularly relevant to neurodegeneration:

• Aggrephagy: Clearance of misfolded protein aggregates — p62 colocalizes with and mediates degradation of [tau](/proteins/tau)[/proteins/[tau-protein](/proteins/tau) tangles, [alpha-synuclein](/proteins/alpha-synuclein) aggregates, [huntingtin](/proteins/huntingtin) polyQ inclusions, and [tdp-43](/proteins/tdp-43) aggregates
• [mitophagy](/mechanisms/mitophagy): p62 binds ubiquitinated mitochondrial outer membrane proteins (tagged by [pink1-protein](/proteins/pink1-protein)/[parkin](/proteins/parkin) and recruits autophagosomes for damaged mitochondria clearance

Role in Neurodegenerative Diseases

ALS and FTD

Mutations in SQSTM1 account for approximately 1-3% of familial [als](/diseases/amyotrophic-lateral-sclerosis) and ~3% of familial [ftd](/diseases/frontotemporal-dementia), supporting the concept of an ALS-FTD continuum ([Fecto et al., 2011](https://pubmed.ncbi.nlm.nih.gov/21944778/)):

• P392L mutation: The most common SQSTM1 mutation, located in the UBA domain, impairs ubiquitin binding and cargo recognition. Also causes Paget's disease of bone
• LIR domain mutations: Disrupt LC3 binding, preventing autophagic targeting of cargo
• Pathogenic mechanisms: ALS-FTLD-linked mutations disrupt selective autophagy and the Nrf2 anti-oxidative stress pathway, leading to accumulation of [tdp-43](/proteins/tdp-43) and [sod1-protein](/proteins/sod1-protein) aggregates ([Goode et al., 2016](https://pubmed.ncbi.nlm.nih.gov/27545679/))
• p62 inclusions: p62-positive, ubiquitin-positive cytoplasmic inclusions are a hallmark pathological finding in ALS motor [neurons](/entities/neurons) and FTD frontal [cortex](/brain-regions/cortex) [neurons](/entities/neurons)
• Dosage sensitivity: Both loss-of-function (impaired autophagy) and gain-of-function (toxic aggregation) mechanisms contribute to disease

Alzheimer's Disease

p62 is found in neurofibrillary tangles and is associated with [Amyloid-Beta](/proteins/amyloid-beta) pathology in [AD]:

• p62 colocalizes with hyperphosphorylated [tau](/proteins/tau) in neurofibrillary tangles
• Reduced p62 expression in AD brain correlates with impaired autophagic clearance of tau]
• p62 mediates selective autophagic degradation of phosphorylated tau]
• [apoe](/proteins/apoe-protein) ε4 genotype is associated with reduced p62 expression and impaired autophagy

Parkinson's Disease

p62 is a component of Lewy bodies in [PD]:

• p62 colocalizes with [alpha-synuclein](/proteins/alpha-synuclein) in Lewy bodies and Lewy neurites
• p62 mediates autophagic degradation of [alpha-synuclein](/proteins/alpha-synuclein) aggregates
• [pink1-protein](/proteins/pink1-protein)/[parkin](/proteins/parkin)-dependent [mitophagy](/mechanisms/mitophagy) requires p62 for ubiquitin-dependent recruitment of autophagosomes to damaged mitochondria
• Impaired p62 function exacerbates [alpha-synuclein](/proteins/alpha-synuclein) accumulation and [dopaminergic-neurodegeneration](/mechanisms/dopaminergic-neurodegeneration)

Huntington's Disease

In HD, p62 participates in the selective autophagic clearance of mutant [huntingtin](/proteins/huntingtin) polyglutamine aggregates. p62-positive inclusions are found in [huntingtin](/proteins/huntingtin) aggregates, and upregulation of p62-mediated autophagy is a potential therapeutic strategy.

Childhood-Onset Neurodegeneration

Complete loss of SQSTM1/p62 function causes a severe childhood-onset neurodegenerative syndrome with ataxia, dystonia, gaze palsy, and cognitive decline, demonstrating the essential role of p62 in neuronal homeostasis ([Haack et al., 2016](https://pubmed.ncbi.nlm.nih.gov/27545679/)).

As a Pathological Marker

p62-positive inclusions are among the most widely used pathological markers in neurodegenerative disease diagnosis:

• p62 immunohistochemistry reliably identifies [tdp-43](/proteins/tdp-43)-positive and ubiquitin-positive inclusions in ALS-FTLD
• p62 staining is used in neuropathological staging of Lewy body diseases, [tauopathies](/mechanisms/tauopathies), and polyglutamine diseases
• Accumulation of p62 indicates impaired autophagic flux, regardless of the primary pathological protein

Therapeutic Targeting

Modulation of p62 function is an active area of therapeutic research:

• [autophagy](/mechanisms/autophagy-lysosome-neurodegeneration) enhancers: Rapamycin and [mtor-neurodegeneration](/mechanisms/mtor-neurodegeneration) inhibitors upregulate p62-dependent autophagy and reduce aggregate burden in preclinical models
• Trehalose: A natural disaccharide that enhances autophagy and reduces [protein-aggregation](/mechanisms/protein-aggregation), partly through p62 upregulation
• Small molecule p62 activators: Compounds that enhance p62-LC3 or p62-ubiquitin interactions to boost selective autophagy
• Nrf2 pathway activation: p62-Keap1 interaction mimetics to activate antioxidant responses
• Gene therapy: AAV-mediated SQSTM1 overexpression in preclinical ALS models

See Also

• [parkin](/proteins/parkin)
• [pink1-protein](/proteins/pink1-protein)
• [sod1-protein](/proteins/sod1-protein)
• [tdp-43](/proteins/tdp-43)

External Links

• [UniProt — SQSTM1 (Q13501)](https://www.uniprot.org/uniprot/Q13501)
• [NCBI Gene — SQSTM1](https://www.ncbi.nlm.nih.gov/gene/8878)
• [OMIM — SQSTM1](https://omim.org/entry/601530)
• [Allen Brain Atlas — SQSTM1](https://human.brain-map.org/microarray/search/show?search_term=SQSTM1)

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 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

Pathway Diagram

The following diagram shows the key molecular relationships involving p62/SQSTM1 discovered through SciDEX knowledge graph analysis: