p62 - Sequestosome 1 (SQSTM1)

📖 Wiki Page

protein1100 wordssynced 2026-04-02

p62 - Sequestosome 1 (SQSTM1)

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">p62 - Sequestosome 1 (SQSTM1)</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>P62</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>p62 - Sequestosome 1 (SQSTM1)</td>
</tr>
<tr>
<td class="label">Type</td>
<td>Protein</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/?query=P62" target="_blank">Search UniProt</a></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 - Sequestosome 1 (SQSTM1)

<div style="float: right; margin: 0 0 1em 1em; width: 300px; border: 1px solid #a0a0a0; padding: 10px; background-color: #f8f8f8; font-size: 0.9em;">
<div style="background-color: #d0e8f0; padding: 5px; font-weight: bold; text-align: center;">p62 / SQSTM1</div>
<div style="padding: 5px;">
<b>Full Name</b>: Sequestosome 1<br/>
<b>Also Known As</b>: p62, SQSTM1, A170, ZIP<br/>
<b>Gene</b>: [SQSTM1](/genes/sqstm1)<br/>
<b>UniProt ID</b>: [Q13501](https://www.uniprot.org/uniprot/Q13501)<br/>
<b>Molecular Weight</b>: 62 kDa<br/>
<b>Subcellular Location</b>: Cytoplasm, Autophagosome, Nucleus<br/>
<b>PDB Structures</b>: [3KB6](https://www.rcsb.org/structure/3KB6), [2K6Q](https://www.rcsb.org/structure/2K6Q)<br/>
</div>
</div>

Overview

Sequestosome 1 (p62/SQSTM1) is a multifunctional scaffold protein that serves as the primary [autophagy](/entities/autophagy) receptor for selective degradation of ubiquitinated protein aggregates. p62 bridges ubiquitinated cargo to [LC3](/proteins/lc3) on autophagosomal membranes, enabling the clearance of protein aggregates, damaged organelles, and pathogens through [autophagy](/mechanisms/autophagy).[@katsuragi2015][@johansen2011]

In neurodegenerative diseases, p62 accumulation in protein inclusions is a pathological hallmark, indicating impaired autophagic clearance. p62 is found in [Alzheimer's disease](/diseases/alzheimers-disease) neurofibrillary tangles, [Parkinson's disease](/diseases/parkinsons-disease) Lewy bodies, and [ALS/FTD](/diseases/amyotrophic-lateral-sclerosis) inclusions. Mutations in SQSTM1 cause familial Paget disease and are associated with ALS/FTD.[@lee2020]

Structure and Domains

p62 contains multiple interaction domains that enable its scaffold function:

PB1 Domain (N-terminal, 1-122): Mediates self-oligomerization through front-to-back interactions. Enables p62 to form helical filaments and phase-separated condensates that concentrate cargo for autophagy.
ZZ Zinc Finger Domain (122-195): Binds to [NEMO](/proteins/nemo) and [RIPK1](/proteins/ripk1), linking p62 to [NF-κB](/entities/nf-kb) signaling.
TB Domain (195-255): Involved in TRAF6 binding and NF-κB activation.
LIR Motif (LC3-Interacting Region, 321-342): The critical sequence (DDDWTHL) that binds to LC3/GABARAP family proteins on autophagosomal membranes. Phosphorylation of S403 and S405 enhances LC3 binding affinity.
KEAP1-Interacting Region (KIR, 347-356): Binds to [KEAP1](/proteins/keap1), competing with [NRF2](/proteins/nrf2) and activating antioxidant responses.
UBA Domain (C-terminal, 386-440): Ubiquitin-associated domain that binds polyubiquitin chains (preferentially K63-linked and K48-linked) on cargo proteins.[@lamark2013]

Phase Separation Properties

p62 undergoes liquid-liquid phase separation (LLPS) when it binds ubiquitinated proteins. The PB1-mediated oligomerization and UBA-ubiquitin interactions drive the formation of p62 condensates that recruit autophagy machinery. This process is enhanced by:[@zaffagnini2018]

Phosphorylation of S403 in the UBA domain
High local concentration of polyubiquitinated substrates
Autophagy inhibition (causing p62 accumulation)

Normal Function

Selective Autophagy

p62 is the primary autophagy receptor for aggregate clearance:

Cargo Recognition: UBA domain binds polyubiquitinated proteins

Condensate Formation: p62 oligomerizes and phase-separates with cargo

Autophagosome Targeting: LIR motif binds LC3-II on forming autophagosomes

Degradation: p62 and cargo are degraded in lysosomes[@kirkin2009]

Signaling Functions

Beyond autophagy, p62 regulates multiple signaling pathways:

NRF2 Activation: p62 competes with NRF2 for KEAP1 binding, activating antioxidant gene expression
NF-κB Signaling: Interacts with TRAF6 to promote IKK activation
mTORC1: Localizes mTORC1 to lysosomes for activation by amino acids
Caspase-8: Modulates extrinsic [apoptosis](/entities/apoptosis) pathways

Role in Neurodegeneration

Alzheimer's Disease

In [Alzheimer's disease](/diseases/alzheimers-disease), p62 pathology is prominent:

Neurofibrillary Tangles: p62 colocalizes with [tau](/proteins/tau) inclusions
Amyloid Response: p62 can bind [amyloid-β](/proteins/amyloid-beta) aggregates
Autophagy Impairment: p62 accumulation indicates defective autophagic flux
Neuroinflammation: p62 regulates microglial inflammatory responses[@salminen2011]

Reduced p62 expression accelerates [tau](/proteins/tau) pathology in mouse models, while p62 overexpression is protective.

Parkinson's Disease

In [Parkinson's disease](/diseases/parkinsons-disease):

Lewy Bodies: p62 is a component of [α-synuclein](/proteins/alpha-synuclein)-containing Lewy bodies
Mitophagy: p62 participates in clearance of damaged mitochondria
DJ-1 Interaction: p62 interacts with [DJ-1](/proteins/dj1) in oxidative stress response
NRF2 Activation: p62-mediated NRF2 activation is protective in PD models[@denton2015]

ALS and FTD

p62/SQSTM1 mutations are directly linked to neurodegeneration:

Genetic Mutations: SQSTM1 mutations cause ~5% of familial ALS cases
[TDP-43](/mechanisms/tdp-43-proteinopathy) Inclusions: p62 colocalizes with [TDP-43](/proteins/tdp-43) inclusions in ALS/FTD
Autophagy Defect: Mutant p62 has impaired cargo recognition or LC3 binding
Protein Aggregates: p62-positive inclusions are found in motor [neurons](/entities/neurons)[@teyssou2013]

Common SQSTM1 mutations in ALS include:

L341V: Disrupts UBA domain
D337E: Affects ubiquitin binding
P392L: Impairs autophagy

Huntington's Disease

In [Huntington's disease](/diseases/huntingtons):

Inclusion Bodies: p62 colocalizes with mutant [huntingtin](/proteins/huntingtin) inclusions
Aggregate Clearance: p62 promotes clearance of [huntingtin](/proteins/huntingtin) aggregates
NRF2 Activation: Protective effect through antioxidant gene induction

Therapeutic Targeting

Autophagy Enhancement

[mTOR](/mechanisms/mtor-signaling-pathway) Inhibitors: Rapamycin and derivatives enhance autophagy and p62-mediated clearance

[TFEB](/entities/tfeb) Activators: Promote lysosomal biogenesis and autophagic flux

[HDAC](/entities/hdac-enzymes) Inhibitors: Upregulate p62 expression

NRF2 Pathway Activation

p62 accumulation activates NRF2 through KEAP1 sequestration:

NRF2 Agonists: Dimethyl fumarate, sulforaphane activate antioxidant response
p62 Stabilizers: Compounds that increase p62 levels may benefit from NRF2 activation[@jiang2015]

Challenges

Temporal Specificity: p62 has both protective and potentially deleterious roles
Pathological Inclusions: p62 accumulation in aggregates may be maladaptive
Signaling Complexity: Multiple pathways converge on p62

Key Publications

[@katsuragi2015]: Bjørkøy G, et al. [p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death](https://doi.org/10.1083/jcb.200507002). J Cell Biol. 2005;171(4):603-614.

[@johansen2011]: Pankiv S, et al. [p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy](https://doi.org/10.1074/jbc.C800074200). J Biol Chem. 2007;282(33):24131-24145.

[@lee2020]: Rubino E, et al. [SQSTM1 mutations in frontotemporal lobar degeneration and amyotrophic lateral sclerosis](https://doi.org/10.1136/jnnp-2011-301839). J Neurol Neurosurg Psychiatry. 2012;83(4):370-377.

[@lamark2013]: Lamark T, et al. [Nucleation and elongation of autophagosomes by p62 and LC3](https://doi.org/10.1016/j.abb.2013.02.006). Arch Biochem Biophys. 2013;534(1):61-67.

[@zaffagnini2018]: Zaffagnini G, et al. [p62 filaments capture and present ubiquitinated cargos for autophagic degradation](https://doi.org/10.1083/jcb.201711199). J Cell Biol. 2018;217(4):1247-1263.

[@kirkin2009]: Kirkin V, et al. [A role for NBR1 in autophagosomal degradation of ubiquitinated substrates](https://doi.org/10.1016/j.molcel.2009.09.010). Mol Cell. 2009;33(4):505-516.

[@salminen2011]: Salminen A, et al. [Impaired autophagy and accumulation of protein aggregates in the elderly: a lesson from the SQSTM1/p62 gene](https://doi.org/10.1111/j.1474-9726.2011.00731.x). Aging Cell. 2012;11(2):187-193.

[@denton2015]: Denton D, et al. [Autophagy: a cellular and immune response against neurodegeneration](https://doi.org/10.1016/j.immuni.2015.09.018). Immunity. 2015;43(5):835-839.

[@teyssou2013]: Teyssou E, et al. [Mutations in SQSTM1 encoding p62 in amyotrophic lateral sclerosis: genetics and neuropathology](https://doi.org/10.1007/s00401-013-1166-2). Acta Neuropathol. 2013;125(4):511-522.

[@jiang2015]: Jiang T, et al. [p62 links autophagy and Nrf2 signaling](https://doi.org/10.1016/j.freeradbiomed.2015.01.034). Free Radic Biol Med. 2015;88(Pt B):199-204.

References

[Katsuragi et al., p62/SQSTM1 in autophagy and neurodegeneration (2015) (2015)](https://doi.org/10.1007/s00018-015-1913-3)

[Unknown, Johansen & Lamark, Selective autophagy of p62 (2011) (2011)](https://doi.org/10.1016/j.tcb.2011.08.002)

[Unknown, Lee & Coughlin, p62 in protein aggregation and disease (2020) (2020)](https://doi.org/10.1007/s00018-020-03467-1)

[Lamark T, et al, Nucleation and elongation of autophagosomes by p62 and LC3 (2013)](https://doi.org/10.1016/j.abb.2013.02.006)

[Zaffagnini G, et al, p62 filaments capture and present ubiquitinated cargos for autophagic degradation (2018)](https://doi.org/10.1083/jcb.201711199)

[Kirkin V, et al, A role for NBR1 in autophagosomal degradation of ubiquitinated substrates (2009)](https://doi.org/10.1016/j.molcel.2009.09.010)

[Salminen A, et al, Impaired autophagy and accumulation of protein aggregates in the elderly: a lesson from the SQSTM1/p62 gene (2011)](https://doi.org/10.1111/j.1474-9726.2011.00731.x)

[Denton D, et al, Autophagy: a cellular and immune response against neurodegeneration (2015)](https://doi.org/10.1016/j.immuni.2015.09.018)

[Teyssou E, et al, Mutations in SQSTM1 encoding p62 in amyotrophic lateral sclerosis: genetics and neuropathology (2013)](https://doi.org/10.1007/s00401-013-1166-2)

[Jiang T, et al, p62 links autophagy and Nrf2 signaling (2015)](https://doi.org/10.1016/j.freeradbiomed.2015.01.034)

Pathway Diagram

The following diagram shows key molecular relationships for p62 - Sequestosome 1 (SQSTM1) based on knowledge graph edges:

Mermaid diagram (expand to render)

Pathway Diagram

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

Mermaid diagram (expand to render)

📖 View canonical wiki page →

p62 - Sequestosome 1 (SQSTM1)

p62 - Sequestosome 1 (SQSTM1)

p62 - Sequestosome 1 (SQSTM1)

Overview

Structure and Domains

Phase Separation Properties

Normal Function

Selective Autophagy

Signaling Functions

Role in Neurodegeneration

Alzheimer's Disease

Parkinson's Disease

ALS and FTD

Huntington's Disease

Therapeutic Targeting

Autophagy Enhancement

NRF2 Pathway Activation

Challenges

Key Publications

See Also

References

Pathway Diagram

Pathway Diagram