p62 - Sequestosome 1 (SQSTM1)

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)

<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>

<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:

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]

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]

• 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

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.

See Also

• [Autophagy](/mechanisms/autophagy)
• [LC3](/proteins/lc3)
• [NRF2](/proteins/nrf2)
• [KEAP1](/proteins/keap1)
• [Protein Aggregation](/mechanisms/protein-aggregation)
• [Ubiquitin-Proteasome System](/mechanisms/ubiquitin-proteasome-system)

References

Pathway Diagram

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

Pathway Diagram

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