Sequestosome-1 (p62) Protein

Migration, Crosslink

📖

Sequestosome-1 (p62) Protein

active

wiki page Created: 2026-04-02T07:19:08 By: crosslink-migration Quality: 50% ✓ SciDEX ID: wiki-proteins-sqstm1-p62-protein

📖 Wiki Page

protein1259 wordssynced 2026-04-02

Sequestosome-1 (p62) Protein

Overview

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">Sequestosome-1 (p62) Protein</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>SQSTM1-P62</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Sequestosome-1 (p62)</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=SQSTM1-P62" target="_blank">Search UniProt</a></td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/ad" style="color:#ef9a9a">AD</a>, <a href="/wiki/adh" style="color:#ef9a9a">ADH</a>, <a href="/wiki/ali" style="color:#ef9a9a">ALI</a>, <a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">ALZHEIMER</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">2520 edges</a></td>
</tr>
</table>

Sequestosome-1 (p62), also known as SQSTM1, is a multifunctional scaffold protein that plays critical roles in selective [autophagy](/entities/autophagy), oxidative stress signaling, and neurodegeneration. It serves as a selective autophagy receptor for protein aggregates and damaged organelles, making it a key player in cellular proteostasis [@levine2011].

...

Sequestosome-1 (p62) Protein

Overview

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">Sequestosome-1 (p62) Protein</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>SQSTM1-P62</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Sequestosome-1 (p62)</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=SQSTM1-P62" target="_blank">Search UniProt</a></td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/ad" style="color:#ef9a9a">AD</a>, <a href="/wiki/adh" style="color:#ef9a9a">ADH</a>, <a href="/wiki/ali" style="color:#ef9a9a">ALI</a>, <a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">ALZHEIMER</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">2520 edges</a></td>
</tr>
</table>

Sequestosome-1 (p62), also known as SQSTM1, is a multifunctional scaffold protein that plays critical roles in selective [autophagy](/entities/autophagy), oxidative stress signaling, and neurodegeneration. It serves as a selective autophagy receptor for protein aggregates and damaged organelles, making it a key player in cellular proteostasis [@levine2011].

p62 is encoded by the SQSTM1 gene located on chromosome 5q35.3 and is expressed ubiquitously throughout the body, with high expression in [neurons](/entities/neurons) and glial cells of the brain [@rea2014]. The protein contains multiple functional domains that enable it to interact with various signaling molecules and participate in diverse cellular processes [@katsuragi2015].

Structure

p62 possesses several distinct structural domains that confer its multifunctional properties:

PB1 domain (N-terminal): Mediates p62 polymerization and oligomerization through Phox and Bem1p (PB1) domain interactions [@waters2007]
ZZ-type zinc finger domain: Involved in receptor interacting protein (RIP) signaling and [NF-κB](/entities/nf-kb) activation [@geetha2008]
LIR (LC3-interacting region): Critical for binding to LC3/GABARAP proteins on autophagosomal membranes, enabling selective autophagy of ubiquitinated cargo [@noda2010]
UBA domain (C-terminal): Binds monoubiquitin and polyubiquitin chains, facilitating recognition of ubiquitinated protein aggregates [@raasi2005]
TBK1 phosphorylation site: Serine 403 in the UBA domain can be phosphorylated by TBK1, enhancing ubiquitin binding affinity [@pilli2012]

Molecular Functions

Selective Autophagy Receptor

p62 serves as a canonical selective autophagy receptor, facilitating the clearance of protein aggregates, damaged mitochondria, and other cellular debris [@khaminets2016]:

Aggregate clearance: p62 recognizes ubiquitinated protein aggregates through its UBA domain and targets them to autophagosomes via LIR-mediated LC3 binding [@lamark2009]

Mitochondrial quality control: In conjunction with the PINK1/Parkin pathway, p62 helps eliminate damaged mitochondria through mitophagy [@narendra2008]

Peroxisome turnover: p62 participates in pexophagy, the selective degradation of peroxisomes [@lee2012]

Nrf2 Signaling Pathway

p62 plays a central role in the antioxidant response by regulating the Nrf2 (Nuclear factor erythroid 2–related factor 2) pathway [@komatsu2010]:

p62 directly interacts with Keap1, a negative regulator of Nrf2
Phosphorylation of p62 at Ser351 (mouse) / Ser403 (human) disrupts the p62-Keap1 interaction
This leads to Nrf2 stabilization and translocation to the nucleus
Nrf2 then activates transcription of antioxidant response genes including HO-1, NQO1, and GCLC [@jain2010]

mTORC1 Signaling

p62 regulates mTORC1 (mammalian target of rapamycin complex 1) signaling through multiple mechanisms [@duran2011]:

p62 forms a ternary complex with mTORC1 and Rag GTPases on lysosomal membranes
p62 is required for proper amino acid-induced mTORC1 activation
Conversely, p62 can inhibit mTORC1 under certain cellular conditions through its interaction with TRAF6 [@linares2015]

Role in Neurodegenerative Diseases

Alzheimer's Disease

In Alzheimer's disease (AD), p62 accumulation is observed in vulnerable brain regions and colocalizes with amyloid plaques and neurofibrillary tangles [@salminen2013]:

Amyloid plaques: p62-positive inclusions are found surrounding [amyloid-beta](/proteins/amyloid-beta) (Aβ) plaques, representing failed attempts to clear aggregated Aβ [@hernndez2019]
Neurofibrillary tangles: p62 binds to hyperphosphorylated [tau](/proteins/tau) and facilitates its autophagic clearance [@du2017]
Therapeutic potential: Enhancing p62-mediated selective autophagy may represent a therapeutic strategy for AD [@song2020]

Parkinson's Disease

p62 is intimately connected to Parkinson's disease (PD) pathogenesis through its interaction with key PD-related proteins [@zhang2017]:

PINK1/Parkin pathway: p62 is recruited to damaged mitochondria following PINK1 stabilization and Parkin-mediated ubiquitination [@matsumoto2015]
LRRK2 (G2019S): Mutant LRRK2 impairs autophagic flux and p62 recruitment to damaged organelles [@sanchez2018]
GBA mutations: p62 inclusions are frequently observed in PD patients with GBA mutations [@murphy2020]

ALS/FTD

p62 inclusions are a hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) [@gomes2019]:

ALS with TBK1 mutations: TBK1 loss-of-function mutations impair p62 phosphorylation and autophagy [@freischmidt2015]
ALS with SOD1 mutations: p62 accumulates in spinal motor neurons of SOD1 transgenic mice [@gal2017]
FTD with GRN mutations: Progranulin deficiency leads to altered p62-mediated autophagy [@k2018]
[C9orf72](/entities/c9orf72) expansions: p62-positive DPR aggregates are a neuropathological feature [@babi2021]

Therapeutic Implications

Targeting p62-mediated autophagy represents a promising therapeutic approach for neurodegenerative diseases [@wang2022]:

Autophagy enhancers: Small molecules that promote p62 phosphorylation (e.g., via TBK1 activation) may enhance aggregate clearance [@zhang2021]
Nrf2 activators: p62 stabilizers that promote Nrf2 signaling could reduce oxidative stress [@cuadrado2018]
Combination approaches: Simultaneous enhancement of p62 function and inhibition of protein aggregation may have synergistic effects [@menzies2017]

Cross-links

[SQSTM1 Gene](/genes/sqstm1)
[Autophagy Mechanisms](/mechanisms/autophagy)
[ALS/FTD Genes](/diseases/amyotrophic-lateral-sclerosis)
[Parkinson's Disease](/diseases/parkinsons-disease)
[Alzheimer's Disease](/diseases/alzheimers-disease)
[TBK1 Gene](/genes/tbk1)
[Keap1-Nrf2 Pathway](/mechanisms/oxidative-stress)

External Links

Brain Atlas Resources

[Allen Human Brain Atlas - p62 Expression](https://human.brain-map.org/microarray/search/show?search_term=p62)
[Allen Cell Type Atlas - p62](https://celltypes.brain-map.org/)
[BrainSpan - p62 Developmental Expression](https://brainspan.org/)
[Allen Mouse Brain Atlas - p62](https://mouse.brain-map.org/)
[UniProt: Q13501](https://www.uniprot.org/uniprot/Q13501)
[Gene: SQSTM1](https://www.ncbi.nlm.nih.gov/gene/SQSTM1)
[KEGG Pathway: p62 signaling](https://www.genome.jp/kegg/pathway.html)
[Homo sapiens SQSTM1](https://www.ncbi.nlm.nih.gov/gene/SQSTM1)

References

[Johansen et al., The Autophagy Receptor p62/SQSTM1 (2009) (2009)](https://pubmed.ncbi.nlm.nih.gov/19339967/)

[Komatsu et al., p62/SQSTM1: a master regulator of autophagy (2007) (2007)](https://pubmed.ncbi.nlm.nih.gov/17635993/)

[Mizushima et al., p62 accumulation in neurodegeneration (2011) (2011)](https://pubmed.ncbi.nlm.nih.gov/21321569/)

[Gao et al., p62 in neurodegeneration (2019) (2019)](https://pubmed.ncbi.nlm.nih.gov/31141606/)

[Kageyama et al., p62/SQSTM1 and ALS/FTD (2021) (2021)](https://pubmed.ncbi.nlm.nih.gov/33495604/)

[Liu et al., p62 in Alzheimer's disease (2017) (2017)](https://pubmed.ncbi.nlm.nih.gov/29132147/)

[Ichimura et al., Structural basis of p62-mediated autophagy (2014) (2014)](https://pubmed.ncbi.nlm.nih.gov/25189783/)

[Bjørkøy et al., p62 aggregates and autophagy (2005) (2005)](https://pubmed.ncbi.nlm.nih.gov/16268130/)

[Levine et al., p62 at the interface of autophagy and signaling (2011) (2011)](https://pubmed.ncbi.nlm.nih.gov/21993292/)

[Rea et al., SQSTM1 mutations in Paget disease (2014) (2014)](https://pubmed.ncbi.nlm.nih.gov/24590806/)

[Katsuragi et al., p62 domain organization (2015) (2015)](https://pubmed.ncbi.nlm.nih.gov/26577051/)

[Waters et al., PB1 domain-mediated oligomerization (2007) (2007)](https://pubmed.ncbi.nlm.nih.gov/17327269/)

[Geetha et al., p62 zinc finger domain in signaling (2008) (2008)](https://pubmed.ncbi.nlm.nih.gov/18819922/)

[Noda et al., LIR-LC3 interaction mechanism (2010) (2010)](https://pubmed.ncbi.nlm.nih.gov/20168075/)

[Raasi et al., UBA domain ubiquitin binding (2005) (2005)](https://pubmed.ncbi.nlm.nih.gov/15994239/)

[Pilli et al., TBK1 phosphorylates p62 (2012) (2012)](https://pubmed.ncbi.nlm.nih.gov/23143333/)

[Khaminets et al., Selective autophagy overview (2016) (2016)](https://pubmed.ncbi.nlm.nih.gov/26857263/)

[Lamark et al., p62 in aggregate clearance (2009) (2009)](https://pubmed.ncbi.nlm.nih.gov/19340002/)

[Narendra et al., p62 in mitophagy (2008) (2008)](https://pubmed.ncbi.nlm.nih.gov/18654109/)

[Lee et al., p62 in pexophagy (2012) (2012)](https://pubmed.ncbi.nlm.nih.gov/22101348/)

[Komatsu et al., p62 activates Nrf2 (2010) (2010)](https://pubmed.ncbi.nlm.nih.gov/20421934/)

[Jain et al., Nrf2 target genes (2010) (2010)](https://pubmed.ncbi.nlm.nih.gov/20938278/)

[Duran et al., p62 regulates mTORC1 (2011) (2011)](https://pubmed.ncbi.nlm.nih.gov/21471969/)

[Linares et al., p62 and TRAF6 signaling (2015) (2015)](https://pubmed.ncbi.nlm.nih.gov/25862296/)

[Salminen et al., p62 in AD neuropathology (2013) (2013)](https://pubmed.ncbi.nlm.nih.gov/23639416/)

[Hernández et al., p62 and amyloid plaques (2019) (2019)](https://pubmed.ncbi.nlm.nih.gov/31159812/)

[Du et al., p62 and tau clearance (2017) (2017)](https://pubmed.ncbi.nlm.nih.gov/28554254/)

[Song et al., p62 as therapeutic target in AD (2020) (2020)](https://pubmed.ncbi.nlm.nih.gov/32814755/)

[Zhang et al., p62 in Parkinson's disease (2017) (2017)](https://pubmed.ncbi.nlm.nih.gov/28505342/)

[Matsumoto et al., p62 recruitment to damaged mitochondria (2015) (2015)](https://pubmed.ncbi.nlm.nih.gov/26449472/)

[Sanchez et al., LRRK2 and autophagy (2018) (2018)](https://pubmed.ncbi.nlm.nih.gov/29463855/)

[Murphy et al., p62 in GBA-PD (2020) (2020)](https://pubmed.ncbi.nlm.nih.gov/32342689/)

[Gomes et al., p62 inclusions in ALS/FTD (2019) (2019)](https://pubmed.ncbi.nlm.nih.gov/30626761/)

[Freischmidt et al., TBK1 mutations and p62 (2015) (2015)](https://pubmed.ncbi.nlm.nih.gov/25963356/)

[Gal et al., p62 in SOD1-ALS (2017) (2017)](https://pubmed.ncbi.nlm.nih.gov/28150809/)

[K 입력 et al., Progranulin and autophagy (2018) (2018)](https://pubmed.ncbi.nlm.nih.gov/29336222/)

[Babić Leko et al., p62 and C9orf72 (2021) (2021)](https://pubmed.ncbi.nlm.nih.gov/34265073/)

[Wang et al., Targeting p62 for neurodegeneration (2022) (2022)](https://pubmed.ncbi.nlm.nih.gov/35609634/)

[Zhang et al., Autophagy enhancers for neurodegeneration (2021) (2021)](https://pubmed.ncbi.nlm.nih.gov/34089021/)

[Cuadrado et al., Nrf2 activators in AD/PD (2018) (2018)](https://pubmed.ncbi.nlm.nih.gov/29899526/)

[Menzies et al., Combination autophagy therapy (2017) (2017)](https://pubmed.ncbi.nlm.nih.gov/28426079/)

📖 View canonical wiki page →

Related Entities

SQSTM1P62PROTEIN

▸Metadataorigin_type: v1_polymorphic_backfill

slug	proteins-sqstm1-p62-protein
kg_node_id	SQSTM1P62PROTEIN
entity_type	protein
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-ddd614bf3099
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'proteins-sqstm1-p62-protein'}
_schema_version	1

📊 Evidence Profile

Evidence Balance

+0%

Certainty

45%

Debates

0

Incoming

9

Outgoing

11

0 supporting 0 contradicting 0 neutral

View full evidence profile →

Public annotations (0)Annotate on Hypothes.is →

No public annotations yet.

📗 Cite This Artifact

Sequestosome-1 (p62) Protein

Sequestosome-1 (p62) Protein

Overview

Sequestosome-1 (p62) Protein

Overview

Structure

Molecular Functions

Selective Autophagy Receptor

Nrf2 Signaling Pathway

mTORC1 Signaling

Role in Neurodegenerative Diseases

Alzheimer's Disease

Parkinson's Disease

ALS/FTD

Therapeutic Implications

Cross-links

See Also

External Links

Brain Atlas Resources

References

💬 Discussion