SQSTM1 — Sequestosome 1 (p62)

SQSTM1 — Sequestosome 1 (p62)

Pathway Diagram

```mermaid
flowchart TD
SQSTM1_gene["SQSTM1<br/>Gene"]
SQSTM1_protein["SQSTM1/p62<br/>Protein"]
NFE2L2["NFE2L2/Nrf2<br/>Transcription Factor"]
autophagy["Autophagy<br/>Process"]
mitophagy["Mitophagy<br/>Process"]
lysophagy["Lysophagy<br/>Process"]
amyloid_beta["Amyloid Beta<br/>Protein"]
alpha_synuclein["alpha-synuclein<br/>Protein"]
ubiquitin["Ubiquitin<br/>Protein"]
lysosome["Lysosome<br/>Organelle"]
autophagosome["Autophagosome<br/>Formation"]
TLR4["TLR4<br/>Receptor"]
NFkB["NF-kappaB<br/>Pathway"]
ALS["Amyotrophic<br/>Lateral Sclerosis"]
lipotoxicity["Lipotoxicity<br/>Protection"]
lysosomal_damage["Lysosomal<br/>Damage"]

SQSTM1_gene -->|"encodes"| SQSTM1_protein
SQSTM1_protein -->|"activates"| NFE2L2
SQSTM1_protein -->|"regulates"| autophagy
SQSTM1_protein -->|"regulates"| mitophagy
SQSTM1_protein -->|"promotes"| lysophagy
SQSTM1_protein -->|"promotes"| autophagosome
SQSTM1_protein -->|"binds"| ubiquitin
SQSTM1_protein -->|"regulates"| lysosome
SQSTM1_protein -->|"interacts_with"| alpha_synuclein
SQSTM1_gene -->|"regulates"| amyloid_beta
amyloid_beta -->|"activates"| SQSTM1_gene
TLR4 -->|"activates"| SQSTM1_gene
NFkB -->|"regulates"| SQSTM1_gene
lysosomal_damage -->|"activates"| SQSTM1_protein
SQSTM1_protein -->|"protects_against"| lipotoxicity
SQSTM1_gene -->|"associated_with"| ALS

SQSTM1 — Sequestosome 1 (p62)

Pathway Diagram

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">SQSTM1 — Sequestosome 1 (p62)</th>
</tr>
<tr> [^5]
<td class="label">Symbol</td>
<td><strong>SQSTM1</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Sequestosome 1 (p62)</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>5q35.3</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/8878" target="_blank">8878</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000161011" target="_blank">ENSG00000161011</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://omim.org/entry/601530" target="_blank">601530</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q13501" target="_blank">Q13501</a></td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[ALS](/diseases/als), [PD](/diseases/parkinsons-disease), [AD](/diseases/alzheimers), [Paget's Disease](/diseases/paget)</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Brain, Liver, Muscle</td>
</tr>
<tr>
<th class="infobox-subheader" colspan="2">Key Mutations</th>
</tr>
<tr>
<td colspan="2" style="font-size:0.85em">P392L, A33V, K238E</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>

SQSTM1 — Sequestosome 1 (p62)

Overview

SQSTM1 (Sequestosome 1), also known as p62, is a gene located on chromosome 5q35.3 that encodes a critical scaffolding protein involved in autophagy, the cellular degradation system that clears misfolded proteins and damaged organelles. Mutations in SQSTM1 are associated with amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), Alzheimer's disease (AD), and Paget's disease of bone. The gene is catalogued as NCBI Gene ID [8878](https://www.ncbi.nlm.nih.gov/gene/8878) and OMIM [601530](https://omim.org/entry/601530).

Function

The SQSTM1 gene encodes p62/sequestosome-1, a multifunctional protein that serves as a master regulator of cellular proteostasis. p62 contains multiple domains that enable its diverse functions in protein quality control and signaling [@psqstm2014].

Domains and Structure

p62 contains several key functional domains:

Role in Autophagy

p62 is central to selective autophagy, a process that specifically targets damaged proteins and organelles for lysosomal degradation [@autophagy2019]:

Signaling Functions

Beyond autophagy, p62 participates in key signaling pathways:

• mTORC1 Signaling: p62 interacts with mTORC1 and regulates nutrient sensing
• NF-κB Signaling: p62 activates NF-κB, influencing inflammation and cell survival
• Nrf2 Activation: p62 stabilizes Nrf2, driving expression of antioxidant genes

Disease Associations

Amyotrophic Lateral Sclerosis (ALS)

SQSTM1 mutations were first linked to ALS in 2011, identifying missense mutations in patients with both familial and sporadic disease [@sequestration2011]. p62-positive inclusions are found in virtually all ALS cases, regardless of SQSTM1 mutation status.

Key features:

• Missense mutations (P392L most common) cause disease in multiple families
• p62 inclusions co-localize with TDP-43 in ALS motor neurons
• Impaired autophagy contributes to TDP-43 aggregation

Parkinson's Disease (PD)

p62 plays a complex role in PD pathogenesis:

• LRRK2 Connection: p62 interacts with LRRK2 and regulates its degradation [@interacts2018]
• Alpha-Synuclein Clearance: p62-mediated selective autophagy targets alpha-synuclein aggregates
• Mitochondrial Quality Control: p62 helps clear damaged mitochondria through mitophagy

Alzheimer's Disease (AD)

In AD, p62 dysfunction contributes to disease progression:

• Tau Clearance: p62 helps clear hyperphosphorylated tau through autophagy [@psqstm2020]
• Amyloid Clearance: p62-mediated autophagy contributes to Aβ degradation
• Synaptic Protection: p62 deficiency leads to increased synaptic loss

Paget's Disease of Bone

SQSTM1 mutations cause Paget's disease of bone (PDB), characterized by abnormal bone remodeling. This represents a connection between skeletal and neurological disease through the same gene.

Molecular Mechanisms

Autophagy-lysosome Pathway Dysfunction

In neurodegenerative diseases, p62 function becomes impaired:

Protein Aggregate Sequestration

p62 forms the core of cellular inclusions found in neurodegeneration:

• ALS: p62-positive inclusions in motor neurons
• PD: p62 in Lewy bodies with alpha-synuclein
• AD: p62 in neurofibrillary tangles with tau

Signaling Dysregulation

p62 mutations affect multiple signaling pathways:

• mTOR Hyperactivation: Impaired p62 leads to dysregulated mTORC1 signaling
• Chronic Inflammation: NF-κB activation contributes to neuroinflammation
• Oxidative Stress: Nrf2 dysregulation impairs antioxidant responses

Key Mutations

| Mutation | Position | Disease Association |
|----------|----------|---------------------|
| P392L | Pro392→Leu | ALS, PDB |
| A33V | Ala33→Val | ALS risk factor |
| K238E | Lys238→Glu | ALS, PD |

The P392L mutation is the most studied, affecting p62's ability to engage autophagy [@sequestration2011].

Therapeutic Implications

p62 is an attractive therapeutic target:

Key Publications

External Links

• NCBI Gene: [https://www.ncbi.nlm.nih.gov/gene/8878](https://www.ncbi.nlm.nih.gov/gene/8878)
• Ensembl: [https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000161011](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000161011)
• OMIM: [https://omim.org/entry/601530](https://omim.org/entry/601530)
• UniProt: [https://www.uniprot.org/uniprot/Q13501](https://www.uniprot.org/uniprot/Q13501)

See Also

• [Genes Index](/genes)
• [Proteins Index](/proteins)
• [Diseases Index](/diseases)
• [Mechanisms Index](/mechanisms)
• [ALS](/diseases/amyotrophic-lateral-sclerosis) — Amyotrophic Lateral Sclerosis
• [PD](/diseases/parkinsons-disease) — Parkinson's Disease
• [AD](/diseases/alzheimers-disease) — Alzheimer's Disease
• [Autophagy](/mechanisms/autophagy-lysosomal-pathway) — Cellular degradation pathways
• [Protein Aggregation](/mechanisms/protein-aggregation) — Aggregate formation mechanisms
• [LRRK2](/genes/lrrk2) — Leucine-rich repeat kinase 2

Brain Atlas Resources

• Allen Human Brain Atlas: [Expression data for SQSTM1](https://human.brain-map.org/microarray/search/show?search_term=SQSTM1)
• Allen Cell Type Atlas: [Cell type expression data](https://celltype.brain-map.org/)
• BrainSpan Atlas: [Developmental transcriptome data](https://www.brainspan.org/)

Recent Publications (2024-2026)

Recent research on SQSTM1/p62 has expanded our understanding of its role in neurodegeneration:

Structural Biology

PB1 Domain (N-terminal)

The PB1 (Phox and Bem1) domain is located at the N-terminus of p62 and serves as a critical module for protein-protein interactions. This domain mediates p62's ability to form higher-order oligomers through homotypic interactions, creating large signaling platforms [@bjorkoy2005]. The PB1 domain consists of a ubiquitin-like fold that interacts with the PB1 domain of other proteins including:

• Atypical PKC isoforms (aPKC, PKCζ): Involved in cell polarity and signaling
• MEKK3: Links p62 to MAP kinase signaling cascades
• ERK1/2: Extracellular signal-regulated kinases

ZZ Zinc Finger Domain

The ZZ domain is a zinc finger structure that mediates interactions with RING finger proteins and other zinc-binding domains. This domain is involved in:

• Binding to TRAF6, an E3 ubiquitin ligase crucial for NF-κB activation
• Interaction with p300/CBP transcriptional co-activators
• Regulation of histone acetylation states

LIR (LC3-Interacting Region)

The LIR is a compact 20-amino acid sequence that recognizes LC3/GABARAP proteins on the growing autophagosome membrane [@pankiv2007]. This region contains a consensus sequence:
[FW]-{ED}[WLF]-[ED][FW]-[IV]

The LIR undergoes a conformational change upon binding to LC3, converting from a disordered state to an α-helical structure [@ichimura2008]. This binding is critical for:

• Recruitment of ubiquitinated cargo to autophagosomes
• Incorporation of p62 itself into the autophagosome
• Formation of p62-LC3 positive feedback loops

UBA Domain (C-terminal)

The UBA (Ubiquitin-Associated) domain is located at the C-terminus and specifically recognizes polyubiquitin chains, particularly K63-linked and K27-linked chains that serve as signals for selective autophagy [@katsuragi2015]. The UBA domain:

• Binds mono- and polyubiquitin with low micromolar affinity
• Shows preference for K63-linked chains over K48-linked chains
• Undergoes conformational changes upon ubiquitin binding

p62 in Protein Quality Control

Ubiquitin-Proteasome System Coordination

p62 serves as a bridge between the ubiquitin-proteasome system (UPS) and autophagy [@protein2021]. While the UPS degrades individual misfolded proteins, autophagy removes larger aggregates that cannot be processed by the proteasome. p62 coordinates these pathways through:

This coordinated approach ensures comprehensive cellular proteostasis.

Aggresome Formation

p62 is a core component of aggresomes, cytoplasmic inclusion bodies that form when the UPS is overwhelmed [@zatloukal2009]. Aggresome formation involves:

• Microtubule-dependent transport of p62-positive aggregates to the microtubule organizing center (MTOC)
• Recruitment of histone deacetylase 6 (HDAC6) and ubiquitin
• Sequestration of damaged proteins for potential degradation

p62 in Neuroinflammation

NF-κB Signaling Regulation

p62 is a potent activator of NF-κB signaling, a pathway critical for inflammatory responses [@korolchuk2009]. The mechanism involves:

In the brain, chronic NF-κB activation contributes to neuroinflammation, a hallmark of neurodegenerative diseases.

Inflammasome Modulation

Beyond NF-κB, p62 regulates inflammasome complexes that process pro-inflammatory cytokines:

• p62 interacts with NLRP3 inflammasome components
• Autophagy of inflammasome components limits IL-1β production
• p62 deficiency leads to exaggerated inflammatory responses

p62 in Specific Neurodegenerative Diseases

Amyotrophic Lateral Sclerosis (ALS)

ALS is characterized by progressive motor neuron death and the presence of cytoplasmic inclusions containing TDP-43 [@watanabe2017]. p62 inclusions are found in:

• Sporadic ALS: 100% of cases
• Familial ALS with SQSTM1 mutations: Direct causation
• C9orf72 expansions: Co-localization with TDP-43

Parkinson's Disease (PD)

In PD, p62 interacts with several disease-related proteins:

• LRRK2: p62 regulates LRRK2 autophagy and is phosphorylated by LRRK2 [@interacts2018]
• α-Synuclein: p62-mediated autophagy clears aggregated α-synuclein
• PINK1/Parkin: p62 participates in mitophagy pathways

Alzheimer's Disease (AD)

p62 plays multiple roles in AD pathogenesis [@psqstm2020]:

• Tau clearance: p62 helps clear hyperphosphorylated tau through autophagy
• Aβ degradation: Autophagy mediated by p62 contributes to amyloid clearance
• Synaptic protection: p62 deficiency exacerbates synaptic loss in AD models

Frontotemporal Dementia (FTD)

FTD shares pathological features with ALS, including TDP-43 inclusions:

• p62-positive inclusions in FTD with motor neuron disease
• SQSTM1 mutations identified in FTD patients
• Overlap between ALS and FTD genetic landscapes

Therapeutic Targeting of p62

Autophagy-Enhancing Compounds

Several compounds enhance p62-mediated autophagy:

| Compound | Mechanism | Status |
|----------|-----------|--------|
| Rapamycin | mTORC1 inhibition | Preclinical |
| Trehalose | mTORC1-independent autophagy | Preclinical |
| Lithium | GSK-3β inhibition | Clinical trials |
| Carbamazepine | TPC2 inhibition | Phase II |
| Urolithin A | Mitophagy enhancement | Phase II/III [@jimenez2024] |

Nrf2 Activators

p62 stabilizes Nrf2, making Nrf2 activators therapeutically relevant:

• Bardoxolone methyl: Nrf2 activator, in trials for CKD
• Sulforaphane: Dietary Nrf2 activator
• Dimethyl fumarate: FDA-approved for MS, activates Nrf2

p62-Specific Approaches

Direct targeting of p62 is being explored:

• UBA domain stabilizers: Enhance ubiquitin binding
• LIR mimetics: Promote LC3 interaction
• Oligomerization modulators: Regulate aggregate formation

Model Systems for p62 Research

Mouse Models

• Sqstm1 knockout mice: Spontaneous neurodegeneration
• P392L knock-in mice: Modeling ALS/PDB mutations
• Conditional knockouts: Tissue-specific deletion

Cellular Models

• iPSC-derived neurons: Patient-specific disease modeling
• Motor neuron cultures: ALS-relevant studies
• Dopaminergic neurons: PD-relevant studies

Biochemical Studies

• Cryo-EM structures: Domain organization
• Ubiquitin chain analysis: Binding specificities
• LC3 interaction mapping: LIR motif studies

p62 as a Biomarker

Fluid Biomarkers

p62 levels in cerebrospinal fluid (CSF) and blood are being investigated as:

• Diagnostic markers: Differentiate disease types
• Progression markers: Track disease severity
• Treatment response: Monitor therapeutic efficacy

Imaging Biomarkers

PET ligands targeting p62 inclusions are in development:

• Labeled ubiquitin derivatives: Detect aggregate burden
• Small molecule probes: p62-specific imaging

Future Directions

Understanding the p62 Paradox

A key mystery remains: how does p62, a pro-autophagy protein, accumulate in inclusions in neurodegenerative diseases? Possible explanations include:

Therapeutic Implications

Resolving this paradox will guide therapeutic development:

• If p62 aggregation is protective → enhance aggregation
• If p62 aggregation is toxic → prevent aggregation or enhance clearance
• If autophagy is impaired → restore autophagic flux

Additional Clinical Perspectives

Diagnostic Considerations

SQSTM1 testing is recommended in cases of:

• Early-onset ALS (<50 years): Especially with bone involvement
• Familial neurodegeneration: With autosomal dominant or recessive patterns
• Atypical Parkinson's disease: Early onset with cognitive involvement
• Combined neurological and skeletal symptoms: Such as PDB with ALS/FTD

Genetic Counseling

For families with SQSTM1 variants:

• Autosomal dominant with incomplete penetrance: Not all carriers develop disease
• Variable expressivity: Different family members may have different phenotypes
• Anticipation: Not typically observed with SQSTM1
• Reproductive options: Preimplantation genetic testing available

Patient Management

Current recommendations for SQSTM1 carriers:

• Neurological monitoring: Regular assessment for motor/cognitive symptoms
• Bone density screening: Given PDB association
• Respiratory monitoring: For ALS progression
• Multidisciplinary care: Neurology, genetics, orthopedics coordination

Emerging Research Technologies

Single-Cell Analysis

Single-cell sequencing approaches are revealing:

• Cell-type specific vulnerability: Which neurons are first affected
• Microglial heterogeneity: Different activation states in disease
• Astrocyte responses: Reactive vs. supportive roles

Proteomics

Mass spectrometry-based proteomics has identified:

• p62 post-translational modifications: Phosphorylation, ubiquitination sites
• Interaction networks: New binding partners
• Aggregate composition: What's actually in inclusions

iPSC Disease Modeling

Patient-derived induced pluripotent stem cells offer:

• Isogenic controls: Mutation correction
• Differentiation protocols: Motor neurons, dopaminergic neurons
• Drug screening platforms: High-throughput testing

Conclusion

SQSTM1/p62 stands at the nexus of multiple neurodegenerative disease pathways. Its dual role in autophagy regulation and protein aggregate formation, combined with its signaling functions in NF-κB and Nrf2 pathways, makes it a critical node in cellular proteostasis. Understanding how this multifunctional protein contributes to disease pathogenesis will be essential for developing effective therapies for ALS, PD, AD, and related conditions.

The continuing identification of SQSTM1 mutations in diverse patient populations, combined with advances in model systems and therapeutic targeting, positions p62 as a promising target for future intervention strategies.

Pathway Diagram

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

Associated Diseases

• Als — associated with

• ALS — associated with

• Alzheimer — associated with

• Alzheimer's Disease — biomarker for

• Alzheimer'S Disease — biomarker for

• amyotrophic lateral sclerosis — associated with

• Amyotrophic Lateral Sclerosis — associated with

• dementia — associated with

• Dementia — associated with

• frontotemporal — associated with

• frontotemporal dementia — associated with

• Frontotemporal Dementia — associated with

• FRONTOTEMPORAL DEMENTIA — associated with

• Frontotemporal Lobar Degeneration — risk factor for

• Parkinson — associated with

• Parkinson's disease — associated with

Structure

AlphaFold DB provides a full-length predicted structure for SQSTM1 (UniProt [Q13501](https://www.uniprot.org/uniprotkb/Q13501/entry), model v6) with mean pLDDT 67.25. View the model at [AlphaFold DB](https://alphafold.ebi.ac.uk/entry/Q13501) or download the [PDB file](https://alphafold.ebi.ac.uk/files/AF-Q13501-F1-model_v6.pdb).

Domain and region confidence from per-residue pLDDT:

• Residues 2-50 (Interaction with LCK): mean pLDDT 79.4 (confident).
• Residues 3-102 (PB1): mean pLDDT 85.9 (confident).
• Residues 43-107 (Interaction with PRKCZ and dimerization): mean pLDDT 88.6 (confident).
• Residues 122-224 (Interaction with GABRR3): mean pLDDT 65.9 (low).
• Residues 170-220 (LIM protein-binding (LB)): mean pLDDT 44.7 (very low).
• Residues 264-390 (Disordered): mean pLDDT 45.6 (very low).
• Residues 269-440 (Interaction with NTRK1): mean pLDDT 56.2 (low).
• Residues 389-434 (UBA): mean pLDDT 87.8 (confident).

UniProt function annotation: Molecular adapter required for selective macroautophagy (aggrephagy) by acting as a bridge between polyubiquitinated proteins and autophagosomes (PubMed:15340068, PubMed:15953362, PubMed:16286508, PubMed:17580304, PubMed:20168092, PubMed:22017874, PubMed:22622177, PubMed:24128730, PubMed:28404643, PubMed:29343546, PubMed:29507397, PubMed:31857589.
Subcellular localization: Cytoplasmic vesicle, autophagosome, Preautophagosomal structure, Cytoplasm, cytosol, Nucleus, PML body, Late endosome, Lysosome, Nucleus, Endoplasmic reticulum, Cytoplasm, myofibril, sarcomere.
Curated disease associations include: Paget disease of bone 3; Frontotemporal dementia and/or amyotrophic lateral sclerosis 3; Neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset.