<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">SQSTM1/p62 Protein</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>SQSTM1</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>SQSTM1/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" 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>
SQSTM1 (sequestosome-1), commonly called p62, is a multifunctional scaffold protein that couples ubiquitin tagging, autophagosome recruitment, and stress-response signaling.[@pankiv2007][@itakura2011] In neurodegeneration biology, p62 is best interpreted as a flux integrator: it accumulates when degradative systems fail, but it is also required for selective cargo capture and clearance when those systems work.[@itakura2011][@komatsu2007] This dual role explains why p62 can appear protective in early stress adaptation yet still mark disease progression in advanced proteinopathy.
<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">SQSTM1/p62 Protein</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>SQSTM1</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>SQSTM1/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" 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>
SQSTM1 (sequestosome-1), commonly called p62, is a multifunctional scaffold protein that couples ubiquitin tagging, autophagosome recruitment, and stress-response signaling.[@pankiv2007][@itakura2011] In neurodegeneration biology, p62 is best interpreted as a flux integrator: it accumulates when degradative systems fail, but it is also required for selective cargo capture and clearance when those systems work.[@itakura2011][@komatsu2007] This dual role explains why p62 can appear protective in early stress adaptation yet still mark disease progression in advanced proteinopathy.
In [neurons](/entities/neurons) and glia, p62 participates in proteostasis triage across protein aggregation, oxidative stress, and inflammatory signaling axes.[@ichimura2013][@jain2010] Mechanistically, it intersects with pathways central to amyotrophic lateral sclerosis (ALS), frontotemporal degeneration (FTD), tauopathies, and related disorders where [autophagy](/entities/autophagy)-lysosome throughput is rate-limiting.[@menzies2015][@son2018]
SQSTM1 is a modular protein with architecture that enables simultaneous signaling and cargo trafficking.
The N-terminal PB1 domain mediates p62 self-assembly and higher-order complex formation. Oligomerization supports cargo clustering and concentrates autophagy machinery around ubiquitinated substrates.[@itakura2011][@komatsu2007]
The LC3-interacting region (LIR) directly binds Atg8-family proteins, functionally docking p62-cargo complexes to autophagosomal membranes.[@pankiv2007] This step is required for efficient selective autophagy of ubiquitinated inclusions.
The C-terminal UBA domain binds polyubiquitin chains and enables cargo selection. Disease-associated changes in p62 function can impair this recognition-to-delivery step and produce apparent "cargo capture without clearance" states.[@pankiv2007][@le2013]
A KEAP1-interacting region allows p62 to modulate NRF2 signaling. Under stress, p62 can sequester KEAP1 and enhance antioxidant transcription programs, creating feedback between proteostasis demand and redox defense.[@ichimura2013][@jain2010]
p62 is a canonical selective autophagy receptor: it links ubiquitinated proteins to autophagosomes via LC3 binding.[@pankiv2007] Experimental disruption of p62 pathways increases aggregate burden and destabilizes cellular quality control.[@komatsu2007]
Static p62 abundance is not equivalent to increased autophagic activity. High p62 may indicate active adaptation or blocked degradation, depending on lysosomal throughput and LC3 flux context.[@itakura2011][@menzies2015] For translational studies, p62 should therefore be interpreted with orthogonal flux measurements, not as a standalone endpoint.
p62 function is dynamically tuned by post-translational modifications. Ubiquitylation can increase receptor activity for selective autophagy under ubiquitin stress, and phosphorylation-dependent regulation influences redox-signaling crosstalk and condensate behavior under stress.[@ichimura2013][@pan2016][@sun2018]
By integrating stress-signaling inputs with degradative handling, p62 sits at a proteostasis-inflammation interface. In neurodegeneration, this coupling likely contributes to self-reinforcing loops between protein accumulation and tissue injury.[@son2018][@goode2020]
SQSTM1 variants have been reported in patients with FTD and FTD-ALS phenotypes.[@le2013][@rubino2014] Functional follow-up studies support a mechanism where mutation-linked p62 dysregulation impairs selective autophagy and anti-oxidative stress buffering.[@goode2020]
From an evidence-quality perspective, SQSTM1 is a contributory risk/modifier axis in many cohorts rather than a single dominant driver in most sporadic disease. That distinction matters for trial design: pathway-stratified enrollment and mechanism-proximal endpoints are more defensible than broad unselected populations.
ALS-linked TBK1 perturbations can reduce p62 phosphorylation dynamics and alter downstream autophagic handling, including effects on pathogenic protein clearance pathways.[@ye2020] This places SQSTM1 within a broader autophagy receptor-kinase network where upstream defects can phenocopy direct receptor dysfunction.
Although SQSTM1 mutations are not primary monogenic causes of classic 4R-[tau](/proteins/tau) syndromes, p62 pathway behavior remains biologically relevant because [tau](/proteins/tau) aggregation and lysosomal insufficiency converge on selective-autophagy reserve.[@menzies2015][@son2018] In this framework, p62 serves as a mechanistic bridge between aggregate burden and degradative capacity.
p62 should be modeled as a state variable, not a binary marker. Interpretation is strongest when combined with:
A therapeutic decrease in p62 can indicate improved clearance, but only if accompanied by evidence of restored substrate turnover. A decrease without cargo movement can also reflect reduced receptor competence. Conversely, a transient increase may occur during effective mobilization of stressed proteomes.
Programs targeting p62-adjacent pathways are likely most actionable in cohorts with documented autophagy-lysosome stress signatures, ALS/FTD-related proteostasis phenotypes, or molecular evidence of receptor-kinase network disruption.[@le2013][@goode2020][@ye2020]
Interventions should prioritize restoration of full cargo-to-lysosome flux, not isolated reduction of p62 signal intensity.[@menzies2015][@son2018]
Targeting phosphorylation/ubiquitylation control points that tune p62 receptor activity may improve selective cargo handling in genetically sensitized contexts.[@ichimura2013][@pan2016][@ye2020]
Because p62 couples degradative stress and NRF2 biology, combination approaches that co-manage aggregate load and oxidative stress may have better mechanistic coherence than single-axis programs.[@ichimura2013][@jain2010][@goode2020]
Interactive diagram showing SQSTM1 key relationships in the SciDEX knowledge graph (15 connections shown).