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), 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]