Affinage

SQSTM1

Sequestosome-1 · UniProt Q13501

Length
440 aa
Mass
47.7 kDa
Annotated
2026-04-28
100 papers in source corpus 32 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SQSTM1/p62 is a multidomain autophagy receptor and signaling scaffold that links polyubiquitinated cargo to the autophagy machinery for selective degradation, with roles spanning aggrephagy, mitophagy, xenophagy, and lysophagy. It polymerizes into filamentous condensates via its PB1 domain, recognizes ubiquitinated substrates through its C-terminal UBA domain, binds N-degrons via its ZZ domain, and engages LC3/GABARAP proteins through a conserved LIR motif (Trp-340/Leu-343) to tether cargo to autophagosomes (PMID:17580304, PMID:16286508, PMID:18776737, PMID:28740232, PMID:31241013). Its activity is tuned by an extensive network of post-translational modifications—including TBK1-mediated S403 phosphorylation, Keap1/Cullin3- and SPOP-mediated K420 ubiquitination (reversed by USP8), ZDHHC19-catalyzed S-acylation, caspase-8 cleavage at D329, and LRRK2-mediated T138 phosphorylation—that regulate oligomerization state, liquid-liquid phase separation, LC3 affinity, and membrane targeting (PMID:29496741, PMID:28380357, PMID:37802024, PMID:30514811, PMID:29519959). Beyond autophagy, p62 scaffolds NF-κB signaling through ZZ-domain-mediated RIP1 interaction, sequesters Keap1 to activate Nrf2 antioxidant responses, attenuates cGAS-STING innate immune signaling via autophagic STING degradation, inhibits the DNA damage E3 ligase RNF168, and facilitates AMPK-ULK1 interaction for autophagy initiation (PMID:28498503, PMID:31434890, PMID:29496741, PMID:27345151, PMID:31913745).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2005 High

    The initial question of how polyubiquitinated protein aggregates are delivered to autophagosomes was addressed by demonstrating that p62 polymerizes via its PB1 domain, forms cytosolic/nuclear bodies, and recruits LC3, establishing p62 as the first mammalian selective autophagy receptor.

    Evidence Co-IP, siRNA knockdown, and fluorescence microscopy in human cells, including mutant huntingtin aggregation model

    PMID:16286508

    Open questions at the time
    • Structural basis of PB1-mediated polymerization not yet resolved
    • Direct binding interface between p62 and LC3 not mapped
    • Whether p62 bodies undergo phase separation versus solid aggregation was unknown
  2. 2007 High

    The molecular basis of p62-LC3 interaction was resolved by identification and mutagenesis of a conserved LIR motif, establishing how the autophagy receptor physically bridges ubiquitinated cargo to the autophagosome membrane.

    Evidence Direct binding assays, co-IP, mutagenesis of LIR motif, and mCherry-GFP autophagy flux imaging; structural detail refined in 2008 identifying Trp-340/Leu-343 as critical residues engaging hydrophobic pockets on LC3

    PMID:17580304 PMID:18776737

    Open questions at the time
    • Post-translational regulation of LIR-LC3 affinity not yet explored
    • Whether other receptors compete for the same LC3 binding surface was unknown
  3. 2010 High

    The scope of p62-mediated selective autophagy was extended to damaged organelles when p62 was shown to be essential for PINK1/Parkin-dependent mitophagy, recruited downstream of Parkin-mediated K27/K63 poly-ubiquitination of mitochondrial substrates including VDAC1.

    Evidence siRNA knockdown and overexpression in multiple cell types with mitochondrial depolarization; co-IP of p62 with ubiquitinated mitochondrial proteins

    PMID:20098416

    Open questions at the time
    • Whether p62 contributes to mitophagy independently of PINK1/Parkin was unresolved
    • Mechanism of p62 recruitment to outer mitochondrial membrane not defined
  4. 2013 Medium

    p62 was placed in innate immune signaling when it was found to bind NOD2 via its TRAF6-binding/UBA domains, stabilize NOD2 oligomers, and amplify NF-κB and p38 MAPK activation, establishing p62 as a signaling scaffold beyond autophagy.

    Evidence Co-IP with domain deletions, electron microscopy of p62-NOD2 complex, NF-κB reporter, and cytokine measurement

    PMID:23437331

    Open questions at the time
    • Whether this scaffolding function is autophagy-dependent was not tested
    • Stoichiometry and structure of the p62-NOD2 complex not defined
    • Not independently replicated
  5. 2014 Medium

    Multiple new interaction axes were established: CHDH was found to recruit p62 to depolarized mitochondria independently of Parkin, forming a ternary complex with LC3 for mitophagy; PKA was identified as a kinase that phosphorylates the PB1 basic surface to disrupt p62 polymerization; and p62 was shown to inhibit HDAC6 deacetylase activity, linking p62 to cytoskeletal regulation.

    Evidence Co-IP with domain mapping, siRNA knockdown, HDAC6 activity assays, kinase assays with PB1 mutagenesis

    PMID:24086678 PMID:25110345 PMID:25483962

    Open questions at the time
    • Physiological importance of PKA-mediated PB1 phosphorylation not validated in vivo
    • HDAC6 interaction shown by single lab only
    • CHDH-p62 axis not tested in genetic models
  6. 2016 High

    p62 was linked to the DNA damage response and NF-κB signaling through distinct domains: accumulated p62 in autophagy-deficient cells directly inhibits RNF168, blocking histone H2A ubiquitination and DSB repair; separately, the ZZ domain mediates RIP1 interaction promoting K63-ubiquitination and NF-κB activation.

    Evidence Co-IP of p62-RNF168 and p62-RIP1, E3 ligase/ubiquitination assays, DNA damage repair assays with xenograft validation, NF-κB reporters with ZZ domain deletions

    PMID:27345151 PMID:28498503

    Open questions at the time
    • Whether RNF168 inhibition is a regulated function or a pathological consequence of autophagy blockade was unclear
    • Structural basis of ZZ-RIP1 interaction not determined
  7. 2017 High

    Two key regulatory mechanisms were defined: the ZZ domain was identified as an N-recognin of the N-end rule pathway that binds Nt-Arg degrons to trigger p62 aggregation and autophagosome biogenesis; and Keap1/Cullin3-mediated ubiquitination at K420 in the UBA domain was found to enhance p62-LC3 association and autophagic flux.

    Evidence 3D modeling and synthetic ZZ ligands for N-degron binding; co-IP, ubiquitination assays, and K420R mutagenesis for Keap1/Cullin3 modification; disease variant analysis

    PMID:28380357 PMID:28740232

    Open questions at the time
    • Identity of endogenous Nt-Arg substrates targeted for autophagy via p62 ZZ domain not defined
    • Structural basis of how K420 ubiquitination enhances LC3 binding was unknown
  8. 2018 High

    Multiple post-translational modifications and signaling connections were uncovered: TBK1 phosphorylates p62 at S403 to promote engulfment of aggregates and autophagic degradation of STING (attenuating IFN signaling); caspase-8 cleaves p62 at D329 generating p62TRM that activates mTORC1; LRRK2 phosphorylates T138 in a PD-relevant manner; and a KIR-lacking splice variant dominantly inhibits Nrf2 by enhancing Keap1 stability.

    Evidence KO cells with IFN measurement, phospho-specific antibodies, in vitro kinase/protease assays, mutagenesis (S403, D329, T138), FTD/PD variant analysis, genetically modified mice for splice variant

    PMID:24492006 PMID:29339380 PMID:29496741 PMID:29519959 PMID:30514811 PMID:34226595

    Open questions at the time
    • How TBK1-mediated S403 phosphorylation and caspase-8-mediated D329 cleavage are coordinated in the same cell was unknown
    • Whether LRRK2-T138 phosphorylation affects p62 autophagic function or only neurotoxicity was not resolved
  9. 2019 High

    Deubiquitination was established as a key counter-regulatory mechanism: USP8 removes K11-linked chains from K420 to inhibit autophagy, while OTUD7B removes K63-linked chains from K7 to enhance oligomerization and promote IRF3 degradation. Additionally, DAXX was shown to drive p62 liquid-liquid phase separation via oligomerization, linking phase condensation to Keap1 sequestration and Nrf2 activation. In vivo, p62 was demonstrated to promote mitochondrial ubiquitination independently of PINK1/Parkin.

    Evidence In vitro deubiquitination assays with K420R/K7 mutagenesis, phase separation assays, Nrf2 reporter, genetic epistasis in Dnm1l-KO mouse liver

    PMID:31241013 PMID:31339428 PMID:31434890 PMID:35100065

    Open questions at the time
    • How USP8 and OTUD7B activities are themselves regulated at p62 condensates is unknown
    • DAXX-driven phase separation not confirmed by independent labs
    • Mechanism by which p62 promotes mitochondrial ubiquitination without PINK1/Parkin is uncharacterized
  10. 2020 High

    Structural and scaffolding functions were resolved at atomic resolution: cryo-EM revealed filamentous PB1 domain assemblies driven by a double arginine finger essential for lysosomal targeting of Keap1 cargo; separately, p62 was shown to scaffold AMPK-ULK1 interaction for autophagy initiation and subsequent Keap1 degradation/Nrf2 activation in hepatocytes.

    Evidence Cryo-EM structures (human and Arabidopsis), correlative cellular EM, polymerization mutagenesis; co-IP of AMPK-ULK1 with SQSTM1 KO mouse model

    PMID:31913745 PMID:31974402

    Open questions at the time
    • Full-length p62 filament structure with cargo/LC3 not yet resolved
    • AMPK-ULK1 scaffolding function not validated outside hepatocyte/lipotoxicity context
  11. 2022 Medium

    A second E3 ligase (SPOP) was identified as ubiquitinating p62 at K420 in a non-degradative manner that opposes condensate formation, dimerization, and ubiquitin-binding—revealing that the same modification site can be written by different E3s with distinct functional outcomes; prostate cancer SPOP mutants lose this activity.

    Evidence Co-IP, ubiquitination assay, K420R mutagenesis, phase condensation assay, autophagy flux, Nrf2 reporter

    PMID:34987184

    Open questions at the time
    • How Keap1/Cullin3 versus SPOP ubiquitination at the same K420 residue produces opposing outcomes mechanistically is not explained
    • Not independently replicated
  12. 2023 High

    S-acylation was identified as a new modification class regulating p62: ZDHHC19 catalyzes and APT1 reverses multi-site cysteine acylation, which enhances p62 droplet affinity for LC3-positive phagophore membranes, directly linking lipid modification to membrane targeting efficiency of phase-separated cargo.

    Evidence S-acylation assay, ZDHHC19/APT1 KO and overexpression, LC3-membrane affinity assay, autophagic flux in multiple cell lines

    PMID:37802024

    Open questions at the time
    • Identity of specific acylated cysteine residues and their individual contributions not resolved
    • Whether S-acylation intersects with K420 ubiquitination or S403 phosphorylation is untested
  13. 2023 Medium

    p62 condensate function was extended to lysophagy: p62 PB1-dependent condensates form on damaged lysosomes, and phosphorylated HSP27 tunes condensate liquidity to facilitate autophagosome formation; ALS-associated p62 mutations impair this process.

    Evidence siRNA knockdown, PB1 mutants, live-cell imaging, condensate analysis, phospho-HSP27 assay, ALS mutation analysis

    PMID:36701233

    Open questions at the time
    • Mechanism of p62 recruitment to damaged lysosomes versus other substrates is undefined
    • Single lab; ALS mutation effects not validated in patient-derived neurons
    • Whether HSP27 regulation is specific to lysophagy or general for all p62 condensates is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • A full-length structural model of p62 in its filamentous/condensate state engaged with cargo, LC3, and phagophore membrane is lacking; how the numerous post-translational modifications (S403, K420, T138, D329, S-acylation) are integrated in space and time to switch p62 between its autophagy receptor and signaling scaffold functions remains unresolved.
  • No full-length p62 structure exists
  • Temporal ordering and mutual dependence of modifications not systematically mapped
  • Whether p62 condensate material properties (liquid vs. solid) determine cargo selectivity in vivo is untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 5 GO:0098772 molecular function regulator activity 3 GO:0042393 histone binding 1
Localization
GO:0005739 mitochondrion 3 GO:0005829 cytosol 3 GO:0031410 cytoplasmic vesicle 3 GO:0005634 nucleus 2 GO:0005764 lysosome 1
Pathway
R-HSA-9612973 Autophagy 9 R-HSA-8953897 Cellular responses to stimuli 5 R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 4 R-HSA-5357801 Programmed Cell Death 1 R-HSA-73894 DNA Repair 1
Partners
KEAP1MAP1LC3BNOD2RIPK1RNF168STING1TBK1USP8

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 p62/SQSTM1 directly binds LC3A, LC3B, GABARAP, and GABARAPL proteins via a conserved 22-residue sequence (LIR/LC3-interacting region motif), mediating autophagic sequestration and lysosomal degradation of p62-positive polyubiquitin-containing bodies. Direct binding assay, co-immunoprecipitation, pH-sensitive mCherry-GFP live imaging, mutagenesis of interaction motif The Journal of biological chemistry High 17580304
2005 p62/SQSTM1 polymerizes via its N-terminal PB1 domain to form protein bodies in the cytosol and nucleus; depletion of p62 inhibits LC3 recruitment to autophagosomes under starvation, and p62/LC3 form a shell surrounding mutant huntingtin aggregates, linking polyubiquitinated cargo to the autophagy machinery. Co-immunoprecipitation, siRNA knockdown, fluorescence microscopy, cell viability assay The Journal of cell biology High 16286508
2010 p62/SQSTM1 is recruited to ubiquitinated mitochondrial clusters downstream of PINK1 kinase activity and Parkin-mediated K27/K63 poly-ubiquitylation, and is essential for mitophagy clearance of depolarized mitochondria; VDAC1 was identified as a Parkin/K27 ubiquitylation target. siRNA knockdown, overexpression, co-immunoprecipitation, fluorescence microscopy of mitochondrial clearance Nature cell biology High 20098416
2008 p62/SQSTM1 interacts with LC3 through an 11-amino-acid LC3-recognition sequence (LRS); structural analysis shows Trp-340 and Leu-343 of p62 engage two hydrophobic pockets in the ubiquitin-fold of LC3. p62 mutants deficient in LRS binding escape autophagic turnover and form ubiquitin/p62-positive inclusions. Structural analysis, mutagenesis (Trp-340, Leu-343), autophagy flux assay Autophagy High 18776737
2018 TBK1 phosphorylates p62/SQSTM1, directing it to deliver ubiquitinated STING to autophagosomes for degradation, thereby attenuating cGAS-STING innate immune signaling. p62-deficient cells show elevated IFN production and failed STING trafficking to autophagy vesicles. p62 knockout cells, co-immunoprecipitation, phosphorylation assay, IFN production measurement The EMBO journal High 29496741
2017 p62/SQSTM1 acts as an N-recognin of the N-end rule pathway: its ZZ domain binds type-1 and type-2 N-terminal degrons (including Nt-Arg), triggering p62 disulfide-linked aggregation and enhanced p62–LC3 interaction, leading to autophagosome biogenesis and selective cargo delivery. 3D modeling, synthetic ZZ-domain ligands, binding assays, autophagosome biogenesis assay, mutagenesis Nature communications High 28740232
2018 The ZZ domain of p62 selectively recognizes arginylated (Nt-R) substrates; binding stimulates p62 aggregation and macroautophagy. A regulatory linker (RL) region in p62 can bind p62ZZ in vitro and may modulate p62 function. p62 is required for mTORC1 activation in response to arginine but is not a direct arginine sensor. Structural determination (crystal), biochemical binding assays, mutagenesis, autophagy flux assay, mTORC1 activity assay Nature communications High 30349045
2020 Cryo-EM structures of human and Arabidopsis p62 PB1 domain assemblies reveal filamentous ultrastructure; polymerization driven by a double arginine finger in the PB1 domain is a general requirement for lysosomal targeting of p62 and for autophagosomal processing of p62-specific cargo KEAP1. Cryo-EM structure determination, correlative cellular EM, oligomerization/polymerization mutagenesis, lysosomal targeting assay Nature communications High 31974402
2017 Keap1/Cullin3 ubiquitinates p62 at lysine 420 within its UBA domain; this modification enhances p62's sequestration and degradation activity and its association with LC3, and rescues proteotoxicity. Disease-associated p62 mutants show diminished UBA domain ubiquitination. Co-immunoprecipitation, ubiquitination assay, mutagenesis (K420R), inclusion body assay, LC3 interaction assay Cell reports High 28380357
2019 USP8 deubiquitinates p62/SQSTM1 by preferentially removing K11-linked ubiquitin chains, principally at K420 within the UBA domain, thereby inhibiting p62 autophagic activity and autophagic flux. Co-immunoprecipitation, in vitro deubiquitination assay, mutagenesis (K420R), autophagy flux measurement Autophagy High 31241013
2016 p62/SQSTM1 accumulating in autophagy-deficient cells directly binds and inhibits nuclear E3 ligase RNF168, preventing histone H2A ubiquitination at DNA double-strand break sites and thereby blocking recruitment of BRCA1, RAP80, and Rad51 for DSB repair. Co-immunoprecipitation of p62 and RNF168, E3 ligase activity assay, DNA damage repair assay, in vivo xenograft radiation sensitivity Molecular cell High 27345151
2019 p62/SQSTM1 promotes mitochondrial ubiquitination independently of PINK1 and PRKN/parkin during mitophagy in vivo (in Dnm1l-knockout liver), while PINK1 is required for degradation of MFN1/MFN2 but not for mitochondrial ubiquitination per se. Genetic knockout of SQSTM1, PINK1, and Dnm1l in mouse liver; mitochondrial ubiquitination and fusion protein levels assessed Autophagy High 31339428
2014 Choline dehydrogenase (CHDH) interacts with SQSTM1 via its cytosol-exposed FB1 domain independently of PARK2, recruits SQSTM1 to depolarized mitochondria, and forms a ternary complex with SQSTM1 and LC3 to load LC3 onto damaged mitochondria for mitophagy. Co-immunoprecipitation, dominant-negative FB1 domain competition, siRNA knockdown of CHDH, mitophagy flux assay Autophagy High 25483962
2014 p62/SQSTM1 interacts with HDAC6; this interaction inhibits HDAC6 deacetylase activity, and absence of p62 leads to hyperactivation of HDAC6 and deacetylation of α-tubulin and cortactin. p62 is required for perinuclear co-localization of cortactin-F-actin assemblies during protein misfolding. Co-immunoprecipitation, domain mapping, HDAC6 deacetylase activity assay, fluorescence microscopy PloS one Medium 24086678
2014 PKA phosphorylates the basic surface of the p62 PB1 domain, disrupting p62 homopolymerization and interaction with aPKCs. PDE4 binds the acidic surface of the PB1 domain, coupling p62 to the cAMP signaling system. Co-immunoprecipitation, phosphorylation assay (PKA), PB1 domain mutagenesis, PDE4 binding assay Biochimica et biophysica acta Medium 25110345
2018 p62/SQSTM1 is phosphorylated at Ser351 upon Salmonella infection (xenophagy), sequentially after translocation to bacteria; both Ser351 phosphorylation and p62 oligomerization are required for Keap1 localization onto microbes and subsequent Nrf2 activation. Sequential imaging of p62 dynamics on Salmonella, phospho-specific antibody, oligomerization-deficient mutants FEBS letters Medium 24492006
2018 OTUD7B deubiquitinase removes K63-linked poly-ubiquitin chains from SQSTM1 at K7, enhancing SQSTM1 oligomerization and promoting selective autophagic degradation of IRF3 to attenuate antiviral interferon signaling. Co-immunoprecipitation, deubiquitination assay, mutagenesis (K7), SQSTM1 oligomerization assay, IRF3 degradation assay Autophagy Medium 35100065
2023 p62/SQSTM1 undergoes reversible S-acylation at multiple cysteines, catalyzed by ZDHHC19 and reversed by APT1/LYPLA1; S-acylation enhances affinity of p62 droplets for LC3-positive phagophore membranes, promoting autophagic membrane localization of p62 droplets and efficient degradation of ubiquitinated cargo. S-acylation assay, ZDHHC19/APT1 KO/overexpression, LC3-membrane affinity assay, autophagic flux measurement Molecular cell High 37802024
2016 VANGL2 interacts with p62/SQSTM1 as a binding partner, placing p62 in a VANGL2–p62–JNK non-canonical Wnt/PCP signaling cascade that promotes proliferation in breast cancer. Yeast two-hybrid, co-immunoprecipitation, siRNA knockdown, JNK pathway activity assay Nature communications Medium 26754771
2019 DAXX physically interacts with p62 and drives p62 liquid-liquid phase condensation by inducing p62 oligomerization; this promotes p62 recruitment of Keap1 and subsequent Nrf2-mediated antioxidant stress response. Yeast two-hybrid screening, co-immunoprecipitation, phase separation assay, Nrf2 reporter assay Nature communications Medium 31434890
2018 p62/SQSTM1 is phosphorylated at S403 by TBK1, regulating efficient engulfment and clearance of p62-containing aggregates; FIP200 controls the threshold of TBK1 activation at p62 condensates via TAX1BP1. Phospho-specific antibody, TBK1 activity assay, FIP200 knockout, p62 condensate imaging Scientific reports Medium 34226595
2019 LRRK2 (leucine-rich repeat kinase 2) phosphorylates p62/SQSTM1 at Thr138 in vitro and in cells; pathogenic LRRK2 PD mutations increase p62 phosphorylation, and this phosphorylation requires p62's C-terminal UBA domain. Co-expression of p62 with LRRK2-G2019S increases neurotoxicity in a Thr138-dependent manner. Mass spectrometry, phospho-specific antibody, in vitro kinase assay, mutagenesis (Thr138), neurotoxicity assay, LRRK2 inhibitor treatment The Biochemical journal Medium 29519959
2018 Caspase-8 cleaves p62/SQSTM1 at Asp329, generating a stable trimmed form (p62TRM) that lacks the KIR domain; p62TRM (but not full-length p62) activates mTORC1 for nutrient sensing, and this cleavage is promoted by RIPK1. FTD-linked D329G/D329H variants are resistant to caspase-8 cleavage and fail to activate mTORC1. Proteolysis assay, caspase-8 mutagenesis, mTORC1 activity assay, disease variant analysis Science signaling Medium 30514811
2011 Autophagy-mediated degradation of PML-RARα oncoprotein in APL cells requires p62/SQSTM1; PML-RARα co-immunoprecipitates with p62 and p62 knockdown inhibits ATRA-induced PML-RARα degradation and myeloid differentiation. Co-immunoprecipitation, siRNA knockdown of p62, autophagy inhibition, myeloid differentiation assay Autophagy Medium 21187718
2013 p62/SQSTM1 associates with the nucleotide-binding domain of NOD2 via its TRAF6-binding or UBA domains, forms a large electron-dense cytoplasmic complex with NOD2, stabilizes NOD2 oligomerization, and enhances NOD2-induced NF-κB and p38 MAPK signaling and IL-1β/TNF-α production. Co-immunoprecipitation, domain deletion mutants, electron microscopy, NF-κB reporter assay, cytokine measurement PloS one Medium 23437331
2021 MOAP-1 is recruited to p62 bodies and disrupts p62 self-oligomerization and liquid-liquid phase separation by interacting with the PB1-ZZ domains of p62, thereby releasing Keap1 from sequestration by p62 bodies and suppressing Nrf2 antioxidant gene expression. Co-immunoprecipitation, PB1-ZZ domain interaction mapping, phase separation assay, Nrf2 target gene expression, MOAP-1 knockout mice with DEN hepatocarcinogenesis model EMBO reports Medium 33393215
2023 p62/SQSTM1 is recruited to damaged lysosomes and required for lysophagic flux; the PB1 domain mediates oligomerization and is specifically required for lysophagy. p62 forms condensates on damaged lysosomes that are tuned by phosphorylated HSP27, which maintains condensate liquidity and facilitates autophagosome formation. ALS-associated p62 mutations impair lysophagy. siRNA knockdown, PB1 domain mutants, live-cell imaging, condensate analysis, phospho-HSP27 assay, ALS patient mutation analysis Cell reports Medium 36701233
2018 A splicing variant of p62/Sqstm1 lacking the Keap1-interacting region (KIR) co-oligomerizes with full-length p62 but fails to interact with Keap1; instead of stabilizing Nrf2, this variant increases Keap1 levels and enhances Nrf2 ubiquitination, thereby negatively regulating the Keap1-Nrf2 pathway. Ensembl database search, biochemical analysis of mouse liver and hepatocytes, co-oligomerization assay, Nrf2 ubiquitination assay, KIR-deletion mutants, genetically modified mice Molecular and cellular biology Medium 29339380
2022 SPOP ubiquitinates p62 at K420 within the UBA domain in a non-degradative manner, decreasing p62 puncta formation, liquid phase condensation, dimerization, and ubiquitin-binding capacity, thereby suppressing p62-dependent autophagy and Nrf2 activation. PCa-associated SPOP mutants lose this activity. Co-immunoprecipitation, ubiquitination assay, mutagenesis (K420), phase condensation assay, autophagy flux measurement, Nrf2 reporter assay Cell death and differentiation Medium 34987184
2016 p62/SQSTM1's ZZ domain mediates interaction with RIP1, and this interaction promotes K63-linked ubiquitination of RIP1 and downstream NF-κB activation. Deletion of the ZZ domain decreases RIP1 ubiquitination, NF-κB activity, and cell proliferation. Domain deletion mutants (ZZ domain), K63-ubiquitination assay, NF-κB reporter, cell proliferation assay Cancer science Medium 28498503
2020 SQSTM1 facilitates interaction between AMPK and ULK1, promoting ULK1 phosphorylation and autophagy induction, followed by KEAP1 autophagic degradation and NFE2L2/NRF2 activation in a non-canonical pathway that protects against lipotoxicity in hepatocytes. Co-immunoprecipitation of AMPK-ULK1 complex, ULK1 phosphorylation assay, SQSTM1 KO mouse model, KEAP1 degradation assay, NRF2 reporter Autophagy Medium 31913745
2019 PTK2/FAK promotes phosphorylation of p62/SQSTM1 at S403 via TBK1, and this phosphorylation impairs autophagic degradation of poly-ubiquitinated proteins and contributes to neurotoxicity in TDP-43 proteinopathies. Expression of non-phosphorylatable p62-S403A reduces ubiquitin aggregates and neurotoxicity. Kinase inhibitor screening, phospho-specific antibody (S403), mutagenesis (S403A), Drosophila TDP-43 model, cell viability assay Autophagy Medium 31690171

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. The Journal of biological chemistry 3810 17580304
2005 p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. The Journal of cell biology 2786 16286508
2010 PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nature cell biology 2347 20098416
2009 Monitoring autophagic degradation of p62/SQSTM1. Methods in enzymology 991 19200883
2015 p62/SQSTM1 functions as a signaling hub and an autophagy adaptor. The FEBS journal 669 26432171
2018 Attenuation of cGAS-STING signaling is mediated by a p62/SQSTM1-dependent autophagy pathway activated by TBK1. The EMBO journal 404 29496741
2012 p62/SQSTM1/A170: physiology and pathology. Pharmacological research 254 22841931
2018 p62/SQSTM1 - steering the cell through health and disease. Journal of cell science 232 30397181
2010 Selective degradation of p62 by autophagy. Seminars in immunopathology 212 20814791
2017 p62/SQSTM1/Sequestosome-1 is an N-recognin of the N-end rule pathway which modulates autophagosome biogenesis. Nature communications 209 28740232
2008 Selective turnover of p62/A170/SQSTM1 by autophagy. Autophagy 209 18776737
2018 p62/SQSTM1: 'Jack of all trades' in health and cancer. The FEBS journal 206 30499183
2013 Mutations in SQSTM1 encoding p62 in amyotrophic lateral sclerosis: genetics and neuropathology. Acta neuropathologica 196 23417734
2010 Autophagy negatively regulates keratinocyte inflammatory responses via scaffolding protein p62/SQSTM1. Journal of immunology (Baltimore, Md. : 1950) 191 21160040
2020 SQSTM1/p62 activates NFE2L2/NRF2 via ULK1-mediated autophagic KEAP1 degradation and protects mouse liver from lipotoxicity. Autophagy 181 31913745
2010 Regulation of TDP-43 aggregation by phosphorylation and p62/SQSTM1. Journal of neurochemistry 177 21062285
2016 Autophagy Regulates Chromatin Ubiquitination in DNA Damage Response through Elimination of SQSTM1/p62. Molecular cell 175 27345151
2011 Autophagy and p62 in cardiac proteinopathy. Circulation research 163 21659648
2019 SQSTM1/p62 and PPARGC1A/PGC-1alpha at the interface of autophagy and vascular senescence. Autophagy 152 31441382
2019 SQSTM1/p62 promotes mitochondrial ubiquitination independently of PINK1 and PRKN/parkin in mitophagy. Autophagy 142 31339428
2010 A reporter cell system to monitor autophagy based on p62/SQSTM1. Autophagy 137 20574168
2008 Hypoxia-activated autophagy accelerates degradation of SQSTM1/p62. Oncogene 137 18931699
2013 Interaction domains of p62: a bridge between p62 and selective autophagy. DNA and cell biology 128 23530606
2011 Autophagy regulates myeloid cell differentiation by p62/SQSTM1-mediated degradation of PML-RARα oncoprotein. Autophagy 128 21187718
2019 p62/SQSTM1 and Selective Autophagy in Cardiometabolic Diseases. Antioxidants & redox signaling 123 30588824
2016 Functional CRISPR screening identifies the ufmylation pathway as a regulator of SQSTM1/p62. eLife 119 27351204
2013 Role of p62/SQSTM1 in liver physiology and pathogenesis. Experimental biology and medicine (Maywood, N.J.) 119 23856904
2017 Keap1/Cullin3 Modulates p62/SQSTM1 Activity via UBA Domain Ubiquitination. Cell reports 116 28380357
2014 P62/SQSTM1 at the interface of aging, autophagy, and disease. Age (Dordrecht, Netherlands) 116 24557832
2004 Transcriptional activation of p62/A170/ZIP during the formation of the aggregates: possible mechanisms and the role in Lewy body formation in Parkinson's disease. Brain research 116 15158159
2019 DEAD Box Protein 5 Inhibits Liver Tumorigenesis by Stimulating Autophagy via Interaction with p62/SQSTM1. Hepatology (Baltimore, Md.) 104 30281815
2019 Upregulation of the Autophagy Adaptor p62/SQSTM1 Prolongs Health and Lifespan in Middle-Aged Drosophila. Cell reports 104 31340141
2014 Choline dehydrogenase interacts with SQSTM1/p62 to recruit LC3 and stimulate mitophagy. Autophagy 102 25483962
2020 Structural basis of p62/SQSTM1 helical filaments and their role in cellular cargo uptake. Nature communications 94 31974402
2018 Activation of p62/SQSTM1-Keap1-Nuclear Factor Erythroid 2-Related Factor 2 Pathway in Cancer. Frontiers in oncology 92 29930914
2013 SQSTM1/p62 interacts with HDAC6 and regulates deacetylase activity. PloS one 92 24086678
2018 ZZ-dependent regulation of p62/SQSTM1 in autophagy. Nature communications 90 30349045
2019 The ubiquitin-specific protease USP8 directly deubiquitinates SQSTM1/p62 to suppress its autophagic activity. Autophagy 86 31241013
2003 Activation of Nrf2 and accumulation of ubiquitinated A170 by arsenic in osteoblasts. Biochemical and biophysical research communications 84 12745069
2019 Cytoplasmic DAXX drives SQSTM1/p62 phase condensation to activate Nrf2-mediated stress response. Nature communications 83 31434890
2016 Identification of p62/SQSTM1 as a component of non-canonical Wnt VANGL2-JNK signalling in breast cancer. Nature communications 82 26754771
2018 Negative Regulation of the Keap1-Nrf2 Pathway by a p62/Sqstm1 Splicing Variant. Molecular and cellular biology 80 29339380
2023 S-acylation of p62 promotes p62 droplet recruitment into autophagosomes in mammalian autophagy. Molecular cell 79 37802024
2022 SPOP mutations promote p62/SQSTM1-dependent autophagy and Nrf2 activation in prostate cancer. Cell death and differentiation 79 34987184
2011 Mycobacterium abscessus activates the NLRP3 inflammasome via Dectin-1-Syk and p62/SQSTM1. Immunology and cell biology 73 21876553
2023 The selective autophagy adaptor p62/SQSTM1 forms phase condensates regulated by HSP27 that facilitate the clearance of damaged lysosomes via lysophagy. Cell reports 72 36701233
2018 CALCOCO2/NDP52 and SQSTM1/p62 differentially regulate coxsackievirus B3 propagation. Cell death and differentiation 68 30154446
2014 Targeting SQSTM1/p62 induces cargo loading failure and converts autophagy to apoptosis via NBK/Bik. Molecular and cellular biology 67 25002530
2015 KLF4-SQSTM1/p62-associated prosurvival autophagy contributes to carfilzomib resistance in multiple myeloma models. Oncotarget 66 26109433
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2014 Dissection of the role of p62/Sqstm1 in activation of Nrf2 during xenophagy. FEBS letters 64 24492006
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2014 An inhibition of p62/SQSTM1 caused autophagic cell death of several human carcinoma cells. Cancer science 60 24618016
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2017 p62/SQSTM1 as an oncotarget mediates cisplatin resistance through activating RIP1-NF-κB pathway in human ovarian cancer cells. Cancer science 58 28498503
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2012 The adaptor protein p62/SQSTM1 in osteoclast signaling pathways. Journal of molecular signaling 50 22216904
2023 Porcine reproductive and respiratory syndrome virus degrades DDX10 via SQSTM1/p62-dependent selective autophagy to antagonize its antiviral activity. Autophagy 49 36779599
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2013 Association of p62/SQSTM1 excess and oral carcinogenesis. PloS one 41 24086340
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