Affinage

SQSTM1

Sequestosome-1 · UniProt Q13501

Length
440 aa
Mass
47.7 kDa
Annotated
2026-06-10
100 papers in source corpus 41 papers cited in narrative 41 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SQSTM1/p62 is a multidomain scaffold that functions as a selective autophagy receptor, physically bridging polyubiquitinated cargo to the autophagic machinery by binding LC3/GABARAP family proteins through a defined LIR/LC3-recognition sequence (Trp340, Leu343) and ubiquitin chains through its UBA domain, thereby targeting protein aggregates, depolarized mitochondria, intracellular bacteria, viruses, and lipid droplets for degradation in autolysosomes (PMID:17580304, PMID:18776737, PMID:19812211, PMID:20098416). Cargo selection extends beyond ubiquitin recognition: the ZZ domain reads N-terminally arginylated substrates and, together with the PB1 domain, gates LIR accessibility to control LC3B engagement, while ZZ-dependent self-polymerization drives sequestration of clients such as ubiquitinated caspase-8 into aggresomes (PMID:30349045, PMID:37984441, PMID:34697296). p62 activity is set by a dense regulatory network converging on its PB1 (K7) and UBA (K420) lysines and on Ser349/Ser403 phosphorylation: TBK1, ULK1, CK1 and CKII phosphorylate p62 to enhance cargo binding and aggregate clearance (PMID:31362587, PMID:27846364, PMID:34226595, PMID:9405250), TRIM21-mediated K63 ubiquitination at K7 and SPOP-mediated K420 ubiquitination inhibit oligomerization and condensation, USP8/USP13/OTUD7B deubiquitination and SSH1-mediated Ser403 dephosphorylation reverse these marks, and ZDHHC19-catalyzed S-acylation promotes phagophore association (PMID:26942676, PMID:31241013, PMID:34987184, PMID:35100065, PMID:33044112, PMID:37776917, PMID:38124295, PMID:39172027). As a signaling hub, phospho-Ser349 p62 sequesters Keap1 to activate Nrf2-driven antioxidant and metabolic reprogramming and couples AMPK–ULK1 to autophagy (PMID:27345495, PMID:31913745, PMID:34987184), and p62 additionally tunes type I interferon output by degrading STING and IRF3 (PMID:29496741, PMID:35100065). Beyond autophagy, p62 traffics GluR1 AMPA receptors via its ZZ domain to support hippocampal LTP (PMID:19004011), shifts DNA repair toward NHEJ by promoting nuclear FLNA/RAD51 degradation (PMID:27391408), and when secreted binds the macrophage insulin receptor to drive NF-κB-dependent glycolysis in sepsis (PMID:33077977). Disease-causing SQSTM1 mutations cluster in the UBA domain in Paget's disease of bone and in the Keap1-interacting region (P348L, G351A, G427R) in ALS/FTLD, where they abolish Ser349/351 phosphorylation and Keap1 binding (PMID:12374763, PMID:27554286, PMID:31362587).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 2008 High

    Established the structural basis by which p62 connects ubiquitinated cargo to the autophagosome, defining it as a bona fide selective autophagy receptor.

    Evidence Direct LC3-p62 binding assays, structural analysis, and LIR/LRS mutagenesis with autophagy flux and inclusion-body readouts

    PMID:17580304 PMID:18776737

    Open questions at the time
    • Did not address how LIR accessibility is regulated within full-length protein
    • In vitro/cellular only; cargo range beyond aggregates not defined here
  2. 2010 High

    Showed p62 cargo selection extends to whole organelles, linking PINK1/Parkin ubiquitylation of mitochondria to mitophagy.

    Evidence Co-IP, siRNA, and immunofluorescence in neuronal and non-neuronal cells with mitochondrial depolarization assays; VDAC1 identified as a Parkin K27 target

    PMID:20098416

    Open questions at the time
    • Degree to which p62 is strictly required vs. accessory for mitophagy left open
  3. 2021 Medium

    Refined the mitophagy role, showing p62 influences early PINK1-dependent steps and mitochondrial gene expression but is dispensable for mitophagy completion in human neurons.

    Evidence SQSTM1 knockout iPSC-derived cortical neurons with mitochondrial function and PINK1/ubiquitin phosphorylation readouts

    PMID:33891871

    Open questions at the time
    • Mechanism connecting p62 to mitochondrial gene expression unresolved
    • Single lab; relationship to in vivo neurodegeneration unclear
  4. 2009 Medium

    Demonstrated p62 functions as an antibacterial autophagy receptor, extending xenophagy as a cargo class.

    Evidence Immunofluorescence co-localization and knockdown/overexpression with Salmonella replication assays

    PMID:19812211

    Open questions at the time
    • Single lab
    • Relative contribution of UBA vs LIR in vivo not quantified
  5. 2016 High

    Defined the Keap1-Nrf2 signaling arm of p62 and the phospho-switch (Ser349) controlling it, linking p62 to antioxidant and metabolic reprogramming.

    Evidence Phosphorylation mapping, Keap1 Co-IP, metabolic flux analysis, and Nrf2 target gene/inhibitor studies in HCC cells

    PMID:27345495

    Open questions at the time
    • Upstream kinase for Ser349 not assigned in this study
    • Generalizability beyond HCC not tested
  6. 2016 High

    Identified TRIM21-mediated K63 ubiquitination at K7 as an inhibitory switch suppressing p62 oligomerization and client sequestration.

    Evidence In vitro ubiquitylation reconstitution, K7 mutagenesis, TRIM21 KO mice, and oxidative stress assays

    PMID:26942676

    Open questions at the time
    • Stimulus controlling TRIM21 activity toward p62 not fully defined here
  7. 2016 Medium

    Mapped CK1 and HSF1-dependent regulation of Ser349/Ser403 phosphorylation as a proteostasis-responsive control of inclusion and autophagosome formation.

    Evidence In vitro CK1 kinase assay, phospho-specific antibodies, HSF1 inhibition, and inclusion formation assays

    PMID:27846364

    Open questions at the time
    • Single lab
    • Interplay of CK1 with TBK1/ULK1 at the same sites not resolved
  8. 2002 Medium

    Linked SQSTM1 to human disease, showing Paget's disease of bone mutations concentrate in the UBA domain.

    Evidence Mutation screening, genetic mapping, and domain analysis across patient families

    PMID:12374763

    Open questions at the time
    • No biochemical reconstitution of mutant UBA in this study
    • Mechanistic link to osteoclast biology not established here
  9. 2016 Medium

    Connected ALS/FTLD-associated mutations to loss of Keap1 binding and impaired Nrf2 activation, defining a disease mechanism via the KIR region.

    Evidence Co-IP, ARE-luciferase reporter assays, and structural modeling of P348L/G351A patient mutations

    PMID:27554286

    Open questions at the time
    • Single lab
    • In vivo neuronal consequences not directly demonstrated
  10. 2018 High

    Established p62 as a regulator of innate immune signaling by directing ubiquitinated STING to autophagosomes to limit type I IFN.

    Evidence p62-deficient cells with STING trafficking, autophagic flux, IFN reporter, and phosphorylation analyses

    PMID:29496741

    Open questions at the time
    • TBK1 site on p62 not pinpointed in this study
    • Single pathway context
  11. 2018 High

    Revealed the ZZ domain as a recognition module for N-terminally arginylated substrates that stimulate p62 aggregation and macroautophagy.

    Evidence Crystal structure of p62ZZ-Nt-R complex, NMR, and autophagy induction assays

    PMID:30349045

    Open questions at the time
    • Physiological Nt-R substrate repertoire in cells not enumerated
    • RL autoregulation only shown in vitro
  12. 2019 High

    Showed stress-activated TBK1/ULK1 phosphorylate the UBA domain to enhance cargo binding, and that ALS/FTLD mutations (including G427R abolishing Ser351) impair this.

    Evidence Kinase assays, mutagenesis, Co-IP, ARE reporter and stress granule assays

    PMID:31362587

    Open questions at the time
    • Relative roles of TBK1 vs ULK1 at the UBA site not dissected
  13. 2019 High

    Defined deubiquitination control of p62 stability and flux, with USP8 removing K11 chains at K420 in the UBA domain.

    Evidence Co-IP, in vitro deubiquitination, K420 mutagenesis, and autophagic flux assays

    PMID:31241013

    Open questions at the time
    • Upstream E3 placing K11 chains at K420 not identified here
  14. 2019 High

    Coupled p62 to AMPK-ULK1 to drive autophagy-dependent Keap1 degradation and Nrf2 activation as a hepatoprotective circuit.

    Evidence sqstm1 KO mice, AMPK-ULK1-p62 Co-IP, phosphorylation and liver injury models

    PMID:31913745

    Open questions at the time
    • Direct vs scaffolded nature of AMPK-ULK1 facilitation not structurally defined
  15. 2020 High

    Identified an extracellular signaling role for secreted p62 acting on the macrophage insulin receptor to drive glycolysis in sepsis.

    Evidence Neutralizing antibody, conditional Insr KO, LPS/CLP sepsis models, and SQSTM1-INSR Co-IP

    PMID:33077977

    Open questions at the time
    • Structural basis of p62-INSR interaction not resolved
    • Relevance to other inflammatory contexts not tested
  16. 2020 Medium

    Identified SSH1 as the phosphatase reversing Ser403, defining a dephosphorylation arm that impairs tau clearance.

    Evidence RNAi/overexpression, S403A mutant, proximity ligation, and autophagic flux/tau clearance in neurons and in vivo

    PMID:33044112

    Open questions at the time
    • Single lab
    • Spatial regulation of SSH1-p62 vs SSH1-cofilin pools unclear
  17. 2022 High

    Established SPOP-mediated non-degradative K420 ubiquitination as an inhibitor of p62 condensation, LLPS, and Keap1 sequestration.

    Evidence Co-IP, ubiquitination assays, LLPS/condensate analysis, and Nrf2 readouts with PCa-associated SPOP mutants

    PMID:34987184

    Open questions at the time
    • Interplay between SPOP K420 marks and USP8 K420 deubiquitination not co-analyzed
  18. 2024 High

    Defined the LIR Accessibility Mechanism, showing ZZ and PB1 domains conformationally gate LIR-LC3B engagement in full-length p62.

    Evidence In vitro binding with purified full-length p62, domain mutagenesis, phospho-mimetic ZZ mutation, and small-molecule ZZ ligands

    PMID:37984441

    Open questions at the time
    • In-cell validation of the conformational switch limited
    • Endogenous trigger of the ZZ phospho-switch not identified
  19. 2024 Medium

    Identified S-acylation by ZDHHC19 (reversed by LYPLA1) as a lipid modification enhancing p62 droplet affinity for phagophore membranes.

    Evidence S-acylation assay, ZDHHC19/LYPLA1 perturbation, autophagic flux and phagophore association assays

    PMID:38124295

    Open questions at the time
    • Acylation site(s) on p62 not specified
    • Single lab
  20. 2024 High

    Integrated PB1 dimerization, K7 ubiquitination, and Ser403 phosphorylation into a lipotoxicity-responsive switch with redox-sensitive TRIM21 control.

    Evidence Systematic mutagenesis (K7, D69, TRIM21 cysteines), in vitro ubiquitination, phospho-immunoblot, oxidative stress assays, TRIM21 KO MEFs

    PMID:39172027

    Open questions at the time
    • In vivo relevance of TRIM21 cysteine oxidation not established
  21. 2016 Medium

    Extended p62 function into the nucleus, showing it promotes FLNA/RAD51 degradation to bias DNA repair toward NHEJ with aging.

    Evidence Co-IP, nuclear fractionation, HR vs NHEJ assays, and aging/dietary restriction models

    PMID:27391408

    Open questions at the time
    • Single lab
    • Mechanism of nuclear p62 import/retention unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the full set of competing post-translational modifications (K7/K420 ubiquitination, Ser349/Ser403 phosphorylation, S-acylation) is integrated in real time to switch p62 between autophagy-receptor and Keap1/NF-κB/STING signaling modes in a tissue-specific manner remains unresolved.
  • No unified quantitative model of PTM crosstalk
  • Tissue-specific deconvolution of autophagy vs signaling roles incomplete
  • Structural basis for several interactions (INSR, nuclear partners) undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0038024 cargo receptor activity 7 GO:0060090 molecular adaptor activity 6 GO:0098772 molecular function regulator activity 3
Localization
GO:0005829 cytosol 3 GO:0005634 nucleus 2 GO:0005739 mitochondrion 2 GO:0005576 extracellular region 1 GO:0005811 lipid droplet 1
Pathway
R-HSA-9612973 Autophagy 6 R-HSA-392499 Metabolism of proteins 5 R-HSA-168256 Immune System 4 R-HSA-8953897 Cellular responses to stimuli 3
Partners
FLNAINSRKEAP1MAP1LC3BSPOPTBK1TRIM21USP8

Evidence

Reading pass · 41 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 specific 22-residue LIR motif, linking polyubiquitinated protein aggregates to the autophagic machinery for degradation in autolysosomes. p62 is also required for the formation of polyubiquitin-containing bodies. Direct binding assay, pH-sensitive mCherry-GFP fluorescent tag live imaging, LIR mutant analysis, immunofluorescence/immuno-electron microscopy The Journal of biological chemistry High 17580304
2008 p62/SQSTM1 interacts with LC3 via an 11-amino-acid LC3-recognition sequence (LRS) containing Trp-340 and Leu-343, which dock into different hydrophobic pockets in the ubiquitin-fold of LC3. Structural analysis confirmed this interaction; p62 mutants defective in LRS binding escape autophagy and form ubiquitin/p62-positive inclusions. Structural analysis (LC3-p62 complex), mutagenesis of LRS, autophagy flux assays, inclusion body formation assays Autophagy High 18776737
2009 p62/SQSTM1 is recruited to ubiquitin-coated Salmonella typhimurium via its UBA domain and directs bacterial autophagy via its LIR domain; p62 expression is required for efficient autophagic clearance of bacteria and restriction of intracellular replication. Immunofluorescence co-localization, knockdown/overexpression in infected cells, bacterial replication assay Journal of immunology Medium 19812211
2010 p62/SQSTM1 is recruited to ubiquitylated mitochondrial clusters after PINK1/Parkin-mediated ubiquitylation (Lys63 and Lys27 chains) and is essential for mitophagic clearance of depolarized mitochondria. VDAC1 was identified as a Parkin-mediated Lys27 poly-ubiquitylation target upstream of this p62 recruitment. Co-immunoprecipitation, siRNA knockdown, immunofluorescence in non-neuronal and neuronal cells, mitochondrial depolarization assay Nature cell biology High 20098416
2016 TRIM21 (RING E3 ligase) directly interacts with p62/SQSTM1 and ubiquitylates it at Lys7 via K63-linked chains, which abrogates p62 oligomerization and sequestration of client proteins (including Keap1), thereby suppressing antioxidant response and redox homeostasis. Co-IP, in vitro ubiquitylation assay, TRIM21 knockout mice, mutagenesis of K7, oxidative stress functional assays Molecular cell High 26942676
2018 TBK1 phosphorylates p62/SQSTM1, enabling it to direct ubiquitinated STING to autophagosomes for degradation following cGAS-STING pathway activation, thereby attenuating type I IFN signaling. p62-deficient cells showed impaired STING trafficking to autophagy vesicles and elevated IFN production. p62-deficient cell lines, immunofluorescence, autophagic flux assays, IFN reporter assays, phosphorylation analysis The EMBO journal High 29496741
2016 Phosphorylation of p62/SQSTM1 at Ser349 promotes interaction with Keap1, leading to competitive inhibition of Keap1-Nrf2 binding and resulting in Nrf2-dependent metabolic reprogramming (glucose to glucuronate pathway, glutamine to glutathione) in HCC cells. Phosphorylation mapping, co-immunoprecipitation, metabolic flux analysis, Nrf2 target gene assays, inhibitor studies Nature communications High 27345495
2019 TBK1, activated by proteotoxic stress, coordinates with ULK1 to phosphorylate p62/SQSTM1 at the UBA domain, enhancing ubiquitinated cargo binding and selective autophagy. ALS/FTLD-linked mutations of TBK1 or p62 reduce this phosphorylation and compromise ubiquitinated cargo clearance. The disease mutation SQSTM1-G427R abolishes Ser351 phosphorylation and impairs Keap1-p62 interaction. Kinase assays, mutagenesis, Co-IP, neuronal morphology assays, ARE reporter assays, stress granule formation assays Autophagy High 31362587
2019 USP8 directly interacts with and deubiquitinates p62/SQSTM1, preferentially removing K11-linked ubiquitin chains, with the principal deubiquitination site being K420 within the UBA domain. USP8-mediated deubiquitination of K420 inhibits p62 degradation and autophagic flux. Co-IP, in vitro deubiquitination assay, mutagenesis of K420, autophagic flux assay Autophagy High 31241013
2018 The ZZ domain of p62/SQSTM1 selectively recognizes arginylated (Nt-R) substrates. Binding of Nt-R substrates to p62ZZ stimulates p62 aggregation and macroautophagy and is required for autophagic targeting. A regulatory linker (RL) region within p62 binds p62ZZ in vitro and may autoregulate p62 function. Crystal structure of p62ZZ in complex with Nt-R, NMR, biochemical binding assays, autophagy induction assays Nature communications High 30349045
2019 SQSTM1 facilitates the interaction between AMPK and ULK1, promoting ULK1 phosphorylation and autophagy induction, which leads to KEAP1 degradation and NFE2L2/NRF2 activation as a hepatoprotective mechanism against lipotoxicity. sqstm1 knockout mice, Co-IP, phosphorylation assays, autophagic flux assays, liver injury models Autophagy High 31913745
2015 TRIB3 physically interacts with p62/SQSTM1 and hinders p62 binding to LC3 and to ubiquitinated proteins, causing accumulation of SQSTM1 aggregates and blockade of autophagic flux. An alpha-helical peptide derived from SQSTM1 disrupts the TRIB3-SQSTM1 interaction and restores autophagic flux. Co-IP, autophagic flux assay, peptide disruption experiment, tumor growth assay Autophagy Medium 26301314
2019 TRIB3 interacts with p62/SQSTM1 and blocks its binding to LC3, leading to SQSTM1 aggregate accumulation and impaired autophagic flux in hepatocytes. Disrupting TRIB3-SQSTM1 interaction with a specific helical peptide restores autophagic flux and reduces liver fibrosis. Co-IP, autophagic flux assays, helical peptide competition, mouse models of fibrosis, patient tissue analysis Autophagy Medium 31286822
2016 SQSTM1/p62 dynamically associates with DNA damage foci and interacts with FLNA (filamin A), promoting proteasomal degradation of FLNA and RAD51 within the nucleus. This reduces nuclear RAD51 levels, shifts DNA repair from homologous recombination (HR) to non-homologous end joining (NHEJ), and this activity increases with cellular aging. Co-IP, nuclear fractionation, DNA repair pathway assays (HR vs NHEJ), p62 knockdown/overexpression, aging model with dietary restriction Autophagy Medium 27391408
2009 p62/SQSTM1 interacts with the GluR1 AMPA receptor intracellular loop L2-3 via its ZZ-type zinc finger domain, and both p62 and aPKC-mediated phosphorylation are required for surface delivery of GluR1. Mice deficient in p62 display impaired hippocampal CA1 LTP and reduced surface GluR1 expression and phosphorylation at S818. Co-IP, domain mapping (ZZ domain), p62 knockout mice, LTP recordings, surface GluR1 trafficking assay Hippocampus High 19004011
2008 Hypoxia activates autophagy which in turn degrades p62/SQSTM1 protein (not at the mRNA level). Attenuation of p62 in normoxia activates ERK1/2 phosphorylation, and forced p62 expression in hypoxia blocks ERK1/2 activation, establishing p62 as a regulator of hypoxic ERK signaling. Autophagy inhibitor treatment, LC3/Atg8 siRNA, immunoblot, ERK1/2 phosphorylation assay Oncogene Medium 18931699
2002 Disease-causing mutations in SQSTM1 associated with Paget's disease of bone all affect the ubiquitin-binding (UBA) domain, establishing that UBA domain integrity is essential for SQSTM1 function in bone cell biology. Mutation screening, genetic mapping, domain analysis of patient variants Human molecular genetics Medium 12374763
2016 ALS/FTLD-associated SQSTM1 mutations mapping precisely to the KIR region (P348L and G351A) selectively abolish Keap1 binding to p62 and reduce the ability of p62 to activate Nrf2 signaling, as shown by co-immunoprecipitation and ARE-luciferase reporter assays. Co-immunoprecipitation, ARE-luciferase reporter assay, structural modeling, patient mutation analysis Molecular and cellular neurosciences Medium 27554286
2016 Casein kinase 1 phosphorylates p62/SQSTM1 at Ser349 when harmful proteins accumulate, and both Ser349 and Ser403 phosphorylation are regulated in an HSF1-dependent manner. Inhibition of these phosphorylation events suppresses inclusion formation and autophagosome formation by ubiquitinated protein aggregates. In vitro kinase assay (CK1), phospho-specific antibodies, HSF1 inhibitor, siRNA knockdown, inclusion formation assays Autophagy Medium 27846364
2019 PTK2/FAK activation by TARDBP/TDP-43 proteinopathy leads to TBK1-mediated phosphorylation of p62/SQSTM1 at Ser403, promoting accumulation of insoluble poly-ubiquitinated proteins. Expression of non-phosphorylatable SQSTM1-S403A repressed ubiquitinated protein accumulation and neurotoxicity, and PTK2 inhibition reduced ubiquitin aggregates in a Drosophila TDP-43 model. Kinase inhibitor screening, PTK2 knockdown, SQSTM1-S403A mutant expression, Drosophila model, phospho-specific immunoblot Autophagy Medium 31690171
2020 Extracellular SQSTM1 released via GSDMD-dependent pyroptosis or active secretion (requiring STING-TBK1-mediated Ser403 phosphorylation and secretory lysosomes) binds the insulin receptor (INSR) on macrophages, activating NF-κB-dependent glycolysis (aerobic glycolysis) and macrophage polarization, contributing to lethal sepsis. SQSTM1 neutralizing antibody, conditional Insr KO (Cre-loxP), LPS/CLP sepsis models, phosphorylation analysis, Co-IP of SQSTM1-INSR Nature microbiology High 33077977
2022 SPOP E3 ligase binds p62/SQSTM1 in the cytoplasm and induces non-degradative K420 ubiquitination in the UBA domain, decreasing p62 puncta formation, liquid phase condensation, dimerization, and ubiquitin-binding capacity, thereby suppressing p62-dependent autophagy and Keap1 sequestration. PCa-associated SPOP mutants lose this capacity. Co-IP, ubiquitination assay, p62 condensate/LLPS analysis, Keap1 sequestration assay, Nrf2 target gene expression, mutagenesis Cell death and differentiation High 34987184
2021 SVV viral 3C protease cleaves SQSTM1/p62 at glutamic acid 355, glutamine 392, and glutamine 395, abolishing its capacity to mediate selective autophagy of viral cargo and to inhibit viral propagation. SQSTM1 interacts with SVV VP1 and VP3 independently of its UBA domain. Co-IP of SQSTM1 with viral capsid proteins, viral titer assay, SQSTM1 overexpression/knockdown, protease cleavage mapping Autophagy Medium 33719859
2018 CVB3 proteinase 2A cleaves SQSTM1 at glycine 241, impairing its association with viral capsid protein VP1, thus evading host virophagy. SQSTM1 knockdown increases CVB3 replication, establishing an antiviral role for SQSTM1 in virophagy. Co-IP of SQSTM1 with VP1, siRNA knockdown, viral titer assay, protease cleavage mapping Cell death and differentiation Medium 30154446
2022 OTUD7B deubiquitinase interacts with SQSTM1/p62 and removes K63-linked poly-ubiquitin chains at K7, thereby activating p62 oligomerization. Oligomerized p62 then serves as a cargo receptor for selective autophagic degradation of IRF3, forming a negative feedback loop on type I IFN signaling. Co-IP, deubiquitination assay, IRF3 degradation assay, autophagy flux assay, IFN reporter Autophagy Medium 35100065
2021 FIP200 controls the threshold of TBK1 activation at SQSTM1/p62-containing aggregates. TBK1 is recruited to SQSTM1/p62 aggregates via selective autophagy receptor TAX1BP1 and phosphorylates SQSTM1/p62 at Ser403 to promote aggregate engulfment and clearance; loss of FIP200 or its TAX1BP1-binding capacity strongly increases TBK1 activation. Co-immunoprecipitation, phospho-specific immunoblot (pS403), FIP200 knockout/mutant cells, aggregate clearance assay Scientific reports Medium 34226595
2024 The ZZ and PB1 domains of p62/SQSTM1 regulate the accessibility of the LIR sequence (LIR Accessibility Mechanism, LAM) to enable or inhibit interaction with LC3B. A phospho-mimetic mutation on the ZZ domain and small compounds binding the ZZ domain both enhance LC3B interaction. This was established with a purified full-length p62 in vitro LC3B interaction assay. In vitro binding assay with purified full-length p62 and LC3B, domain deletion/mutagenesis, phospho-mimetic mutation, small molecule ZZ-domain ligand Protein science High 37984441
2020 SSH1 (slingshot protein phosphatase 1) directly dephosphorylates p62/SQSTM1 at Ser403, impairing SQSTM1-mediated autophagic flux and clearance of phospho-MAPT/tau. This action is separable from SSH1's canonical function of activating cofilin (CFL). RNAi knockdown, overexpression of SSH1, fluorescent autophagic flux reporters, SQSTM1-S403A mutant, proximity ligation assay, primary neurons and in vivo brain Autophagy Medium 33044112
2021 TRIM44 promotes SQSTM1/p62 oligomerization by binding K48-linked ubiquitin chains on aggregated proteins, activating autophagy and accelerating aggregate protein removal. TRIM44 connects the UPS to the autophagy pathway through p62. Co-IP, siRNA knockdown, SQSTM1 oligomerization assay, aggregate clearance assay Autophagy Low 34382902
2023 USP13 directly binds p62/SQSTM1 and removes ubiquitin at Lys7 (K7) of the PB1 domain, enhancing p62 protein stability and facilitating p62 oligomerization, leading to increased autophagy and Keap1 degradation, thus promoting Nrf2 activation. Co-IP, in vitro deubiquitination assay, K7 mutagenesis, autophagic flux assay, Keap1 degradation/Nrf2 reporter Free radical biology & medicine Medium 37776917
2024 SQSTM1/p62 undergoes S-acylation catalyzed by ZDHHC19 and reversed by LYPLA1/APT1. S-acylation enhances the affinity of SQSTM1 droplets for the phagophore membrane, thereby promoting efficient autophagic degradation of ubiquitinated substrates. S-acylation assay, ZDHHC19/LYPLA1 knockout/overexpression, autophagic flux assay, phagophore membrane association assay Autophagy Medium 38124295
2024 Palmitic acid induces SQSTM1/p62 Ser403 phosphorylation via a mechanism requiring PB1 domain K7-D69 hydrogen bond formation and dimerization, which facilitates TBK1 recruitment and TBK1-mediated S403 phosphorylation. TRIM21 ubiquitinates SQSTM1 at K7, abolishing PB1 dimerization and S403 phosphorylation. TRIM21 is oxidized at C92/C111/C114 to reduce its own E3 activity, thus permitting elevated SQSTM1 aggregation and antioxidant Keap1-sequestration under lipotoxic stress. Mutagenesis (K7, D69, TRIM21 cysteine residues), Co-IP, in vitro ubiquitination, phospho-specific immunoblot, oxidative stress assay, TRIM21 KO MEFs Autophagy High 39172027
1997 A170/SQSTM1 is phosphorylated in macrophages; in-gel kinase assay identified two 40 and 44 kDa kinases in macrophage extracts with properties (substrate specificity, pharmacology, immunoreactivity) matching casein kinase II (CK II) alpha and alpha' subunits as the responsible kinases. In-gel kinase assay, recombinant A170 substrate, pharmacological characterization, immunoreactivity comparison with CK II Biochemical and biophysical research communications Medium 9405250
2017 p62/SQSTM1 interacts with vimentin (identified by Co-IP-mass spectrometry), and this interaction mediates p62-promoted breast cancer cell invasion. Vimentin protein levels are regulated by p62 expression, and p62 genetic ablation suppresses breast cancer metastasis in zebrafish and mouse models. Co-IP-mass spectrometry, p62 knockdown/overexpression, vimentin immunoblot, invasion assay (microfluidic, 3D culture), zebrafish/mouse in vivo metastasis model Carcinogenesis Medium 28968743
2020 SQSTM1/p62 acts as a cargo receptor for lipophagy; it co-localizes with lipid droplets (LDs) and ubiquitinated proteins including perilipin1 on LDs after ethanol treatment. SQSTM1 knockdown reduces LC3 co-localization with LDs and alters ethanol-induced lipid elevation, establishing SQSTM1 as mediating autophagosome targeting to LDs. Co-localization imaging, SQSTM1 siRNA knockdown, perilipin1 knockdown, lipid quantification Scientific reports Low 28951592
2019 SQSTM1/p62 forms a complex with PKM2 (pyruvate kinase M2) that targets PKM2 for selective autophagic degradation in an SQSTM1-dependent manner, thereby reducing mature IL-1β production in macrophages. Co-IP, SQSTM1 knockdown, immunofluorescence, cytokine ELISA, autophagic flux assay Autophagy Medium 31500508
2021 SQSTM1/p62 interacts with and mediates selective autophagic degradation of NOD2, and S-palmitoylation of NOD2 by ZDHHC5 restricts this p62-mediated autophagic degradation by reducing NOD2-p62 interaction. Co-IP, palmitoylation inhibitor assay, ZDHHC5 overexpression, autophagic flux assay, NOD2 stability assay Cell death and differentiation Medium 35066577
2021 p62/SQSTM1 mediates aggresome formation by sequestering ubiquitinated caspase-8 via p62 self-polymerization (dependent on ZZ domain activation), and this sequestration is required for ionizing radiation-induced apoptosis in HNSCC cells. ZZ domain small molecule ligand activation, p62 polymerization assay, ubiquitinated caspase-8 Co-IP, radiation-induced apoptosis assay, ZZ domain mutants Cell death & disease Medium 34697296
2021 SQSTM1/p62 regulates mitochondrial gene expression and autophagic flux in human iPSC-derived cortical neurons. SQSTM1 depletion causes altered mitochondrial gene expression and functionality, but SQSTM1 is not essential for mitophagy completion despite affecting early PINK1-dependent mitophagy processes (PINK1 recruitment and ubiquitin phosphorylation on depolarized mitochondria). SQSTM1 knockout iPSC-derived cortical neurons, mitochondrial function assays, autophagic flux assay, PINK1/ubiquitin phosphorylation immunoblot Stem cell reports Medium 33891871
2020 SQSTM1/p62 controls mitochondrial DNA (mtDNA) expression machinery in renal tubular epithelial cells via p38-dependent upregulation of MRPL12 (mitochondrial ribosomal protein L12) with ATF2 binding to the MRPL12 promoter. TEC-specific SQSTM1/p62 knockout mice show kidney injury phenotype consistent with impaired mtDNA expression. p62 KO mice (TEC-specific), p38/ATF2 pathway analysis, MRPL12 promoter binding assay, mtDNA expression assays iScience Medium 32805647
2021 The SQSTM1/p62 UBA domain regulates Ajuba localization and NF-κB signaling. Co-expression with wild-type p62 (UBA-intact) inhibits Ajuba-mediated NF-κB activation and reduces nuclear Ajuba levels by forming non-degradative holding complexes. UBA-deficient p62 retains Ajuba protection from degradation but does not inhibit NF-κB signaling. Co-expression/Co-IP, NF-κB reporter assay, nuclear/cytoplasmic fractionation, autophagy inhibition/proteasomal stress assays PloS one Medium 34735553

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 3849 17580304
2010 PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nature cell biology 2372 20098416
2009 Monitoring autophagic degradation of p62/SQSTM1. Methods in enzymology 998 19200883
2015 p62/SQSTM1 functions as a signaling hub and an autophagy adaptor. The FEBS journal 677 26432171
2009 The adaptor protein p62/SQSTM1 targets invading bacteria to the autophagy pathway. Journal of immunology (Baltimore, Md. : 1950) 470 19812211
2018 Attenuation of cGAS-STING signaling is mediated by a p62/SQSTM1-dependent autophagy pathway activated by TBK1. The EMBO journal 415 29496741
2016 p62/Sqstm1 promotes malignancy of HCV-positive hepatocellular carcinoma through Nrf2-dependent metabolic reprogramming. Nature communications 289 27345495
2022 Selective Autophagy Receptor p62/SQSTM1, a Pivotal Player in Stress and Aging. Frontiers in cell and developmental biology 283 35237597
2002 Domain-specific mutations in sequestosome 1 (SQSTM1) cause familial and sporadic Paget's disease. Human molecular genetics 271 12374763
2006 p62/SQSTM1: a missing link between protein aggregates and the autophagy machinery. Autophagy 266 16874037
2012 p62/SQSTM1/A170: physiology and pathology. Pharmacological research 258 22841931
2018 p62/SQSTM1 - steering the cell through health and disease. Journal of cell science 236 30397181
2018 p62/SQSTM1: 'Jack of all trades' in health and cancer. The FEBS journal 209 30499183
2008 Selective turnover of p62/A170/SQSTM1 by autophagy. Autophagy 209 18776737
2020 SQSTM1/p62 activates NFE2L2/NRF2 via ULK1-mediated autophagic KEAP1 degradation and protects mouse liver from lipotoxicity. Autophagy 191 31913745
2016 TRIM21 Ubiquitylates SQSTM1/p62 and Suppresses Protein Sequestration to Regulate Redox Homeostasis. Molecular cell 191 26942676
2019 ALS-FTLD-linked mutations of SQSTM1/p62 disrupt selective autophagy and NFE2L2/NRF2 anti-oxidative stress pathway. Autophagy 182 31362587
2019 SQSTM1/p62: A Potential Target for Neurodegenerative Disease. ACS chemical neuroscience 156 30657305
2019 SQSTM1/p62 and PPARGC1A/PGC-1alpha at the interface of autophagy and vascular senescence. Autophagy 156 31441382
2021 m6A reader YTHDC1 modulates autophagy by targeting SQSTM1 in diabetic skin. Autophagy 150 34657574
2019 Disrupting the TRIB3-SQSTM1 interaction reduces liver fibrosis by restoring autophagy and suppressing exosome-mediated HSC activation. Autophagy 143 31286822
2008 Hypoxia-activated autophagy accelerates degradation of SQSTM1/p62. Oncogene 137 18931699
2019 p62/SQSTM1 and Selective Autophagy in Cardiometabolic Diseases. Antioxidants & redox signaling 129 30588824
2016 SQSTM1/p62 mediates crosstalk between autophagy and the UPS in DNA repair. Autophagy 129 27391408
2014 SQSTM1 mutations--bridging Paget disease of bone and ALS/FTLD. Experimental cell research 122 24486447
2013 Role of p62/SQSTM1 in liver physiology and pathogenesis. Experimental biology and medicine (Maywood, N.J.) 119 23856904
2014 P62/SQSTM1 at the interface of aging, autophagy, and disease. Age (Dordrecht, Netherlands) 118 24557832
2019 SQSTM1-dependent autophagic degradation of PKM2 inhibits the production of mature IL1B/IL-1β and contributes to LIPUS-mediated anti-inflammatory effect. Autophagy 108 31500508
2018 ZZ-dependent regulation of p62/SQSTM1 in autophagy. Nature communications 91 30349045
2019 The ubiquitin-specific protease USP8 directly deubiquitinates SQSTM1/p62 to suppress its autophagic activity. Autophagy 87 31241013
2003 Activation of Nrf2 and accumulation of ubiquitinated A170 by arsenic in osteoblasts. Biochemical and biophysical research communications 84 12745069
2022 SPOP mutations promote p62/SQSTM1-dependent autophagy and Nrf2 activation in prostate cancer. Cell death and differentiation 80 34987184
2022 Extracellular SQSTM1 exacerbates acute pancreatitis by activating autophagy-dependent ferroptosis. Autophagy 80 36426912
2021 Selective autophagy receptor SQSTM1/ p62 inhibits Seneca Valley virus replication by targeting viral VP1 and VP3. Autophagy 76 33719859
2019 Nrf2 and SQSTM1/p62 jointly contribute to mesenchymal transition and invasion in glioblastoma. Oncogene 75 31444413
2020 Extracellular SQSTM1 mediates bacterial septic death in mice through insulin receptor signalling. Nature microbiology 72 33077977
2018 CALCOCO2/NDP52 and SQSTM1/p62 differentially regulate coxsackievirus B3 propagation. Cell death and differentiation 69 30154446
2020 Regulation of FN1 degradation by the p62/SQSTM1-dependent autophagy-lysosome pathway in HNSCC. International journal of oral science 67 33318468
2020 Structure and function of p62/SQSTM1 in the emerging framework of phase separation. The FEBS journal 63 33332721
2016 HSF1 stress response pathway regulates autophagy receptor SQSTM1/p62-associated proteostasis. Autophagy 63 27846364
2022 OTUD7B deubiquitinates SQSTM1/p62 and promotes IRF3 degradation to regulate antiviral immunity. Autophagy 62 35100065
2014 YY1-MIR372-SQSTM1 regulatory axis in autophagy. Autophagy 61 24991827
2022 Palmitoylation restricts SQSTM1/p62-mediated autophagic degradation of NOD2 to modulate inflammation. Cell death and differentiation 58 35066577
2017 Ethanol-triggered Lipophagy Requires SQSTM1 in AML12 Hepatic Cells. Scientific reports 57 28951592
1997 Low micromolar levels of hydrogen peroxide and proteasome inhibitors induce the 60-kDa A170 stress protein in murine peritoneal macrophages. Biochemical and biophysical research communications 57 9125146
2010 SQSTM1 gene analysis and gene-environment interaction in Paget's disease of bone. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 56 20200946
2004 SQSTM1 and Paget's disease of bone. Calcified tissue international 56 15365659
2017 p62/SQSTM1 interacts with vimentin to enhance breast cancer metastasis. Carcinogenesis 53 28968743
2018 Biallelic SQSTM1 mutations in early-onset, variably progressive neurodegeneration. Neurology 47 29959261
2019 PTK2/FAK regulates UPS impairment via SQSTM1/p62 phosphorylation in TARDBP/TDP-43 proteinopathies. Autophagy 46 31690171
2016 ALS-FTLD associated mutations of SQSTM1 impact on Keap1-Nrf2 signalling. Molecular and cellular neurosciences 46 27554286
2021 TRIM44 links the UPS to SQSTM1/p62-dependent aggrephagy and removing misfolded proteins. Autophagy 45 34382902
2016 Rare variants in SQSTM1 and VCP genes and risk of sporadic inclusion body myositis. Neurobiology of aging 45 27594680
2022 SQSTM1, lipid droplets and current state of their lipophagy affairs. Autophagy 42 35799322
2017 Both p62/SQSTM1-HDAC6-dependent autophagy and the aggresome pathway mediate CDK1 degradation in human breast cancer. Scientific reports 39 28855742
2019 SQSTM1/p62-Directed Metabolic Reprogramming Is Essential for Normal Neurodifferentiation. Stem cell reports 38 30827875
2009 AMPA receptor trafficking and synaptic plasticity require SQSTM1/p62. Hippocampus 38 19004011
2021 p62/SQSTM1 in liver diseases: the usual suspect with multifarious identities. The FEBS journal 37 34882306
2018 Expression and role of autophagy-associated p62 (SQSTM1) in multidrug resistant ovarian cancer. Gynecologic oncology 37 29699801
2023 LLPS of SQSTM1/p62 and NBR1 as outcomes of lysosomal stress response limits cancer cell metastasis. Proceedings of the National Academy of Sciences of the United States of America 36 37847732
2021 Garcinia cambogia attenuates adipogenesis by affecting CEBPB and SQSTM1/p62-mediated selective autophagic degradation of KLF3 through RPS6KA1 and STAT3 suppression. Autophagy 36 34101546
2021 FIP200 controls the TBK1 activation threshold at SQSTM1/p62-positive condensates. Scientific reports 36 34226595
2017 Tamoxifen activates Nrf2-dependent SQSTM1 transcription to promote endometrial hyperplasia. Theranostics 36 28638475
2020 Extracellular SQSTM1 as an inflammatory mediator. Autophagy 35 33111608
2014 IL-1β induces p62/SQSTM1 and represses androgen receptor expression in prostate cancer cells. Journal of cellular biochemistry 33 25103771
2021 The role of SQSTM1 (p62) in mitochondrial function and clearance in human cortical neurons. Stem cell reports 31 33891871
2018 Myopathy With SQSTM1 and TIA1 Variants: Clinical and Pathological Features. Frontiers in neurology 31 29599744
2015 The TRIB3-SQSTM1 interaction mediates metabolic stress-promoted tumorigenesis and progression via suppressing autophagic and proteasomal degradation. Autophagy 30 26301314
2014 Feasibility analysis of p62 (SQSTM1)-encoding DNA vaccine as a novel cancer immunotherapy. International reviews of immunology 30 25277339
2024 S-acylation regulates SQSTM1/p62-mediated selective autophagy. Autophagy 29 38124295
2020 The selective autophagy receptor SQSTM1/p62 improves lifespan and proteostasis in an evolutionarily conserved manner. Autophagy 29 32041473
2017 GBP3 promotes glioma cell proliferation via SQSTM1/p62-ERK1/2 axis. Biochemical and biophysical research communications 28 29128363
2024 USP13 facilitates a ferroptosis-to-autophagy switch by activation of the NFE2L2/NRF2-SQSTM1/p62-KEAP1 axis dependent on the KRAS signaling pathway. Autophagy 26 39360581
2021 p62/SQSTM1-induced caspase-8 aggresomes are essential for ionizing radiation-mediated apoptosis. Cell death & disease 25 34697296
2017 Autophagy regulates DNA repair through SQSTM1/p62. Autophagy 25 28650265
2008 Sequestosome 1 (SQSTM1) mutations in Paget's disease of bone from the United States. Calcified tissue international 25 18379713
2024 The PB1 and the ZZ domain of the autophagy receptor p62/SQSTM1 regulate the interaction of p62/SQSTM1 with the autophagosome protein LC3B. Protein science : a publication of the Protein Society 24 37984441
2022 Neuropeptide Y Promotes Human M2 Macrophage Polarization and Enhances p62/SQSTM1-Dependent Autophagy and NRF2 Activation. International journal of molecular sciences 24 36361795
2019 Knockdown of BNIP3L or SQSTM1 alters cellular response to mitochondria target drugs. Autophagy 24 30563411
2019 SQSTM1/p62 variants in 486 patients with familial ALS from Germany and Sweden. Neurobiology of aging 24 31859009
2015 AMBRA1 and SQSTM1 expression pattern in prostate cancer. Apoptosis : an international journal on programmed cell death 24 26423274
2013 p62/SQSTM1 is required for cell survival of apoptosis-resistant bone metastatic prostate cancer cell lines. The Prostate 24 24122957
2000 Oxidative stress-related proteins A170 and heme oxygenase-1 are differently induced in the rat cerebellum under kainate-mediated excitotoxicity. Neuroscience letters 23 10713395
2022 Low shear stress inhibits endothelial mitophagy via caveolin-1/miR-7-5p/SQSTM1 signaling pathway. Atherosclerosis 22 35952464
2021 Dual roles of p62/SQSTM1 in the injury and recovery phases of acetaminophen-induced liver injury in mice. Acta pharmaceutica Sinica. B 22 35024307
2020 SQSTM1/p62 Controls mtDNA Expression and Participates in Mitochondrial Energetic Adaption via MRPL12. iScience 22 32805647
2023 USP13 deubiquitinates p62/SQSTM1 to induce autophagy and Nrf2 release for activating antioxidant response genes. Free radical biology & medicine 21 37776917
2021 SQSTM1/p62 regulate breast cancer progression and metastasis by inducing cell cycle arrest and regulating immune cell infiltration. Genes & diseases 21 35873020
2017 Tumor SQSTM1 (p62) expression and T cells in colorectal cancer. Oncoimmunology 21 28405513
2025 p62/SQSTM1 in cancer: phenomena, mechanisms, and regulation in DNA damage repair. Cancer metastasis reviews 20 39954143
1997 Phosphorylation of A170 stress protein by casein kinase II-like activity in macrophages. Biochemical and biophysical research communications 20 9405250
2020 SSH1 impedes SQSTM1/p62 flux and MAPT/Tau clearance independent of CFL (cofilin) activation. Autophagy 18 33044112
2019 Mechanistic insight into the regulation of SQSTM1/p62. Autophagy 18 30653391
2020 Aichi virus 3C protease modulates LC3- and SQSTM1/p62-involved antiviral response. Theranostics 17 32802187
2023 Loss of SQSTM1/p62 Induces Obesity and Exacerbates Alcohol-Induced Liver Injury in Aged Mice. Cellular and molecular gastroenterology and hepatology 16 36754207
2021 The SQSTM1/p62 UBA domain regulates Ajuba localisation, degradation and NF-κB signalling function. PloS one 16 34735553
1999 Effects of kainate-mediated excitotoxicity on the expression of rat counterparts of A170 and MSP23 stress proteins in the brain. Brain research. Molecular brain research 16 10366737
2024 Targeting S6K/NFκB/SQSTM1/Polθ signaling to suppress radiation resistance in prostate cancer. Cancer letters 15 38925361
2024 TRIM21-mediated ubiquitination of SQSTM1/p62 abolishes its Ser403 phosphorylation and enhances palmitic acid cytotoxicity. Autophagy 15 39172027
2022 P62/SQSTM1 beyond Autophagy: Physiological Role and Therapeutic Applications in Laboratory and Domestic Animals. Life (Basel, Switzerland) 15 35455030

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