{"gene":"SQSTM1","run_date":"2026-06-10T07:46:41","timeline":{"discoveries":[{"year":2007,"finding":"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.","method":"Direct binding assay, pH-sensitive mCherry-GFP fluorescent tag live imaging, LIR mutant analysis, immunofluorescence/immuno-electron microscopy","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct binding demonstrated in vitro, mapped interaction motif with mutagenesis, functional validation with live imaging, widely replicated","pmids":["17580304"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Structural analysis (LC3-p62 complex), mutagenesis of LRS, autophagy flux assays, inclusion body formation assays","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1 / Strong — structural analysis combined with mutagenesis and functional inclusion-body assays in a single study","pmids":["18776737"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Immunofluorescence co-localization, knockdown/overexpression in infected cells, bacterial replication assay","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-localization plus functional knockdown in cells, single lab","pmids":["19812211"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Co-immunoprecipitation, siRNA knockdown, immunofluorescence in non-neuronal and neuronal cells, mitochondrial depolarization assay","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, siRNA with defined mitophagy phenotype, multiple cell types, widely replicated finding","pmids":["20098416"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Co-IP, in vitro ubiquitylation assay, TRIM21 knockout mice, mutagenesis of K7, oxidative stress functional assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro ubiquitylation reconstitution, mutagenesis, KO mouse model, multiple orthogonal methods","pmids":["26942676"],"is_preprint":false},{"year":2018,"finding":"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.","method":"p62-deficient cell lines, immunofluorescence, autophagic flux assays, IFN reporter assays, phosphorylation analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — p62 KO cells with defined molecular phenotype (STING trafficking defect), IFN signaling readout, multiple orthogonal methods","pmids":["29496741"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Phosphorylation mapping, co-immunoprecipitation, metabolic flux analysis, Nrf2 target gene assays, inhibitor studies","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — site-specific phosphorylation mapped, Co-IP of p62-Keap1, metabolic readouts, inhibitor validation","pmids":["27345495"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Kinase assays, mutagenesis, Co-IP, neuronal morphology assays, ARE reporter assays, stress granule formation assays","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1 / Moderate — kinase assay with mutagenesis, Co-IP, multiple functional readouts in one study","pmids":["31362587"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Co-IP, in vitro deubiquitination assay, mutagenesis of K420, autophagic flux assay","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro deubiquitination reconstitution with site-specific mutagenesis, functional autophagic flux readout","pmids":["31241013"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Crystal structure of p62ZZ in complex with Nt-R, NMR, biochemical binding assays, autophagy induction assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus NMR and biochemical validation in one study","pmids":["30349045"],"is_preprint":false},{"year":2019,"finding":"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.","method":"sqstm1 knockout mice, Co-IP, phosphorylation assays, autophagic flux assays, liver injury models","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse phenotype, Co-IP of AMPK-ULK1-p62 complex, mechanistic pathway validation with multiple methods","pmids":["31913745"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Co-IP, autophagic flux assay, peptide disruption experiment, tumor growth assay","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, functional flux assay, peptide competition, single lab","pmids":["26301314"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Co-IP, autophagic flux assays, helical peptide competition, mouse models of fibrosis, patient tissue analysis","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, functional autophagic flux, peptide disruption in vivo, single lab with multiple methods","pmids":["31286822"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Co-IP, nuclear fractionation, DNA repair pathway assays (HR vs NHEJ), p62 knockdown/overexpression, aging model with dietary restriction","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, defined pathway epistasis (HR vs NHEJ), nuclear localization with functional consequence, single lab","pmids":["27391408"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Co-IP, domain mapping (ZZ domain), p62 knockout mice, LTP recordings, surface GluR1 trafficking assay","journal":"Hippocampus","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP with domain mapping, KO mouse LTP phenotype, surface trafficking assay — multiple orthogonal methods","pmids":["19004011"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Autophagy inhibitor treatment, LC3/Atg8 siRNA, immunoblot, ERK1/2 phosphorylation assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic autophagy inhibition, functional ERK signaling readout, single lab","pmids":["18931699"],"is_preprint":false},{"year":2002,"finding":"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.","method":"Mutation screening, genetic mapping, domain analysis of patient variants","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Strong — genetic mapping with domain localization replicated across multiple families and populations, but no in vitro biochemical reconstitution in this paper","pmids":["12374763"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Co-immunoprecipitation, ARE-luciferase reporter assay, structural modeling, patient mutation analysis","journal":"Molecular and cellular neurosciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional reporter assay with mutagenesis, single lab","pmids":["27554286"],"is_preprint":false},{"year":2016,"finding":"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.","method":"In vitro kinase assay (CK1), phospho-specific antibodies, HSF1 inhibitor, siRNA knockdown, inclusion formation assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro kinase assay, functional phosphorylation analysis with HSF1 inhibition, single lab","pmids":["27846364"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Kinase inhibitor screening, PTK2 knockdown, SQSTM1-S403A mutant expression, Drosophila model, phospho-specific immunoblot","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis with functional readout, in vivo Drosophila model, single lab","pmids":["31690171"],"is_preprint":false},{"year":2020,"finding":"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.","method":"SQSTM1 neutralizing antibody, conditional Insr KO (Cre-loxP), LPS/CLP sepsis models, phosphorylation analysis, Co-IP of SQSTM1-INSR","journal":"Nature microbiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO model, neutralizing antibody, Co-IP, multiple in vivo sepsis models, mechanistic pathway elucidated","pmids":["33077977"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Co-IP, ubiquitination assay, p62 condensate/LLPS analysis, Keap1 sequestration assay, Nrf2 target gene expression, mutagenesis","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro ubiquitination, domain mutagenesis, LLPS assay, multiple functional readouts in one study","pmids":["34987184"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Co-IP of SQSTM1 with viral capsid proteins, viral titer assay, SQSTM1 overexpression/knockdown, protease cleavage mapping","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, protease cleavage site mapping, functional viral replication assay, single lab","pmids":["33719859"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Co-IP of SQSTM1 with VP1, siRNA knockdown, viral titer assay, protease cleavage mapping","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, protease cleavage site mapping, functional siRNA knockdown with viral titer readout, single lab","pmids":["30154446"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Co-IP, deubiquitination assay, IRF3 degradation assay, autophagy flux assay, IFN reporter","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, deubiquitination assay, functional IFN signaling readout, single lab","pmids":["35100065"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Co-immunoprecipitation, phospho-specific immunoblot (pS403), FIP200 knockout/mutant cells, aggregate clearance assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, phosphorylation analysis, KO cells with functional readout, single lab","pmids":["34226595"],"is_preprint":false},{"year":2024,"finding":"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.","method":"In vitro binding assay with purified full-length p62 and LC3B, domain deletion/mutagenesis, phospho-mimetic mutation, small molecule ZZ-domain ligand","journal":"Protein science","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with purified full-length protein, mutagenesis, pharmacological validation, multiple orthogonal approaches","pmids":["37984441"],"is_preprint":false},{"year":2020,"finding":"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).","method":"RNAi knockdown, overexpression of SSH1, fluorescent autophagic flux reporters, SQSTM1-S403A mutant, proximity ligation assay, primary neurons and in vivo brain","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic manipulation with defined mutant constructs, multiple cell types including in vivo, functional tau clearance readout, single lab","pmids":["33044112"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Co-IP, siRNA knockdown, SQSTM1 oligomerization assay, aggregate clearance assay","journal":"Autophagy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP and oligomerization assay, single lab, single method set","pmids":["34382902"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Co-IP, in vitro deubiquitination assay, K7 mutagenesis, autophagic flux assay, Keap1 degradation/Nrf2 reporter","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro deubiquitination with site-specific mutagenesis and functional Nrf2 readout, single lab","pmids":["37776917"],"is_preprint":false},{"year":2024,"finding":"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.","method":"S-acylation assay, ZDHHC19/LYPLA1 knockout/overexpression, autophagic flux assay, phagophore membrane association assay","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — identification of writer (ZDHHC19) and eraser (LYPLA1) enzymes for a novel PTM, functional autophagic flux readout, single lab","pmids":["38124295"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Mutagenesis (K7, D69, TRIM21 cysteine residues), Co-IP, in vitro ubiquitination, phospho-specific immunoblot, oxidative stress assay, TRIM21 KO MEFs","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro ubiquitination reconstitution, systematic mutagenesis, KO cells, multiple functional readouts, single rigorous study","pmids":["39172027"],"is_preprint":false},{"year":1997,"finding":"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.","method":"In-gel kinase assay, recombinant A170 substrate, pharmacological characterization, immunoreactivity comparison with CK II","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in-gel kinase assay with recombinant substrate and pharmacological validation, single lab","pmids":["9405250"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Co-IP-mass spectrometry, p62 knockdown/overexpression, vimentin immunoblot, invasion assay (microfluidic, 3D culture), zebrafish/mouse in vivo metastasis model","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP-MS, in vivo model, functional invasion assay, single lab","pmids":["28968743"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Co-localization imaging, SQSTM1 siRNA knockdown, perilipin1 knockdown, lipid quantification","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — co-localization imaging and knockdown phenotype, no direct binding assay, single lab","pmids":["28951592"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Co-IP, SQSTM1 knockdown, immunofluorescence, cytokine ELISA, autophagic flux assay","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, knockdown with defined cytokine readout, autophagic flux confirmation, single lab","pmids":["31500508"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Co-IP, palmitoylation inhibitor assay, ZDHHC5 overexpression, autophagic flux assay, NOD2 stability assay","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, functional stability assay, pharmacological and genetic manipulation, single lab","pmids":["35066577"],"is_preprint":false},{"year":2021,"finding":"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.","method":"ZZ domain small molecule ligand activation, p62 polymerization assay, ubiquitinated caspase-8 Co-IP, radiation-induced apoptosis assay, ZZ domain mutants","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological ZZ activation, Co-IP of ubiquitinated caspase-8, defined apoptotic phenotype, single lab","pmids":["34697296"],"is_preprint":false},{"year":2021,"finding":"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).","method":"SQSTM1 knockout iPSC-derived cortical neurons, mitochondrial function assays, autophagic flux assay, PINK1/ubiquitin phosphorylation immunoblot","journal":"Stem cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human iPSC-derived neuron KO model, multiple mitochondrial functional readouts, single lab","pmids":["33891871"],"is_preprint":false},{"year":2020,"finding":"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.","method":"p62 KO mice (TEC-specific), p38/ATF2 pathway analysis, MRPL12 promoter binding assay, mtDNA expression assays","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — TEC-specific KO with in vivo kidney phenotype, promoter binding and signaling pathway analysis, single lab","pmids":["32805647"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Co-expression/Co-IP, NF-κB reporter assay, nuclear/cytoplasmic fractionation, autophagy inhibition/proteasomal stress assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping, functional NF-κB reporter, subcellular fractionation, single lab","pmids":["34735553"],"is_preprint":false}],"current_model":"SQSTM1/p62 is a multidomain scaffold protein that acts as a selective autophagy receptor by directly binding LC3/GABARAP family proteins via its LIR motif and polyubiquitinated cargoes via its UBA domain, driving degradation of protein aggregates, damaged organelles, bacteria, and viruses in autolysosomes; its autophagic activity is regulated by multiple post-translational modifications including TBK1/CK1-mediated phosphorylation (Ser349, Ser403), TRIM21-mediated K63-ubiquitination at K7 (inhibitory), SPOP-mediated K420-ubiquitination (inhibitory), USP8/USP13-mediated deubiquitination, SSH1-mediated dephosphorylation of Ser403, and ZDHHC19-mediated S-acylation (activating); additionally, p62 functions as a signaling hub activating Nrf2 (by sequestering Keap1 in a Ser349-phosphorylation-dependent manner), mTORC1, and NF-κB pathways, regulates AMPA receptor trafficking through its ZZ domain, can be secreted extracellularly to bind insulin receptor and drive inflammatory macrophage responses, and plays roles in DNA repair pathway choice by promoting nuclear FLNA/RAD51 degradation."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2008,"claim":"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","pmids":["17580304","18776737"],"confidence":"High","gaps":["Did not address how LIR accessibility is regulated within full-length protein","In vitro/cellular only; cargo range beyond aggregates not defined here"]},{"year":2010,"claim":"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","pmids":["20098416"],"confidence":"High","gaps":["Degree to which p62 is strictly required vs. accessory for mitophagy left open"]},{"year":2021,"claim":"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","pmids":["33891871"],"confidence":"Medium","gaps":["Mechanism connecting p62 to mitochondrial gene expression unresolved","Single lab; relationship to in vivo neurodegeneration unclear"]},{"year":2009,"claim":"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","pmids":["19812211"],"confidence":"Medium","gaps":["Single lab","Relative contribution of UBA vs LIR in vivo not quantified"]},{"year":2016,"claim":"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","pmids":["27345495"],"confidence":"High","gaps":["Upstream kinase for Ser349 not assigned in this study","Generalizability beyond HCC not tested"]},{"year":2016,"claim":"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","pmids":["26942676"],"confidence":"High","gaps":["Stimulus controlling TRIM21 activity toward p62 not fully defined here"]},{"year":2016,"claim":"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","pmids":["27846364"],"confidence":"Medium","gaps":["Single lab","Interplay of CK1 with TBK1/ULK1 at the same sites not resolved"]},{"year":2002,"claim":"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","pmids":["12374763"],"confidence":"Medium","gaps":["No biochemical reconstitution of mutant UBA in this study","Mechanistic link to osteoclast biology not established here"]},{"year":2016,"claim":"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","pmids":["27554286"],"confidence":"Medium","gaps":["Single lab","In vivo neuronal consequences not directly demonstrated"]},{"year":2018,"claim":"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","pmids":["29496741"],"confidence":"High","gaps":["TBK1 site on p62 not pinpointed in this study","Single pathway context"]},{"year":2018,"claim":"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","pmids":["30349045"],"confidence":"High","gaps":["Physiological Nt-R substrate repertoire in cells not enumerated","RL autoregulation only shown in vitro"]},{"year":2019,"claim":"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","pmids":["31362587"],"confidence":"High","gaps":["Relative roles of TBK1 vs ULK1 at the UBA site not dissected"]},{"year":2019,"claim":"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","pmids":["31241013"],"confidence":"High","gaps":["Upstream E3 placing K11 chains at K420 not identified here"]},{"year":2019,"claim":"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","pmids":["31913745"],"confidence":"High","gaps":["Direct vs scaffolded nature of AMPK-ULK1 facilitation not structurally defined"]},{"year":2020,"claim":"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","pmids":["33077977"],"confidence":"High","gaps":["Structural basis of p62-INSR interaction not resolved","Relevance to other inflammatory contexts not tested"]},{"year":2020,"claim":"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","pmids":["33044112"],"confidence":"Medium","gaps":["Single lab","Spatial regulation of SSH1-p62 vs SSH1-cofilin pools unclear"]},{"year":2022,"claim":"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","pmids":["34987184"],"confidence":"High","gaps":["Interplay between SPOP K420 marks and USP8 K420 deubiquitination not co-analyzed"]},{"year":2024,"claim":"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","pmids":["37984441"],"confidence":"High","gaps":["In-cell validation of the conformational switch limited","Endogenous trigger of the ZZ phospho-switch not identified"]},{"year":2024,"claim":"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","pmids":["38124295"],"confidence":"Medium","gaps":["Acylation site(s) on p62 not specified","Single lab"]},{"year":2024,"claim":"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","pmids":["39172027"],"confidence":"High","gaps":["In vivo relevance of TRIM21 cysteine oxidation not established"]},{"year":2016,"claim":"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","pmids":["27391408"],"confidence":"Medium","gaps":["Single lab","Mechanism of nuclear p62 import/retention unclear"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,2,3,9,26]},{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[0,3,5,24,34,35,36]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[6,10,40]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,9,21]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[13,40]},{"term_id":"GO:0005811","term_label":"lipid droplet","supporting_discovery_ids":[34]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[20]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[3,38]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0,1,2,3,9,30]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[6,7,31]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[5,20,24,35]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[4,8,21,29,31]}],"complexes":[],"partners":["MAP1LC3B","KEAP1","TBK1","TRIM21","SPOP","USP8","FLNA","INSR"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13501","full_name":"Sequestosome-1","aliases":["EBI3-associated protein of 60 kDa","EBIAP","p60","Phosphotyrosine-independent ligand for the Lck SH2 domain of 62 kDa","Ubiquitin-binding protein p62","p62"],"length_aa":440,"mass_kda":47.7,"function":"Molecular adapter required for selective macroautophagy (aggrephagy) by acting as a bridge between polyubiquitinated proteins and autophagosomes (PubMed:15340068, PubMed:15953362, PubMed:16286508, PubMed:17580304, PubMed:20168092, PubMed:22017874, PubMed:22622177, PubMed:24128730, PubMed:28404643, PubMed:29343546, PubMed:29507397, PubMed:31857589, PubMed:33509017, PubMed:34471133, PubMed:34893540, PubMed:35831301, PubMed:37306101, PubMed:37802024). Promotes the recruitment of ubiquitinated cargo proteins to autophagosomes via multiple domains that bridge proteins and organelles in different steps (PubMed:16286508, PubMed:20168092, PubMed:22622177, PubMed:24128730, PubMed:28404643, PubMed:29343546, PubMed:29507397, PubMed:34893540, PubMed:37802024). SQSTM1 first mediates the assembly and removal of ubiquitinated proteins by undergoing liquid-liquid phase separation upon binding to ubiquitinated proteins via its UBA domain, leading to the formation of insoluble cytoplasmic inclusions, known as p62 bodies (PubMed:15911346, PubMed:20168092, PubMed:22017874, PubMed:24128730, PubMed:29343546, PubMed:29507397, PubMed:31857589, PubMed:37802024). SQSTM1 then interacts with ATG8 family proteins on autophagosomes via its LIR motif, leading to p62 body recruitment to autophagosomes, followed by autophagic clearance of ubiquitinated proteins (PubMed:16286508, PubMed:17580304, PubMed:20168092, PubMed:22622177, PubMed:24128730, PubMed:28404643, PubMed:37802024). SQSTM1 is itself degraded along with its ubiquitinated cargos (PubMed:16286508, PubMed:17580304, PubMed:37802024). Also required to recruit ubiquitinated proteins to PML bodies in the nucleus (PubMed:20168092). Also involved in autophagy of peroxisomes (pexophagy) in response to reactive oxygen species (ROS) by acting as a bridge between ubiquitinated PEX5 receptor and autophagosomes (PubMed:26344566). Acts as an activator of the NFE2L2/NRF2 pathway via interaction with KEAP1: interaction inactivates the BCR(KEAP1) complex by sequestering the complex in inclusion bodies, promoting nuclear accumulation of NFE2L2/NRF2 and subsequent expression of cytoprotective genes (PubMed:20452972, PubMed:28380357, PubMed:33393215, PubMed:37306101). Promotes relocalization of 'Lys-63'-linked ubiquitinated STING1 to autophagosomes (PubMed:29496741). Involved in endosome organization by retaining vesicles in the perinuclear cloud: following ubiquitination by RNF26, attracts specific vesicle-associated adapters, forming a molecular bridge that restrains cognate vesicles in the perinuclear region and organizes the endosomal pathway for efficient cargo transport (PubMed:27368102, PubMed:33472082). Sequesters tensin TNS2 into cytoplasmic puncta, promoting TNS2 ubiquitination and proteasomal degradation (PubMed:25101860). May regulate the activation of NFKB1 by TNF, nerve growth factor (NGF) and interleukin-1 (PubMed:10356400, PubMed:10747026, PubMed:11244088, PubMed:12471037, PubMed:16079148, PubMed:19931284). May play a role in titin/TTN downstream signaling in muscle cells (PubMed:15802564). Adapter that mediates the interaction between TRAF6 and CYLD (By similarity)","subcellular_location":"Cytoplasmic vesicle, autophagosome; Preautophagosomal structure; Cytoplasm, cytosol; Nucleus, PML body; Late endosome; Lysosome; Nucleus; Endoplasmic reticulum; Cytoplasm, myofibril, sarcomere","url":"https://www.uniprot.org/uniprotkb/Q13501/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SQSTM1","classification":"Not Classified","n_dependent_lines":19,"n_total_lines":1208,"dependency_fraction":0.015728476821192054},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000161011","cell_line_id":"CID000059","localizations":[{"compartment":"vesicles","grade":3},{"compartment":"cytoplasmic","grade":2},{"compartment":"nuclear_punctae","grade":2},{"compartment":"nucleoplasm","grade":1}],"interactors":[{"gene":"NIPSNAP1","stoichiometry":10.0},{"gene":"CAPZB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000059","total_profiled":1310},"omim":[{"mim_id":"621446","title":"OCULOPHARYNGODISTAL MYOPATHY 5; OPDM5","url":"https://www.omim.org/entry/621446"},{"mim_id":"621078","title":"MYOPATHY, MYOFIBRILLAR, 13, WITH RIMMED VACUOLES; MFM13","url":"https://www.omim.org/entry/621078"},{"mim_id":"620947","title":"SPINOCEREBELLAR ATAXIA 51; SCA51","url":"https://www.omim.org/entry/620947"},{"mim_id":"620636","title":"NEURODEGENERATION, CHILDHOOD-ONSET, WITH CEREBELLAR ATAXIA AND COGNITIVE DECLINE; CONDCAC","url":"https://www.omim.org/entry/620636"},{"mim_id":"620096","title":"RING FINGER PROTEIN 185; RNF185","url":"https://www.omim.org/entry/620096"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Vesicles","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal muscle","ntpm":992.1}],"url":"https://www.proteinatlas.org/search/SQSTM1"},"hgnc":{"alias_symbol":["p62","p60","p62B","A170"],"prev_symbol":["PDB3","OSIL"]},"alphafold":{"accession":"Q13501","domains":[{"cath_id":"3.10.20.90","chopping":"4-30_42-102","consensus_level":"high","plddt":90.5259,"start":4,"end":102},{"cath_id":"3.30.60.90","chopping":"123-169","consensus_level":"high","plddt":90.9023,"start":123,"end":169},{"cath_id":"1.10.8","chopping":"393-435","consensus_level":"high","plddt":88.1328,"start":393,"end":435}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13501","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13501-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13501-F1-predicted_aligned_error_v6.png","plddt_mean":67.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SQSTM1","jax_strain_url":"https://www.jax.org/strain/search?query=SQSTM1"},"sequence":{"accession":"Q13501","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13501.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13501/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13501"}},"corpus_meta":[{"pmid":"17580304","id":"PMC_17580304","title":"p62/SQSTM1 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Structural analysis confirmed this interaction; p62 mutants defective in LRS binding escape autophagy and form ubiquitin/p62-positive inclusions.\",\n      \"method\": \"Structural analysis (LC3-p62 complex), mutagenesis of LRS, autophagy flux assays, inclusion body formation assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structural analysis combined with mutagenesis and functional inclusion-body assays in a single study\",\n      \"pmids\": [\"18776737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Immunofluorescence co-localization, knockdown/overexpression in infected cells, bacterial replication assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-localization plus functional knockdown in cells, single lab\",\n      \"pmids\": [\"19812211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, immunofluorescence in non-neuronal and neuronal cells, mitochondrial depolarization assay\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, siRNA with defined mitophagy phenotype, multiple cell types, widely replicated finding\",\n      \"pmids\": [\"20098416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP, in vitro ubiquitylation assay, TRIM21 knockout mice, mutagenesis of K7, oxidative stress functional assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro ubiquitylation reconstitution, mutagenesis, KO mouse model, multiple orthogonal methods\",\n      \"pmids\": [\"26942676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"p62-deficient cell lines, immunofluorescence, autophagic flux assays, IFN reporter assays, phosphorylation analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — p62 KO cells with defined molecular phenotype (STING trafficking defect), IFN signaling readout, multiple orthogonal methods\",\n      \"pmids\": [\"29496741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Phosphorylation mapping, co-immunoprecipitation, metabolic flux analysis, Nrf2 target gene assays, inhibitor studies\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — site-specific phosphorylation mapped, Co-IP of p62-Keap1, metabolic readouts, inhibitor validation\",\n      \"pmids\": [\"27345495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Kinase assays, mutagenesis, Co-IP, neuronal morphology assays, ARE reporter assays, stress granule formation assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — kinase assay with mutagenesis, Co-IP, multiple functional readouts in one study\",\n      \"pmids\": [\"31362587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP, in vitro deubiquitination assay, mutagenesis of K420, autophagic flux assay\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro deubiquitination reconstitution with site-specific mutagenesis, functional autophagic flux readout\",\n      \"pmids\": [\"31241013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Crystal structure of p62ZZ in complex with Nt-R, NMR, biochemical binding assays, autophagy induction assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus NMR and biochemical validation in one study\",\n      \"pmids\": [\"30349045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"sqstm1 knockout mice, Co-IP, phosphorylation assays, autophagic flux assays, liver injury models\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse phenotype, Co-IP of AMPK-ULK1-p62 complex, mechanistic pathway validation with multiple methods\",\n      \"pmids\": [\"31913745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP, autophagic flux assay, peptide disruption experiment, tumor growth assay\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, functional flux assay, peptide competition, single lab\",\n      \"pmids\": [\"26301314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP, autophagic flux assays, helical peptide competition, mouse models of fibrosis, patient tissue analysis\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, functional autophagic flux, peptide disruption in vivo, single lab with multiple methods\",\n      \"pmids\": [\"31286822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP, nuclear fractionation, DNA repair pathway assays (HR vs NHEJ), p62 knockdown/overexpression, aging model with dietary restriction\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, defined pathway epistasis (HR vs NHEJ), nuclear localization with functional consequence, single lab\",\n      \"pmids\": [\"27391408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP, domain mapping (ZZ domain), p62 knockout mice, LTP recordings, surface GluR1 trafficking assay\",\n      \"journal\": \"Hippocampus\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP with domain mapping, KO mouse LTP phenotype, surface trafficking assay — multiple orthogonal methods\",\n      \"pmids\": [\"19004011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Autophagy inhibitor treatment, LC3/Atg8 siRNA, immunoblot, ERK1/2 phosphorylation assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic autophagy inhibition, functional ERK signaling readout, single lab\",\n      \"pmids\": [\"18931699\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"Mutation screening, genetic mapping, domain analysis of patient variants\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Strong — genetic mapping with domain localization replicated across multiple families and populations, but no in vitro biochemical reconstitution in this paper\",\n      \"pmids\": [\"12374763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, ARE-luciferase reporter assay, structural modeling, patient mutation analysis\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional reporter assay with mutagenesis, single lab\",\n      \"pmids\": [\"27554286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro kinase assay (CK1), phospho-specific antibodies, HSF1 inhibitor, siRNA knockdown, inclusion formation assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro kinase assay, functional phosphorylation analysis with HSF1 inhibition, single lab\",\n      \"pmids\": [\"27846364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Kinase inhibitor screening, PTK2 knockdown, SQSTM1-S403A mutant expression, Drosophila model, phospho-specific immunoblot\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis with functional readout, in vivo Drosophila model, single lab\",\n      \"pmids\": [\"31690171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"SQSTM1 neutralizing antibody, conditional Insr KO (Cre-loxP), LPS/CLP sepsis models, phosphorylation analysis, Co-IP of SQSTM1-INSR\",\n      \"journal\": \"Nature microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO model, neutralizing antibody, Co-IP, multiple in vivo sepsis models, mechanistic pathway elucidated\",\n      \"pmids\": [\"33077977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP, ubiquitination assay, p62 condensate/LLPS analysis, Keap1 sequestration assay, Nrf2 target gene expression, mutagenesis\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro ubiquitination, domain mutagenesis, LLPS assay, multiple functional readouts in one study\",\n      \"pmids\": [\"34987184\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP of SQSTM1 with viral capsid proteins, viral titer assay, SQSTM1 overexpression/knockdown, protease cleavage mapping\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, protease cleavage site mapping, functional viral replication assay, single lab\",\n      \"pmids\": [\"33719859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP of SQSTM1 with VP1, siRNA knockdown, viral titer assay, protease cleavage mapping\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, protease cleavage site mapping, functional siRNA knockdown with viral titer readout, single lab\",\n      \"pmids\": [\"30154446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP, deubiquitination assay, IRF3 degradation assay, autophagy flux assay, IFN reporter\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, deubiquitination assay, functional IFN signaling readout, single lab\",\n      \"pmids\": [\"35100065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, phospho-specific immunoblot (pS403), FIP200 knockout/mutant cells, aggregate clearance assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, phosphorylation analysis, KO cells with functional readout, single lab\",\n      \"pmids\": [\"34226595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro binding assay with purified full-length p62 and LC3B, domain deletion/mutagenesis, phospho-mimetic mutation, small molecule ZZ-domain ligand\",\n      \"journal\": \"Protein science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with purified full-length protein, mutagenesis, pharmacological validation, multiple orthogonal approaches\",\n      \"pmids\": [\"37984441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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).\",\n      \"method\": \"RNAi knockdown, overexpression of SSH1, fluorescent autophagic flux reporters, SQSTM1-S403A mutant, proximity ligation assay, primary neurons and in vivo brain\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic manipulation with defined mutant constructs, multiple cell types including in vivo, functional tau clearance readout, single lab\",\n      \"pmids\": [\"33044112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP, siRNA knockdown, SQSTM1 oligomerization assay, aggregate clearance assay\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and oligomerization assay, single lab, single method set\",\n      \"pmids\": [\"34382902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP, in vitro deubiquitination assay, K7 mutagenesis, autophagic flux assay, Keap1 degradation/Nrf2 reporter\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro deubiquitination with site-specific mutagenesis and functional Nrf2 readout, single lab\",\n      \"pmids\": [\"37776917\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"S-acylation assay, ZDHHC19/LYPLA1 knockout/overexpression, autophagic flux assay, phagophore membrane association assay\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — identification of writer (ZDHHC19) and eraser (LYPLA1) enzymes for a novel PTM, functional autophagic flux readout, single lab\",\n      \"pmids\": [\"38124295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Mutagenesis (K7, D69, TRIM21 cysteine residues), Co-IP, in vitro ubiquitination, phospho-specific immunoblot, oxidative stress assay, TRIM21 KO MEFs\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro ubiquitination reconstitution, systematic mutagenesis, KO cells, multiple functional readouts, single rigorous study\",\n      \"pmids\": [\"39172027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"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.\",\n      \"method\": \"In-gel kinase assay, recombinant A170 substrate, pharmacological characterization, immunoreactivity comparison with CK II\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in-gel kinase assay with recombinant substrate and pharmacological validation, single lab\",\n      \"pmids\": [\"9405250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP-mass spectrometry, p62 knockdown/overexpression, vimentin immunoblot, invasion assay (microfluidic, 3D culture), zebrafish/mouse in vivo metastasis model\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP-MS, in vivo model, functional invasion assay, single lab\",\n      \"pmids\": [\"28968743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Co-localization imaging, SQSTM1 siRNA knockdown, perilipin1 knockdown, lipid quantification\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — co-localization imaging and knockdown phenotype, no direct binding assay, single lab\",\n      \"pmids\": [\"28951592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP, SQSTM1 knockdown, immunofluorescence, cytokine ELISA, autophagic flux assay\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, knockdown with defined cytokine readout, autophagic flux confirmation, single lab\",\n      \"pmids\": [\"31500508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP, palmitoylation inhibitor assay, ZDHHC5 overexpression, autophagic flux assay, NOD2 stability assay\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, functional stability assay, pharmacological and genetic manipulation, single lab\",\n      \"pmids\": [\"35066577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"ZZ domain small molecule ligand activation, p62 polymerization assay, ubiquitinated caspase-8 Co-IP, radiation-induced apoptosis assay, ZZ domain mutants\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological ZZ activation, Co-IP of ubiquitinated caspase-8, defined apoptotic phenotype, single lab\",\n      \"pmids\": [\"34697296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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).\",\n      \"method\": \"SQSTM1 knockout iPSC-derived cortical neurons, mitochondrial function assays, autophagic flux assay, PINK1/ubiquitin phosphorylation immunoblot\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human iPSC-derived neuron KO model, multiple mitochondrial functional readouts, single lab\",\n      \"pmids\": [\"33891871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"p62 KO mice (TEC-specific), p38/ATF2 pathway analysis, MRPL12 promoter binding assay, mtDNA expression assays\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — TEC-specific KO with in vivo kidney phenotype, promoter binding and signaling pathway analysis, single lab\",\n      \"pmids\": [\"32805647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Co-expression/Co-IP, NF-κB reporter assay, nuclear/cytoplasmic fractionation, autophagy inhibition/proteasomal stress assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping, functional NF-κB reporter, subcellular fractionation, single lab\",\n      \"pmids\": [\"34735553\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SQSTM1/p62 is a multidomain scaffold protein that acts as a selective autophagy receptor by directly binding LC3/GABARAP family proteins via its LIR motif and polyubiquitinated cargoes via its UBA domain, driving degradation of protein aggregates, damaged organelles, bacteria, and viruses in autolysosomes; its autophagic activity is regulated by multiple post-translational modifications including TBK1/CK1-mediated phosphorylation (Ser349, Ser403), TRIM21-mediated K63-ubiquitination at K7 (inhibitory), SPOP-mediated K420-ubiquitination (inhibitory), USP8/USP13-mediated deubiquitination, SSH1-mediated dephosphorylation of Ser403, and ZDHHC19-mediated S-acylation (activating); additionally, p62 functions as a signaling hub activating Nrf2 (by sequestering Keap1 in a Ser349-phosphorylation-dependent manner), mTORC1, and NF-κB pathways, regulates AMPA receptor trafficking through its ZZ domain, can be secreted extracellularly to bind insulin receptor and drive inflammatory macrophage responses, and plays roles in DNA repair pathway choice by promoting nuclear FLNA/RAD51 degradation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #1, #2, #3]. 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 [#9, #26, #37]. 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 [#7, #18, #25, #32], 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 [#4, #8, #21, #24, #27, #29, #30, #31]. As a signaling hub, phospho-Ser349 p62 sequesters Keap1 to activate Nrf2-driven antioxidant and metabolic reprogramming and couples AMPK–ULK1 to autophagy [#6, #10, #21], and p62 additionally tunes type I interferon output by degrading STING and IRF3 [#5, #24]. Beyond autophagy, p62 traffics GluR1 AMPA receptors via its ZZ domain to support hippocampal LTP [#14], shifts DNA repair toward NHEJ by promoting nuclear FLNA/RAD51 degradation [#13], and when secreted binds the macrophage insulin receptor to drive NF-\\u03baB-dependent glycolysis in sepsis [#20]. 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 [#16, #17, #7].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established the structural basis by which p62 connects ubiquitinated cargo to the autophagosome, defining it as a bona fide selective autophagy receptor.\",\n      \"evidence\": \"Direct LC3-p62 binding assays, structural analysis, and LIR/LRS mutagenesis with autophagy flux and inclusion-body readouts\",\n      \"pmids\": [\"17580304\", \"18776737\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address how LIR accessibility is regulated within full-length protein\", \"In vitro/cellular only; cargo range beyond aggregates not defined here\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed p62 cargo selection extends to whole organelles, linking PINK1/Parkin ubiquitylation of mitochondria to mitophagy.\",\n      \"evidence\": \"Co-IP, siRNA, and immunofluorescence in neuronal and non-neuronal cells with mitochondrial depolarization assays; VDAC1 identified as a Parkin K27 target\",\n      \"pmids\": [\"20098416\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Degree to which p62 is strictly required vs. accessory for mitophagy left open\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Refined the mitophagy role, showing p62 influences early PINK1-dependent steps and mitochondrial gene expression but is dispensable for mitophagy completion in human neurons.\",\n      \"evidence\": \"SQSTM1 knockout iPSC-derived cortical neurons with mitochondrial function and PINK1/ubiquitin phosphorylation readouts\",\n      \"pmids\": [\"33891871\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting p62 to mitochondrial gene expression unresolved\", \"Single lab; relationship to in vivo neurodegeneration unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrated p62 functions as an antibacterial autophagy receptor, extending xenophagy as a cargo class.\",\n      \"evidence\": \"Immunofluorescence co-localization and knockdown/overexpression with Salmonella replication assays\",\n      \"pmids\": [\"19812211\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Relative contribution of UBA vs LIR in vivo not quantified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined the Keap1-Nrf2 signaling arm of p62 and the phospho-switch (Ser349) controlling it, linking p62 to antioxidant and metabolic reprogramming.\",\n      \"evidence\": \"Phosphorylation mapping, Keap1 Co-IP, metabolic flux analysis, and Nrf2 target gene/inhibitor studies in HCC cells\",\n      \"pmids\": [\"27345495\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream kinase for Ser349 not assigned in this study\", \"Generalizability beyond HCC not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified TRIM21-mediated K63 ubiquitination at K7 as an inhibitory switch suppressing p62 oligomerization and client sequestration.\",\n      \"evidence\": \"In vitro ubiquitylation reconstitution, K7 mutagenesis, TRIM21 KO mice, and oxidative stress assays\",\n      \"pmids\": [\"26942676\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stimulus controlling TRIM21 activity toward p62 not fully defined here\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Mapped CK1 and HSF1-dependent regulation of Ser349/Ser403 phosphorylation as a proteostasis-responsive control of inclusion and autophagosome formation.\",\n      \"evidence\": \"In vitro CK1 kinase assay, phospho-specific antibodies, HSF1 inhibition, and inclusion formation assays\",\n      \"pmids\": [\"27846364\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Interplay of CK1 with TBK1/ULK1 at the same sites not resolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Linked SQSTM1 to human disease, showing Paget's disease of bone mutations concentrate in the UBA domain.\",\n      \"evidence\": \"Mutation screening, genetic mapping, and domain analysis across patient families\",\n      \"pmids\": [\"12374763\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No biochemical reconstitution of mutant UBA in this study\", \"Mechanistic link to osteoclast biology not established here\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected ALS/FTLD-associated mutations to loss of Keap1 binding and impaired Nrf2 activation, defining a disease mechanism via the KIR region.\",\n      \"evidence\": \"Co-IP, ARE-luciferase reporter assays, and structural modeling of P348L/G351A patient mutations\",\n      \"pmids\": [\"27554286\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"In vivo neuronal consequences not directly demonstrated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established p62 as a regulator of innate immune signaling by directing ubiquitinated STING to autophagosomes to limit type I IFN.\",\n      \"evidence\": \"p62-deficient cells with STING trafficking, autophagic flux, IFN reporter, and phosphorylation analyses\",\n      \"pmids\": [\"29496741\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"TBK1 site on p62 not pinpointed in this study\", \"Single pathway context\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed the ZZ domain as a recognition module for N-terminally arginylated substrates that stimulate p62 aggregation and macroautophagy.\",\n      \"evidence\": \"Crystal structure of p62ZZ-Nt-R complex, NMR, and autophagy induction assays\",\n      \"pmids\": [\"30349045\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological Nt-R substrate repertoire in cells not enumerated\", \"RL autoregulation only shown in vitro\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed stress-activated TBK1/ULK1 phosphorylate the UBA domain to enhance cargo binding, and that ALS/FTLD mutations (including G427R abolishing Ser351) impair this.\",\n      \"evidence\": \"Kinase assays, mutagenesis, Co-IP, ARE reporter and stress granule assays\",\n      \"pmids\": [\"31362587\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative roles of TBK1 vs ULK1 at the UBA site not dissected\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined deubiquitination control of p62 stability and flux, with USP8 removing K11 chains at K420 in the UBA domain.\",\n      \"evidence\": \"Co-IP, in vitro deubiquitination, K420 mutagenesis, and autophagic flux assays\",\n      \"pmids\": [\"31241013\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream E3 placing K11 chains at K420 not identified here\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Coupled p62 to AMPK-ULK1 to drive autophagy-dependent Keap1 degradation and Nrf2 activation as a hepatoprotective circuit.\",\n      \"evidence\": \"sqstm1 KO mice, AMPK-ULK1-p62 Co-IP, phosphorylation and liver injury models\",\n      \"pmids\": [\"31913745\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs scaffolded nature of AMPK-ULK1 facilitation not structurally defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified an extracellular signaling role for secreted p62 acting on the macrophage insulin receptor to drive glycolysis in sepsis.\",\n      \"evidence\": \"Neutralizing antibody, conditional Insr KO, LPS/CLP sepsis models, and SQSTM1-INSR Co-IP\",\n      \"pmids\": [\"33077977\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of p62-INSR interaction not resolved\", \"Relevance to other inflammatory contexts not tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified SSH1 as the phosphatase reversing Ser403, defining a dephosphorylation arm that impairs tau clearance.\",\n      \"evidence\": \"RNAi/overexpression, S403A mutant, proximity ligation, and autophagic flux/tau clearance in neurons and in vivo\",\n      \"pmids\": [\"33044112\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Spatial regulation of SSH1-p62 vs SSH1-cofilin pools unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established SPOP-mediated non-degradative K420 ubiquitination as an inhibitor of p62 condensation, LLPS, and Keap1 sequestration.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, LLPS/condensate analysis, and Nrf2 readouts with PCa-associated SPOP mutants\",\n      \"pmids\": [\"34987184\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay between SPOP K420 marks and USP8 K420 deubiquitination not co-analyzed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined the LIR Accessibility Mechanism, showing ZZ and PB1 domains conformationally gate LIR-LC3B engagement in full-length p62.\",\n      \"evidence\": \"In vitro binding with purified full-length p62, domain mutagenesis, phospho-mimetic ZZ mutation, and small-molecule ZZ ligands\",\n      \"pmids\": [\"37984441\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In-cell validation of the conformational switch limited\", \"Endogenous trigger of the ZZ phospho-switch not identified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified S-acylation by ZDHHC19 (reversed by LYPLA1) as a lipid modification enhancing p62 droplet affinity for phagophore membranes.\",\n      \"evidence\": \"S-acylation assay, ZDHHC19/LYPLA1 perturbation, autophagic flux and phagophore association assays\",\n      \"pmids\": [\"38124295\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Acylation site(s) on p62 not specified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Integrated PB1 dimerization, K7 ubiquitination, and Ser403 phosphorylation into a lipotoxicity-responsive switch with redox-sensitive TRIM21 control.\",\n      \"evidence\": \"Systematic mutagenesis (K7, D69, TRIM21 cysteines), in vitro ubiquitination, phospho-immunoblot, oxidative stress assays, TRIM21 KO MEFs\",\n      \"pmids\": [\"39172027\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of TRIM21 cysteine oxidation not established\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extended p62 function into the nucleus, showing it promotes FLNA/RAD51 degradation to bias DNA repair toward NHEJ with aging.\",\n      \"evidence\": \"Co-IP, nuclear fractionation, HR vs NHEJ assays, and aging/dietary restriction models\",\n      \"pmids\": [\"27391408\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Mechanism of nuclear p62 import/retention unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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-\\u03baB/STING signaling modes in a tissue-specific manner remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 2, 3, 9, 26]},\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [0, 3, 5, 24, 34, 35, 36]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [6, 10, 40]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 9, 21]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [13, 40]},\n      {\"term_id\": \"GO:0005811\", \"supporting_discovery_ids\": [34]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [20]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [3, 38]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0, 1, 2, 3, 9, 30]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [6, 7, 31]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5, 20, 24, 35]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [4, 8, 21, 29, 31]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MAP1LC3B\", \"KEAP1\", \"TBK1\", \"TRIM21\", \"SPOP\", \"USP8\", \"FLNA\", \"INSR\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}