| Feature (domain/motif or process) | Mechanistic role | Key evidence (including quantitative numbers when available) | Recent source (first author, journal, publication month/year) | URL/DOI |
|---|---|---|---|---|
| Identity / target verification | UniProt Q13501 corresponds to human SQSTM1/p62 (sequestosome-1); AlphaFold model AF-Q13501-F1 is used for domain mapping in recent literature, matching the requested human protein. | Recent p62 structural work explicitly cites AF-Q13501-F1 for p62 domain/residue mapping, consistent with UniProt Q13501 and the human SQSTM1/p62 annotation. (pqac-00000008) | Masato, *Cell Death & Disease*, Jun 2024 | https://doi.org/10.1038/s41419-024-06763-x |
| PB1 domain | N-terminal oligomerization/polymerization module that helps build p62 bodies/condensates, supports aggregate capture, and regulates accessibility of the LC3-binding LIR; also implicated in signaling scaffolds. | 2024 in vitro work showed PB1 contributes to regulation of LC3B binding via a proposed LIR-sequence Accessibility Mechanism (LAM). In proteomics/interactome studies, PB1 was required for interaction with aggregation-prone K18-tau; removal abrogated binding. PB1 is also listed among core domains in recent reviews/tables of p62 function. (pqac-00000006, pqac-00000017, pqac-00000007) | Alcober-Boquet, *Protein Science*, Dec 2024; Rondón-Ortiz, *JBC*, Sep 2024 | https://doi.org/10.1002/pro.4840; https://doi.org/10.1016/j.jbc.2024.107621 |
| ZZ domain | Regulatory zinc-finger module that modulates p62 conformation and promotes/exposes the LIR for LC3B engagement; also a signaling/drug-targeting interface. | Alcober-Boquet et al. identified ZZ-dependent control of LC3B interaction; a phosphomimetic Thr138Glu mutant increased LC3B binding, and a small-molecule ZZ binder also enhanced binding, supporting pharmacologic tunability of p62–LC3 interaction. (pqac-00000006, pqac-00000000) | Alcober-Boquet, *Protein Science*, Dec 2024 | https://doi.org/10.1002/pro.4840 |
| LIR motif | Canonical LC3/GABARAP-binding motif that tethers p62-bound cargo to autophagosomal membranes during selective autophagy. | Direct p62–LC3B interaction was quantified in AlphaScreen assays: 7 nM His-Trx-p62 + 3.5 nM GST-LC3B produced 60,861 ± 2,473 AU versus background 1,573 ± 108 AU; an LIR peptide competitor reduced signal to ~1,714 ± 104 AU; assay Z' = 0.87, showing robust measurable LIR-dependent binding. (pqac-00000004, pqac-00000006) | Alcober-Boquet, *Protein Science*, Dec 2024 | https://doi.org/10.1002/pro.4840 |
| KIR motif | KEAP1-interacting region that enables p62 to sequester/degrade KEAP1 and thereby activate NRF2-dependent antioxidant transcription. | Recent mechanistic synthesis describes p62 as a scaffold in KEAP1–NRF2 signaling; Choi et al. further show stress-induced SQSTM1 is required for KEAP1 degradation and NRF2 activation, placing the KIR-containing region at the core of this signaling function. Domain architecture tables and recent interactome work also explicitly list KIR. (pqac-00000006, pqac-00000005, pqac-00000002) | Choi, *Autophagy*, Jul 2024; Rondón-Ortiz, *JBC*, Sep 2024 | https://doi.org/10.1080/15548627.2024.2374692; https://doi.org/10.1016/j.jbc.2024.107621 |
| UBA domain | C-terminal ubiquitin-binding module that recognizes ubiquitinated cargo for aggrephagy/selective autophagy; also participates in regulated ubiquitination of p62 itself. | Recent summaries and experiments identify UBA as the ubiquitin-recognition module of p62. In NS1-BP/stress-granule work, p62 lysines K420 and K435 were functionally important for ubiquitination-dependent phenotypes; in other recent studies UBA-dependent interactions were required for some proximity-labeled partners. (pqac-00000007, pqac-00000020, pqac-00000019) | Jeon, *Nature Communications*, Dec 2024; Rondón-Ortiz, *JBC*, Sep 2024 | https://doi.org/10.1038/s41467-024-55446-w; https://doi.org/10.1016/j.jbc.2024.107621 |
| Selective autophagy receptor / aggrephagy | p62 bridges ubiquitinated proteins/aggregates to LC3/GABARAP-positive autophagosomes and helps organize cargo into higher-order assemblies/condensates. | Multiple recent sources describe p62 as a selective autophagy receptor/adaptor that binds ubiquitinylated cargo and ATG8-family proteins. Human SQSTM1 is also reported to form bodies/condensates and scaffold aggregate handling. (pqac-00000001, pqac-00000002, pqac-00000005) | Gibertini, *IJMS*, May 2023; Rondón-Ortiz, *JBC*, Sep 2024; Choi, *Autophagy*, Jul 2024 | https://doi.org/10.3390/ijms24098456; https://doi.org/10.1016/j.jbc.2024.107621; https://doi.org/10.1080/15548627.2024.2374692 |
| p62–LC3B binding regulation (LAM model) | PB1/ZZ domains regulate whether the LIR is exposed or occluded, tuning autophagosome engagement. | Figure-level evidence and biochemical assays support a LIR-sequence Accessibility Mechanism (LAM) in which PB1 and ZZ regulate LIR exposure; the 2024 paper provides both a domain schematic and a mechanistic model for how modification or ligand binding can increase LC3 access. (pqac-00000025, pqac-00000026, pqac-00000006) | Alcober-Boquet, *Protein Science*, Dec 2024 | https://doi.org/10.1002/pro.4840 |
| Cellular localization | Predominantly cytosolic but also present in nucleus; forms cytoplasmic bodies/condensates and associates with autophagosomes, aggregates, and stress-related structures. | Recent proximity-labeling work states SQSTM1 is mainly cytosolic, also detected in the nucleus, and may shuttle ubiquitinylated nuclear proteins to the cytosol; multiple studies describe SQSTM1 bodies/condensates and recruitment to aggregates. (pqac-00000002, pqac-00000023) | Rondón-Ortiz, *JBC*, Sep 2024 | https://doi.org/10.1016/j.jbc.2024.107621 |
| Condensates / interactome remodeling | p62 bodies act as dynamic hubs whose protein neighborhood changes with proteotoxic stress and tau aggregation. | TurboID::SQSTM1 proteomics identified 236 unique proximity proteins and an overlapping subset of 83 linked to autophagy/catabolic processes. Under MG132, 51 proteins were enriched using Log2FC > 0.58 and FDR < 0.05. Tau fibrils changed 24 proteins at 24 h and 98 proteins at 48 h (Log2FC > 0.58, p < 0.05; n = 4). (pqac-00000023, pqac-00000019, pqac-00000022) | Rondón-Ortiz, *JBC*, Sep 2024 | https://doi.org/10.1016/j.jbc.2024.107621 |
| AMPK–p62–NRF2 feedback loop | Under metabolic stress, p62 both activates and is induced by AMPK/lysosomal stress pathways, creating a positive feedback loop that promotes KEAP1 degradation, NRF2 signaling, and antioxidant defense. | Choi et al. report a “double-positive feedback loop” between AMPK and SQSTM1/p62: metabolic stress increased p62 expression/phosphorylation; p62 promoted autophagic KEAP1 degradation and facilitated AXIN–STK11–AMPK complex formation on lysosomes; phosphorylation at S24 and S226 was critical for AMPK and NRF2 activation. (pqac-00000005) | Choi, *Autophagy*, Jul 2024 | https://doi.org/10.1080/15548627.2024.2374692 |
| Stress granules / granulophagy via NS1-BP | p62 helps target stress granules for autophagic clearance; NS1-BP restrains p62 ubiquitination and supports GABARAP recruitment to stress granules. | In NS1-BP knockout cells, p62 ubiquitination increased and p62 underwent autophagic degradation; WT p62, but not K420R or K435R mutants, restored ubiquitination-dependent phenotypes. NS1-BP loss altered stress-granule number/size/dynamics and reduced contact between ubiquitinated p62 aggregates and stress granules. (pqac-00000020, pqac-00000021) | Jeon, *Nature Communications*, Dec 2024 | https://doi.org/10.1038/s41467-024-55446-w |
| Disease relevance / Paget disease of bone (clinical translation) | Germline SQSTM1 mutations are a major risk factor for Paget disease of bone; preventive treatment strategies are now being tested in mutation carriers. | In the ZiPP program, SQSTM1 mutation carriers were prospectively screened and treated. Background estimates in the trial report note ~80% penetrance by the seventh decade in carriers from familial PDB settings. (pqac-00000015, pqac-00000010) | Phillips, *Efficacy and Mechanism Evaluation*, Jun 2024; Phillips, *Ann Rheum Dis*, Apr 2024 | https://doi.org/10.3310/ftkc2007; https://doi.org/10.1136/ard-2023-224990 |
| ZiPP RCT: trial population and baseline disease burden | Real-world implementation of SQSTM1 genetic testing plus radionuclide scanning in relatives at risk for Paget disease. | 1,307 people were offered SQSTM1 testing, 750 were tested, 350 (46.7%) were mutation-positive, and 222 enrolled in the RCT. Median follow-up was 84 months; 180/222 (81%) completed the study. Baseline PDB lesions were present in 21/222 (9.5%); arm-specific baseline prevalence was 8.1% (ZA) vs 10.8% (placebo). (pqac-00000014, pqac-00000012, pqac-00000010) | Phillips, *EME*, Jun 2024; Phillips, *Ann Rheum Dis*, Apr 2024 | https://doi.org/10.3310/ftkc2007; https://doi.org/10.1136/ard-2023-224990 |
| ZiPP RCT: prevention/progression outcomes | A single 5 mg zoledronic acid infusion favorably modified early SQSTM1-associated Paget lesions, though the primary endpoint was underpowered due to few new lesions. | New lesions: 0/90 in ZA vs 2/90 (2.2%) in placebo; OR 0.41 (95% CI 0.00–3.43), p = 0.25. Composite poor outcome: 0 in ZA vs 8 in placebo; OR 0.08 (95% CI 0.00–0.42), p = 0.003. At study end, lesions remained in 1/111 ZA vs 11/111 placebo participants. (pqac-00000010, pqac-00000012, pqac-00000009) | Phillips, *EME*, Jun 2024; Phillips, *Ann Rheum Dis*, Apr 2024 | https://doi.org/10.3310/ftkc2007; https://doi.org/10.1136/ard-2023-224990 |
| ZiPP RCT: lesion-level efficacy and biomarkers | Demonstrates measurable lesion regression and suppression of bone turnover in SQSTM1 carriers, supporting biomarker-guided preventive intervention. | Existing-lesion disappearance was 13/15 (86.6%) with ZA vs 1/29 (3.4%) with placebo, p < 0.0001. In the lesion-level analysis, ZA baseline lesions = 15: 13 disappeared, 2 diminished, 0 new lesions; placebo baseline lesions = 25 with 1 disappeared, 12 reduced, 8 stable, 4 increased, ending with 26 lesions. Bone-turnover markers CTX and PINP fell with p < 0.0001 and BAP with p = 0.0003 in ZA vs placebo. PDB-related skeletal events were 3 with ZA vs 13 with placebo. (pqac-00000010, pqac-00000013) | Phillips, *EME*, Jun 2024 | https://doi.org/10.3310/ftkc2007 |


*Table: This table summarizes the core functional annotation of human SQSTM1/p62 (UniProt Q13501), combining domain-level mechanism, recent molecular studies, and 2024 clinical trial data. It is designed to support a concise, evidence-based narrative on p62 function, localization, signaling, and translational relevance.*