| Category | Key claims | Evidence type (review/primary/DB) | Key citations (context IDs) | Source (paper title, year, DOI URL) |
|---|---|---|---|---|
| Identity/domains | Human **LONP2** corresponds to UniProt **Q86WA8**, a nuclear-encoded peroxisomal Lon A family protease of ~852 aa/~95 kDa with N-terminal substrate-recognition region, **AAA+ ATPase** domain (Walker motifs), serine protease domain, and C-terminal **PTS1/SRL** targeting motif; it shares ~39.6% identity with mitochondrial LONP1. | Review | (pqac-00000001, pqac-00000015) | *The peroxisomal Lon protease LonP2 in aging and disease: functions and comparisons with mitochondrial Lon protease LonP1* (2017), https://doi.org/10.1111/brv.12253 |
| Localization/import | LONP2 is localized to the **peroxisomal matrix** and imported via a **C-terminal PTS1** recognized by the peroxisomal import machinery; mammalian studies localized LonP2 to peroxisomes, with enrichment in the dense core of rat liver peroxisomes. | Review | (pqac-00000008, pqac-00000001) | *The peroxisomal Lon protease LonP2 in aging and disease: functions and comparisons with mitochondrial Lon protease LonP1* (2017), https://doi.org/10.1111/brv.12253 |
| Localization/import | In LONP2-silenced cells, import of a luminal **CFP-SKL** reporter fails while membrane import (**PEX3-YFP**) remains intact, indicating a selective defect in matrix/lumenal protein homeostasis rather than membrane protein targeting. | Primary | (pqac-00000003, pqac-00000017) | *Depletion of LONP2 unmasks differential requirements for peroxisomal function between cell types and in cholesterol metabolism* (2023), https://doi.org/10.1186/s13062-023-00416-3 |
| Enzymatic activity | LONP2 is an **ATPase** and **ATP-stimulated serine protease** (EC 3.4.21.53); purified LonP2 degrades misfolded **α- and β-casein** in vitro in an ATP-dependent manner, and catalytic-serine mutation abolishes proteolysis. | Review summarizing primary biochemistry | (pqac-00000001, pqac-00000015) | *The peroxisomal Lon protease LonP2 in aging and disease: functions and comparisons with mitochondrial Lon protease LonP1* (2017), https://doi.org/10.1111/brv.12253 |
| Enzymatic activity | Human/vertebrate peroxisomal Lon protease architecture includes **AAA ATPase** and serine protease domains; protease-inactive mutant **Ser743Ala** was used to probe function in cells. | Primary | (pqac-00000012, pqac-00000014) | *Two Proteases, Trypsin Domain-containing 1 (Tysnd1) and Peroxisomal Lon Protease (PsLon), Cooperatively Regulate Fatty Acid β-Oxidation in Peroxisomal Matrix* (2011), https://doi.org/10.1074/jbc.m111.285197 |
| Substrates | A supported substrate relationship is **TYSND1 → LONP2**: TYSND1 self-cleaves into 15- and 45-kDa fragments, and these processed forms are degraded by peroxisomal Lon/PsLon. | Primary | (pqac-00000011, pqac-00000012) | *Two Proteases, Trypsin Domain-containing 1 (Tysnd1) and Peroxisomal Lon Protease (PsLon), Cooperatively Regulate Fatty Acid β-Oxidation in Peroxisomal Matrix* (2011), https://doi.org/10.1074/jbc.m111.285197 |
| Substrates | LONP2 also preferentially removes **oxidatively damaged/misfolded proteins**; oxidized catalase becomes susceptible to LonP2-dependent degradation, whereas native catalase is resistant. | Review summarizing primary biochemistry | (pqac-00000010, pqac-00000004) | *The peroxisomal Lon protease LonP2 in aging and disease: functions and comparisons with mitochondrial Lon protease LonP1* (2017), https://doi.org/10.1111/brv.12253 |
| Cellular pathways/phenotypes | Acute LONP2 depletion triggers **peroxisomal proteotoxic stress**, causing accumulation of TYSND1, **fewer and enlarged/elongated peroxisomes**, and failure of luminal import while many steady-state peroxisomal protein levels remain initially preserved. | Primary | (pqac-00000002, pqac-00000003, pqac-00000017) | *Depletion of LONP2 unmasks differential requirements for peroxisomal function between cell types and in cholesterol metabolism* (2023), https://doi.org/10.1186/s13062-023-00416-3 |
| Cellular pathways/phenotypes | LONP2 loss reveals cell-type-specific signaling responses: strong **integrated stress response (ISR)** activation in COS-7 cells, plus shared **retinoic acid signaling repression**, **sphingolipid upregulation**, and **cholesterol accumulation in endomembrane compartments** in both COS-7 and U2OS cells. | Primary | (pqac-00000002, pqac-00000013) | *Depletion of LONP2 unmasks differential requirements for peroxisomal function between cell types and in cholesterol metabolism* (2023), https://doi.org/10.1186/s13062-023-00416-3 |
| Cellular pathways/phenotypes | The 2023 lipidomics dataset comprised **2,094 lipid features** with **206 annotated**, supporting links between LONP2 deficiency, altered very-long-chain lipid handling, sphingomyelin remodeling, and cholesterol trafficking defects. | Primary | (pqac-00000013) | *Depletion of LONP2 unmasks differential requirements for peroxisomal function between cell types and in cholesterol metabolism* (2023), https://doi.org/10.1186/s13062-023-00416-3 |
| Cellular pathways/phenotypes | In the Okumoto study, peroxisomal β-oxidation of **1-14C-lignoceric acid** was significantly decreased after **TYSND1** knockdown and partially reduced after **PsLon/LONP2** knockdown, supporting a modulatory role in peroxisomal fatty-acid β-oxidation. | Primary | (pqac-00000009, pqac-00000011) | *Two Proteases, Trypsin Domain-containing 1 (Tysnd1) and Peroxisomal Lon Protease (PsLon), Cooperatively Regulate Fatty Acid β-Oxidation in Peroxisomal Matrix* (2011), https://doi.org/10.1074/jbc.m111.285197 |
| Cellular pathways/phenotypes | General peroxisomal QC context: most organisms use a **peroxisomal LON protease** to degrade misfolded/dysfunctional matrix proteins, while membrane-protein QC relies mainly on the **ubiquitin–proteasome system**. | Review | (pqac-00000005) | *Import and quality control of peroxisomal proteins* (2023), https://doi.org/10.1242/jcs.260999 |
| Disease links | Direct human disease mechanism data remain limited, but authoritative databases list **LONP2** associations including **Buratti-Harel syndrome** and other disease terms; these database links appear to be driven by shared evidence and should be interpreted cautiously pending dedicated functional validation. | DB | (pqac-00000000) | Open Targets LONP2 associations (accessed via Open Targets context), evidence linked to PMID 32430360 |
| Disease links | Expert reviews emphasize that, compared with LONP1, **much less is known** about LONP2 in human aging and disease, and mechanistic/clinical studies are still sparse. | Review/expert analysis | (pqac-00000004, pqac-00000015) | *The peroxisomal Lon protease LonP2 in aging and disease: functions and comparisons with mitochondrial Lon protease LonP1* (2017), https://doi.org/10.1111/brv.12253 |


*Table: This table condenses the strongest gathered evidence on human LONP2/Q86WA8, covering verified identity, localization, enzymatic function, substrates, pathway roles, and disease evidence. It is designed as a citation-ready scaffold for the final research report.*