| Biological process/pathway | Localization | Molecular role/mechanism | Key experimental evidence (assays/models) | Quantitative/statistical highlights | Key reference with publication date and URL |
|---|---|---|---|---|---|
| ER-associated degradation (ERAD) and membrane protein extraction | ER membrane; also reported at mitochondrial outer membrane and peroxisomes | FAF2 is an ER-tethered p97/VCP adaptor. Its UBX domain binds p97, and a UBH-UBX module enhances p97-UFD1L-NPLOC4 engagement with ubiquitinated substrates, boosting mechanical unfolding/extraction; FAF2 forms ternary complexes with p97 and ubiquitinated clients such as CD4. UBA is less important than UBH/UBX for extraction in these assays. (pqac-00000002, pqac-00000027, pqac-00000031) | Reconstituted extraction of ubiquitinated mCD4 from microsomes; tandem IP showing CD4–FAF2–p97 complex; FAF2 knockout/depletion assays monitoring CD4, TCRα, mTAP2, ABCG2-F208S degradation; ATPase and unfolding assays with purified p97-UN ± FAF2 constructs. (pqac-00000002, pqac-00000027, pqac-00000031) | FAF2 knockout increased steady-state CD4 by ~10-fold; FAF2 UBH-UBX raised p97 ATPase from ~2.7 s^-1 to ~4.3 s^-1 and increased unfolding ~2-fold; UBH mutants abolished/strongly impaired stimulation. (pqac-00000002, pqac-00000027, pqac-00000028) | Huo et al., *Nature Communications* (Nov 2025). https://doi.org/10.1038/s41467-025-65166-4 |
| Lipid droplet turnover / lipolysis control | ER and lipid droplets | LD-localized FAF2/UBXD8 recruits p97/VCP to lipid droplets, binds ATGL, and restrains ATGL-mediated triacylglycerol hydrolysis by promoting dissociation of ATGL from its activator CGI-58; UBAC2 restricts FAF2 trafficking from ER to LDs. (pqac-00000018, pqac-00000019, pqac-00000020) | Immunolocalization and LD fractionation after oleate loading; UBAC2 overexpression or knockdown to alter FAF2 partitioning; LD size/number quantification by BODIPY; ^14C-oleate pulse-chase TAG turnover; co-IP of UBXD8 with ATGL; split-YFP complementation for ATGL–CGI-58 interaction; ATGL-null MEFs. (pqac-00000016, pqac-00000017, pqac-00000019, pqac-00000020) | ATGL overexpression reduced LD content ~3- to 4-fold, largely abrogated by UBXD8-S; ATGL half-life ~45 min and >12 h with MG132, but UBXD8 did not change ATGL stability; dominant-negative p97/VCP and UBX deletion blocked UBXD8 LD effects; significance typically P < 0.05, with ~500–600 droplets quantified in some analyses. (pqac-00000019, pqac-00000020) | Olzmann et al., *PNAS* (Jan 2013). https://doi.org/10.1073/pnas.1213738110 |
| ER–mitochondria contact site regulation and lipid saturation control | ER–mitochondria contact sites / MAMs | The p97–UBXD8 complex localizes to ERMCS and limits excessive contacts by promoting INSIG1 turnover, enabling SREBP1 activation and SCD1-dependent lipid desaturation. Loss of the complex increases membrane saturation/order, stabilizing contacts; unsaturated fatty acids or SCD1 rescue the phenotype. (pqac-00000010, pqac-00000011, pqac-00000012) | Split-luciferase and SPLICS/split-GFP contact reporters; MAM fractionation; TMT proteomics of WT vs UBXD8 KO ERMCS; lipidomics of MAM fractions; pyrene-based membrane order assays; rescue with wild-type p97/UBXD8, SCD1 overexpression, oleic acid, or palmitic acid control; TEM/confocal contact measurements. (pqac-00000010, pqac-00000012, pqac-00000013, pqac-00000014, pqac-00000035) | Proteomics identified 4,499 proteins in ERMCS fractions, with 102 enriched and 112 depleted in UBXD8 KO; ~two-thirds of measured PC/PE/LPC/LPE species increased in UBXD8 KO ([log2 KO:WT] > 1, P < 0.05); many TG and DG species were ≥2-fold elevated; rescue comparisons showed strong significance (e.g., p = 7.46 × 10^-10; other panels p = 9 × 10^-9 to 1.89 × 10^-7). Oleic acid, but not palmitic acid, rescued increased contacts. (pqac-00000008, pqac-00000009, pqac-00000012, pqac-00000013, pqac-00000014) | Ganji et al., *Nature Communications* (Feb 2023). https://doi.org/10.1038/s41467-023-36298-2 |
| Peroxisomal membrane protein quality control and suppression of basal pexophagy | Peroxisomes; also ER/lipid droplets/mitochondria reported | FAF2 partners with p97/VCP, UFD1, and NPLOC4 to extract ubiquitylated peroxisomal membrane proteins such as PMP70/PEX16, thereby preventing OPTN recruitment and inappropriate basal pexophagy. HP/membrane-association is critical; UBA is dispensable in this context. (pqac-00000001, pqac-00000004, pqac-00000007, pqac-00000032) | FAF2 knockout HCT116 cells; mKeima-SKL FACS pexophagy assay; IP of 3HA-FAF2 with PMP70, PEX16, USP30, p97/VCP, NPLOC4, UFD1; proximity ligation assay with PMP70; p97 inhibition (NMS-873); domain-mutant reconstitution; PMP70 knockdown rescue experiments. (pqac-00000001, pqac-00000006, pqac-00000007) | FAF2 loss significantly accelerated pexophagy; one assay showed basal pexophagy rising from 3.9% to 15.5 ± 0.5% in FAF2 KO, rescued to 3.2 ± 0.2% by WT FAF2 but only to 7.0 ± 0.4% by a UBH mutant; reported statistics included p = 1.25E-04 and p = 6.46E-03, with multiple panels at p < 0.0001. (pqac-00000001, pqac-00000005, pqac-00000007) | Koyano et al., *Nature Communications* (Oct 2024). https://doi.org/10.1038/s41467-024-53558-x |
| General stimulation of mammalian p97-UFD1-NPL4 unfoldase | Membrane-associated sites including ER, lipid droplets, and nuclear outer membrane/peripheral membranes | FAF2 is a UBX-family cofactor that lowers the ubiquitin-chain threshold required for mammalian p97-UFD1-NPL4 substrate processing. Its UBX domain is essential, the UBA domain is dispensable, and a coiled-coil region is required/sufficient together with UBX to stimulate unfoldase activity. (pqac-00000022, pqac-00000023, pqac-00000024, pqac-00000025) | In vitro CMG helicase disassembly assays with soluble FAF2ΔM; truncation/domain mutants; tests of dependence on UFD1-NPL4 and NPL4 groove; genetic interaction analyses with related UBX proteins. (pqac-00000022, pqac-00000023, pqac-00000025, pqac-00000026) | In the presence of FAF2/FAF1/UBXN7, human p97-UFD1-NPL4 could process substrates bearing ≥5 ubiquitins, reducing the otherwise high ubiquitin threshold toward the yeast-like minimum. (pqac-00000022, pqac-00000024, pqac-00000026) | Fujisawa et al., *eLife* (Aug 2022). https://doi.org/10.7554/eLife.76763 |
| Interaction network / adaptor classification | ER-tethered adaptor with links to mitochondria and membrane-trafficking systems | Systematic proteomics places FAF2/UBXD8 within the membrane-tethered UBXD adaptors of the VCP/p97 network, associated with ERAD, lipid droplet homeostasis, and possible mitochondrial/mitophagy-related functions. Interactors include AMFR, DERLIN2, AUP1, BAG6, UBAC2, and shared VCP-network components; UFD1L/NPLOC4 broadly associate with UBXD adaptors. (pqac-00000029, pqac-00000030, pqac-00000033) | Comparative AP-MS of VCP and 13 UBXD adaptors in human cells with CompPASS filtering, reciprocal validation, and localization analyses. (pqac-00000029, pqac-00000030, pqac-00000034) | Network study identified 169 high-confidence interacting proteins under stringent criteria and showed UFD1L/NPLOC4 association with 11/14 UBXD proteins in the dataset; FAF2 clustered with membrane/ERAD factors and partially colocalized with mitochondria. (pqac-00000029, pqac-00000030) | Raman et al., *Nature Cell Biology* (Sep 2015). https://doi.org/10.1038/ncb3238 |


*Table: This table summarizes experimentally supported functions, localizations, mechanisms, and quantitative findings for human FAF2/UBXD8/ETEA/UBXN3B. It is useful as a concise evidence map linking FAF2 to ERAD, lipid droplet biology, ER–mitochondria contacts, peroxisome quality control, and p97/VCP-dependent substrate extraction.*