Affinage

Showing UBD — FAT10 is a alias.

UBD

Ubiquitin D · UniProt O15205

Length
165 aa
Mass
18.5 kDa
Annotated
2026-06-10
100 papers in source corpus 48 papers cited in narrative 48 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FAT10 (UBD) is a ubiquitin-like protein modifier that conjugates to target proteins through its C-terminal diglycine motif and directs them, together with itself, to the 26S proteasome for degradation (PMID:11445583, PMID:15831455). Activation proceeds through a dedicated enzymatic cascade: the E1 enzyme UBA6 activates FAT10 by adenylation and thioester formation requiring its active-site cysteine and FAT10's diglycine motif (PMID:17889673, PMID:22427669), and transfers it to the E2 enzyme USE1, which auto-FAT10ylates itself in cis and is the first identified substrate of the pathway (PMID:20975683); specificity for UBA6/USE1 is encoded in FAT10's C-terminal CYCI tetrapeptide (PMID:26555268), and Parkin acts as an E3 ligase that drives auto-FAT10ylation and modification of Mitofusin2 (PMID:33730565). FAT10-mediated proteolysis is ubiquitin-independent and instead requires NUB1L, which docks FAT10 to the proteasome via the VWA domain of Rpn10 and via Rpn1 (PMID:14757770, PMID:19166848, PMID:22434192); NUB1 exploits FAT10's intrinsic structural plasticity and low thermodynamic stability to trap its unfolded N-terminal domain and deliver it to the proteasome, enabling co-degradation of FAT10 and substrate without de-conjugation (PMID:30127417, PMID:38984715, PMID:40217121). Beyond covalent conjugation, FAT10 acts noncovalently to stabilize or sequester binding partners: it binds the SUMO E1 AOS1/UBA2 to inhibit SUMO activation (PMID:31575873), the spindle-checkpoint protein MAD2 to displace it from kinetochores and drive chromosomal instability (PMID:16495226, PMID:25422469), and competes with ubiquitin on shared lysines of substrates such as β-catenin to stabilize them and promote oncogenic signaling (PMID:25056121, PMID:27312528). FAT10 is induced by TNF-α/NF-κB signaling and negatively regulated by p53 (PMID:16501612, PMID:22025632), and functions in immune regulation, antiviral signaling through RIG-I suppression (PMID:26996158, PMID:31433974), antigen presentation and thymic selection (PMID:22349260, PMID:26401002), and mitochondrial quality control by inhibiting Parkin-dependent mitophagy (PMID:33730565).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1999 Medium

    Established the first FAT10 binding partner, linking the protein to mitotic checkpoint control before its enzymology was understood.

    Evidence Yeast two-hybrid screen and reciprocal co-IP identifying MAD2 association

    PMID:10200259

    Open questions at the time
    • Interaction interface not mapped at this stage
    • Functional consequence for the checkpoint not yet demonstrated
  2. 2001 Medium

    Demonstrated that FAT10 is a covalent protein modifier whose conjugation depends on its C-terminal diglycine and has cellular consequences.

    Evidence Tetracycline-repressible expression with diglycine mutant and apoptosis readouts in mouse fibroblasts

    PMID:11445583

    Open questions at the time
    • Conjugating enzymes unidentified
    • Substrate identities unknown
  3. 2005 High

    Defined FAT10 as a proteasomal degradation signal acting independently of ubiquitin, distinguishing it from canonical ubiquitin-mediated turnover.

    Evidence Cycloheximide chase, proteasome inhibition, lysine-mutant FAT10, ubiquitylation-deficient cells and FAT10-GFP fusion assays

    PMID:15831455

    Open questions at the time
    • Mechanism of proteasome docking not yet resolved
    • A 2011 study (#13) reported ubiquitin-dependence, leaving the requirement contested
  4. 2007 High

    Identified UBA6 as the activating E1 enzyme, establishing the entry point of the FAT10 conjugation cascade.

    Evidence In vitro thioester assay with active-site cysteine mutagenesis plus cellular RNAi

    PMID:17889673

    Open questions at the time
    • Downstream E2 not yet identified at this point
  5. 2010 High

    Identified USE1 as the dedicated E2 and first pathway substrate, completing the E1-E2 transfer chain and revealing cis auto-modification.

    Evidence In vitro FAT10 transfer assay, cis vs trans auto-FAT10ylation, siRNA knockdown

    PMID:20975683

    Open questions at the time
    • E3 ligases for general substrates not defined
    • Mechanism of cis-only auto-modification unexplained
  6. 2009 High

    Established NUB1L as the strict cofactor coupling FAT10 to the proteasome, explaining ubiquitin-independent delivery.

    Evidence In vitro degradation of FAT10-DHFR by purified 26S proteasome and cellular NUB1L knockdown

    PMID:14757770 PMID:19166848

    Open questions at the time
    • Structural basis of NUB1L-FAT10-proteasome engagement not yet resolved
  7. 2012 High

    Mapped the proteasomal docking site, showing FAT10/NUB1L engage the Rpn10 VWA domain and Rpn1, providing the receptor for ubiquitin-independent delivery.

    Evidence Co-IP, domain mapping, siRNA depletion and yeast complementation with VWA-only Rpn10

    PMID:22434192

    Open questions at the time
    • How the engaged substrate is unfolded at the proteasome not addressed
    • Stoichiometry of the delivery complex unknown
  8. 2012 High

    Defined the endogenous FAT10 substrate landscape by proteomics, anchoring FAT10 to autophagy and confirming hundreds of conjugates.

    Evidence Immunopurification of endogenous conjugates with mass spectrometry identifying 569 interactors and validating p62/SQSTM1 modification

    PMID:22797925

    Open questions at the time
    • Site-specific modification stoichiometry on most substrates unknown
    • Functional consequence beyond p62 degradation not established
  9. 2014 High

    Localized the MAD2-binding interface to FAT10's first UBL domain and showed its disruption abolishes pro-tumorigenic activity, separating a noncovalent function from conjugation.

    Evidence NMR structure, residue-specific mutagenesis, and in vitro/in vivo tumor assays

    PMID:25422469

    Open questions at the time
    • How displaced MAD2 fails to localize to kinetochores mechanistically unresolved
  10. 2016 Medium

    Demonstrated that FAT10 stabilizes oncogenic substrates by directly competing with ubiquitin for shared lysines.

    Evidence Co-IP, lysine-mutant analysis and dual conjugate detection on eEF1A1, alongside β-catenin stabilization (#21)

    PMID:25056121 PMID:27312528

    Open questions at the time
    • Generality of competition versus active conjugation across substrates not quantified
  11. 2019 High

    Revealed a noncovalent regulatory function: FAT10 inhibits SUMO activation by directly impeding the SUMO E1, expanding its role beyond degradation.

    Evidence In vitro thioester competition assay and cellular PML-body and SUMO-conjugation readouts

    PMID:31575873

    Open questions at the time
    • In vivo consequences of SUMO suppression not defined
  12. 2021 High

    Identified Parkin as a FAT10 E3 ligase and a reciprocal regulatory loop in which FAT10ylation of Parkin inhibits mitophagy.

    Evidence In vitro FAT10ylation reconstitution, co-IP, and mitochondrial depolarization assays

    PMID:33730565

    Open questions at the time
    • Whether other E3 ligases serve different substrate classes unknown
  13. 2024 High

    Explained why FAT10 functions as a degron: its intrinsic structural instability and rapid unfolding promote proteasomal engagement and destabilize attached substrates.

    Evidence NMR relaxation, hydrogen-deuterium exchange, force spectroscopy and in vitro degradation assays

    PMID:30127417 PMID:38984715

    Open questions at the time
    • Behavior on physiological multi-domain substrates in vivo not fully tested
  14. 2025 High

    Visualized the delivery mechanism, showing NUB1 traps FAT10's unfolded N-terminal UBL and docks it to proteasomal Rpn1 independently of ubiquitin and p97.

    Evidence Cryo-EM, in vitro reconstitution, HDX and mutagenesis of the NUB1-proteasome complex

    PMID:40217121

    Open questions at the time
    • Hand-off from NUB1 to the ATPase translocation channel not resolved
    • Regulation of NUB1 activation in cells unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How FAT10 substrate selection is achieved for its hundreds of conjugates, and what E3 ligases beyond Parkin direct specific FAT10ylation, remains unresolved.
  • No general substrate-recognition code defined
  • Few E3 ligases identified
  • Balance between covalent conjugation and noncovalent sequestration per substrate unclear

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0031386 protein tag activity 3 GO:0140313 molecular sequestering activity 2
Localization
GO:0005829 cytosol 3 GO:0005634 nucleus 2
Pathway
R-HSA-168256 Immune System 4 R-HSA-392499 Metabolism of proteins 4 R-HSA-1640170 Cell Cycle 2 R-HSA-9612973 Autophagy 2
Partners
AOS1HDAC6MAD2NUB1LOTUB1RPN10UBA6USE1

Evidence

Reading pass · 48 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 FAT10 noncovalently associates with MAD2, a spindle-assembly checkpoint protein, as determined by yeast two-hybrid screening and immunoprecipitation studies. Yeast two-hybrid screen, co-immunoprecipitation Proceedings of the National Academy of Sciences of the United States of America Medium 10200259
2001 FAT10 forms covalent conjugates with cellular proteins via its C-terminal diglycine motif (isopeptide bond), and expression of wild-type but not diglycine-mutant FAT10 induces caspase-dependent apoptosis in mouse fibroblasts. Tetracycline-repressible expression system, annexin V staining, DNA fragmentation assay, diglycine mutant The Journal of biological chemistry Medium 11445583
2004 NUB1L (NEDD8 ultimate buster-1L) interacts noncovalently with FAT10 more strongly than with NEDD8, and NUB1L coexpression accelerates FAT10 degradation approximately 8-fold, likely by linking FAT10 to the proteasome via RPN10. Yeast two-hybrid screen, co-immunoprecipitation, GST pull-down, cycloheximide chase degradation assay The Journal of biological chemistry High 14757770
2005 FAT10 and its conjugates are rapidly degraded by the proteasome in a ubiquitin-independent manner; mutation of all lysines on FAT10 or expression in ubiquitylation-deficient cells does not impair FAT10 degradation; N-terminal fusion of FAT10 to long-lived proteins accelerates their degradation as potently as ubiquitin fusion. Cycloheximide chase, proteasome inhibitor treatment, ubiquitylation-deficient cell lines, FAT10-GFP fusion protein degradation assay Molecular and cellular biology High 15831455
2006 FAT10 overexpression reduces kinetochore localization of MAD2 during prometaphase, abbreviates mitotic phase, and causes increased chromosomal instability (multinucleation, variable chromosome number) in cells. Immunofluorescence, flow cytometry, double-thymidine synchronization, nocodazole treatment, chromosome counting The Journal of biological chemistry Medium 16495226
2006 p53 negatively regulates FAT10 expression by binding to a p53-binding site in the FAT10 promoter (5'UTR region), as shown by promoter-luciferase assays and chromatin immunoprecipitation. Promoter-luciferase assay, siRNA knockdown, ChIP, p53 transfection into p53-null cells Oncogene Medium 16501612
2007 UBA6 (E1-L2) is the E1-activating enzyme for FAT10; it forms a thioester with FAT10 in vitro requiring UBA6's active-site cysteine and FAT10's C-terminal diglycine motif; RNAi silencing of UBA6 blocks FAT10 conjugate formation in cells. In vitro thioester formation assay, active-site cysteine mutagenesis, RNAi knockdown, endogenous co-immunoprecipitation Molecular cell High 17889673
2008 FAT10 interacts with HDAC6 via the HDAC6 BUZ domain and first catalytic domain (catalytic activity not required); under proteasome impairment, FAT10 and FAT10 conjugates localize to aggresomes in a microtubule-dependent manner, and aggresome formation is reduced in HDAC6-deficient fibroblasts. Co-immunoprecipitation, domain mapping, live-cell imaging, microtubule depolymerization, HDAC6-deficient fibroblasts Journal of cell science High 19033385
2009 FAT10-mediated degradation of FAT10-DHFR by purified 26S proteasome in vitro is ubiquitin-independent but strictly requires NUB1L; NUB1L knockdown attenuates FAT10-DHFR degradation in intact cells. In vitro proteasome degradation assay with purified components, siRNA knockdown, cycloheximide chase FEBS letters High 19166848
2009 FAT10 deficiency in renal tubular epithelial cells impairs TNF-α-induced IκBα degradation and p65 nuclear translocation, and reduces LMP2 expression; re-expression of FAT10 restores NF-κB activation, and LMP2 transfection rescues IκBα degradation in FAT10-deficient cells. FAT10-/- mouse-derived cells, lentiviral transduction, Western blot, nuclear fractionation, NF-κB reporter assay Journal of the American Society of Nephrology : JASN Medium 19959714
2010 USE1 (UBA6-specific E2 enzyme) is both the first E2 conjugating enzyme and the first identified substrate in the FAT10 pathway; activated FAT10 is transferred from UBA6 onto USE1 in vitro; USE1 auto-FAT10ylates itself in cis but not in trans; siRNA-mediated USE1 knockdown strongly reduces FAT10 conjugate formation. In vitro FAT10 transfer assay, co-immunoprecipitation, siRNA knockdown, cis vs trans auto-FAT10ylation assay Nature communications High 20975683
2011 TNF-α induces FAT10 expression through TNFR1 and NF-κB, and FAT10 mediates TNF-α-induced abbreviated mitotic phase, reduction of MAD2 kinetochore localization, and chromosomal instability; shRNA against FAT10 reverses these effects. shRNA knockdown, flow cytometry, immunofluorescence, chromosome counting, TNF-α treatment with receptor blocking Journal of cell science Medium 22025632
2011 FAT10 is covalently attached (via C-terminal glycine) to huntingtin and other polyglutamine proteins; FAT10 preferentially binds huntingtin with short polyQ chains; FAT10 knockdown enhances aggregation of ataxin-1, ataxin-3, and DRPLA proteins. Co-immunoprecipitation, FAT10 knockdown, aggregation assay in Huntington disease cell model The Journal of biological chemistry Medium 21757738
2011 FAT10 degradation requires ubiquitination: degradation is inhibited in cells expressing a non-polymerizable ubiquitin mutant and in cells with a thermolabile ubiquitin-activating E1 enzyme; FAT10 as a degradation signal for stable proteins also requires ubiquitination for proteasomal targeting. Ubiquitin mutant expression, thermolabile E1 mutant cell line, cycloheximide chase Molecular biology of the cell Medium 22072791
2012 FAT10 and NUB1L bind to the VWA domain of 26S proteasome subunit Rpn10 (hRpn10/S5a) to enable FAT10-mediated proteolysis; NUB1L additionally binds Rpn1; depletion of hRpn10 causes accumulation of FAT10-conjugates in human cells; human Rpn10 with VWA domain alone functionally reconstitutes Rpn10-deficient yeast for FAT10 degradation. Co-immunoprecipitation, yeast complementation, siRNA knockdown, domain deletion mapping Nature communications High 22434192
2012 Endogenous FAT10 conjugates include the autophagy adaptor p62/SQSTM1 as a covalent mono-FAT10ylated substrate at multiple lysines; FAT10 colocalizes with p62 in p62 bodies; FAT10ylation of p62 leads to its proteasomal degradation; mass spectrometry identified 569 FAT10-interacting proteins including HDAC6 and UBA6. Immunopurification of endogenous FAT10 conjugates, mass spectrometry, co-immunoprecipitation, colocalization imaging, proteasome inhibitor treatment Journal of cell science High 22797925
2012 FAT10 modification promotes MHC class I antigen presentation of viral pp65 antigen; this presentation partially relies on Rpn10 and is supported by NUB1 but is not influenced by immunoproteasomes or PA28, distinguishing FAT10 from ubiquitin-dependent presentation. Antigen presentation assays, proteasome inhibitor treatment, siRNA knockdown of pathway components Cellular and molecular life sciences : CMLS Medium 22349260
2012 AIPL1 (LCA blindness protein) binds noncovalently to free FAT10 and FAT10ylated proteins, forms a ternary complex with FAT10 and NUB1, and antagonizes NUB1-mediated FAT10-DHFR degradation; AIPL1 also co-immunoprecipitates UBA6. Co-immunoprecipitation, degradation assay, AIPL1 mutant analysis PloS one Medium 22347407
2012 FAT10 covalently modifies LRRFIP2 at two distinct sites; FATylation of LRRFIP2 translocates it to the cellular insoluble fraction, preventing its membrane recruitment with MYD88 and thereby inhibiting TLR4-mediated NF-κB activation. Co-immunoprecipitation, subcellular fractionation, NF-κB reporter assay, LPS stimulation Biochemical and biophysical research communications Medium 23036196
2012 Uba6 activates FAT10 through a three-step mechanism similar to Uba1 (adenylation and thioester formation); FAT10 binds Uba6 with higher affinity than ubiquitin but shows lower catalytic activity in E1-E2 transthiolation; FAT10 forms a ternary complex with Uba6 together with ubiquitin. Biochemical kinetics, ATP-PPi exchange assay, E1-E2 transthiolation assay, mechanism-based E1 inhibitor studies, biophysical binding assays The Journal of biological chemistry High 22427669
2014 The MAD2-binding interface of FAT10 is located on its first ubiquitin-like domain; NMR structure of this domain was determined; mutation of specific MAD2-binding residues abrogates FAT10-MAD2 interaction without disrupting FAT10's other interactions; disruption of FAT10-MAD2 binding dramatically reduces FAT10-mediated tumor growth, aneuploidy, proliferation, migration, invasion, and apoptosis resistance. NMR structure determination, site-directed mutagenesis, co-immunoprecipitation, in vitro and in vivo tumor assays Proceedings of the National Academy of Sciences of the United States of America High 25422469
2014 FAT10 directly binds β-catenin, preventing its ubiquitination and degradation, thereby activating the β-catenin/TCF4 pathway and upregulating HOXB9 expression to promote HCC invasion and metastasis. Co-immunoprecipitation, RNAi knockdown, rescue experiments with HOXB9 overexpression, in vitro invasion assays, in vivo mouse models Cancer research Medium 25056121
2014 FAT10 decorates cytosolic Salmonella Typhimurium in human cells; FAT10-decorated bacteria colocalize with ubiquitin, p62, NDP52, and LC3B; FAT10 colocalizes with p62-positive microdomains; FAT10-deficient NRAMP1-transgenic mice show higher susceptibility to oral S. Typhimurium infection. Immunofluorescence colocalization, siRNA knockdown, FAT10-deficient mouse infection model Journal of cell science Medium 25271057
2015 UBE1 (ubiquitin E1) is a substrate of FAT10; FAT10ylation of UBE1 depends on the diglycine motif of FAT10 and the UBA6/USE1 conjugation pathway; FAT10ylated UBE1 undergoes proteasomal degradation; UBE1 does not act as a second E1 for FAT10. Co-immunoprecipitation, mass spectrometry, siRNA knockdown of UBA6/USE1, proteasome inhibitor treatment PloS one Medium 25768649
2015 Crystal structure of USE1 (UBE2Z) reveals domain organization; specificity of FAT10 conjugation toward UBA6 and USE1 lies within the C-terminal CYCI tetrapeptide of FAT10; this motif slows the transfer rate of FAT10 from UBA6 onto USE1. X-ray crystallography, site-directed mutagenesis, biochemical transfer assays The Journal of biological chemistry High 26555268
2015 FAT10 is selectively expressed in medullary thymic epithelial cells (mTECs) and alters the repertoire of MHC class I-presented peptides and thymic negative selection; FAT10-deficient mice show altered T cell repertoire and impaired negative selection in TCR-transgenic models. FAT10-/- mice, TCR Vβ-segment screening, MHC class I peptide elution, TCR-transgenic mouse analysis Journal of immunology Medium 26401002
2016 FAT10 competes with ubiquitin for binding to the same lysines on eEF1A1; FAT10 overexpression decreases ubiquitin-eEF1A1 conjugates and increases FAT10-eEF1A1 conjugates, stabilizing eEF1A1 and promoting cancer cell proliferation. Co-immunoprecipitation, ubiquitination assays, lysine mutants, Western blot, proliferation assays Cancer research Medium 27312528
2016 FAT10 noncovalently associates with the 2CARD domain of RIG-I; FAT10 inhibits viral RNA-induced IRF3 and NF-κB activation by modulating RIG-I protein solubility; FAT10 is recruited to the RIG-I-TRIM25 complex where it is stabilized by TRIM25; FAT10 sequesters active RIG-I away from mitochondria and inhibits antiviral stress granule formation. Co-immunoprecipitation, domain mapping, luciferase reporter assay, fractionation/solubility assay, immunofluorescence colocalization Scientific reports Medium 26996158
2018 FAT10 directly binds to Nav1.5 at lysine residues in its C-terminal fragments and prevents Nedd4-2 (ubiquitin E3 ligase) binding, stabilizing Nav1.5 membrane expression; cardiac-specific Fat10 knockout causes reduced peak Na+ current, increased late Na+ current, and ventricular arrhythmia after myocardial infarction. Cardiac-specific Cre-lox knockout, patch-clamp electrophysiology, co-immunoprecipitation, immunofluorescence Cell death & disease High 33414395
2018 High-resolution NMR/crystal structures of the two individual ubiquitin-like domains (UBDs) of FAT10 show typical ubiquitin-fold but entirely different surface properties from each other and from ubiquitin; deletion of the flexible linker abrogates FAT10 conjugation; mutation of the linker blocks USE1 auto-FAT10ylation but not bulk conjugate formation; FAT10-mediated degradation is independent of VCP/p97 when FAT10's unstructured N-terminal heptapeptide is present; intrinsic instability of FAT10 enables rapid co-degradation of FAT10 and its substrates without de-conjugation. NMR structure, domain deletion and mutagenesis, in vitro degradation assays, VCP/p97 inhibition Nature communications High 30127417
2018 UBD/FAT10 expression inversely correlates with APOL1 G1/G2 variant-mediated cell toxicity; disease-associated APOL1 alleles increase UBD mRNA but decrease UBD protein; UBD appears to mitigate APOL1-mediated toxicity by targeting APOL1 for proteasomal degradation. Admixture mapping, cell-based expression assays, Western blot, cell toxicity assays Proceedings of the National Academy of Sciences of the United States of America Low 29531077
2019 FAT10 directly binds to and impedes the SUMO E1 activating enzyme AOS1/UBA2, competing with SUMO for activation and thioester formation in vitro; FAT10 overexpression downregulates SUMO conjugation and SUMO-dependent PML body formation in cells; activation of FAT10 by AOS1/UBA2 does not lead to covalent FAT10 conjugation to substrates. In vitro thioester formation assay, competition assay, Western blot, immunofluorescence of PML bodies Nature communications High 31575873
2019 ZNF598 delivers FAT10 to RIG-I, resulting in inhibition of RIG-I polyubiquitination required for downstream IFN signaling; ZNF598 ubiquitin ligase activity is dispensable for this suppression; ZNF598-mediated suppression is abolished by FAT10 knockout. Co-immunoprecipitation, FAT10 knockout cells, RIG-I ubiquitination assay, IFN reporter assay Cell reports Medium 31433974
2019 FAT10 noncovalently interacts with OTUB1 and stimulates its deubiquitylase activity toward Lys-48-linked diubiquitin; covalent FAT10ylation of OTUB1 leads to its proteasomal degradation; FAT10-OTUB1 interaction also strengthens OTUB1's noncatalytic inhibition of Lys-63 polyubiquitylation of TRAF3; FAT10 increases OTUB1 interaction with UbcH5B. Co-immunoprecipitation, in vitro DUB activity assay, co-immunoprecipitation with E2 enzyme, proteasome inhibitor treatment The Journal of biological chemistry Medium 30718280
2020 FAT10 directly interacts with PPARα in hepatocytes; FAT10 silencing increases PPARα target gene expression and promotes fatty acid oxidation; FAT10 overexpression in vivo inhibits PPARα lipid regulatory activity in response to fasting and agonist treatment. Co-immunoprecipitation, siRNA knockdown, in vivo hepatocyte FAT10 overexpression, fatty acid oxidation assay Metabolism: clinical and experimental Medium 37926201
2021 Parkin is an E3 ligase for FAT10; FAT10 becomes conjugated to Parkin and targets it for proteasomal degradation; Parkin binds the FAT10 E2 enzyme USE1 and auto-FAT10ylates itself; Parkin facilitates FAT10ylation of Mitofusin2 in vitro and in cells; on mitochondrial depolarization, FAT10ylation of Parkin inhibits its ubiquitin-ligase activity and impairs mitophagy. In vitro FAT10ylation assay, co-immunoprecipitation, proteasome inhibitor treatment, mitochondrial depolarization assay, dopaminergic cell death assay Cell reports High 33730565
2021 UBD/FAT10 interacts with p53 in colorectal cancer cells, promotes its proteasomal degradation, and shortens p53 half-life, leading to decreased p21 and increased cyclins/CDKs and cell proliferation; in vivo tumor growth driven by UBD depends on p53 decrease. Co-immunoprecipitation, cycloheximide chase, proteasome inhibitor treatment, xenograft mouse model Frontiers in oncology Medium 34350116
2022 Crystal structures of human Uba6 in complex with ubiquitin reveal two conformations: open (adenylation-active) and closed (thioester-active); an allosteric inositol hexakisphosphate (InsP6) binding site on Uba6 inhibits its activity by altering open-closed conformational interconversion; these structures provide the molecular basis for FAT10 and ubiquitin activation. X-ray crystallography, biochemical activity assays, biophysical binding assays, site-directed mutagenesis Nature communications High 35986001
2022 FAT10 directly binds FOXM1 and stabilizes it by competing with ubiquitin for binding to FOXM1, inhibiting ubiquitination-mediated FOXM1 degradation, thereby promoting EMT and gemcitabine resistance in pancreatic cancer. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, rescue experiments Cell death & disease Medium 35614040
2023 FAT10 directly binds Smad3 at K378 via its C-terminal glycine residues and mediates Smad3 degradation through the FAT10-proteasome system independently of ubiquitin; FAT10-/- mice show excessive cardiac fibrosis after myocardial infarction; FAT10 restoration suppresses fibrosis in a Smad3-dependent manner. IP-mass spectrometry, co-immunoprecipitation, FAT10-/- mouse model, in vivo rescue, in vitro fibroblast assays International journal of biological sciences Medium 36778114
2023 FAT10 and NUB1L cooperate to activate 26S proteasome gate opening in a ubiquitin- and USP14-independent manner; FAT10 binding to UBA domains of NUB1L interferes with NUB1L dimerization, increasing NUB1L affinity for RPN1 and thereby activating proteasomal peptidolytic activities. In vitro proteasome activity assay, co-immunoprecipitation, domain binding assays Life science alliance Medium 37188463
2024 FAT10 structural plasticity (lower thermodynamic stability, faster mechanical unfolding, absent long-range salt bridges, partially unstructured regions) is critical for its function as a proteasomal degradation tag; Fat10's unfolding destabilizes conjugated substrates creating partially unstructured regions that enhance proteasomal engagement and degradation rate. NMR relaxation analysis, hydrogen-deuterium exchange, temperature-dependent chemical shift, force spectroscopy (mechanical unfolding), in vitro degradation assays eLife High 38984715
2025 NUB1 uses intrinsic instability of FAT10 to trap its N-terminal ubiquitin-like domain in an unfolded state and deliver it to the 26S proteasome for engagement; cryo-EM structures visualize the NUB1 complex bound to proteasomal Rpn1 during FAT10 delivery; this delivery is ubiquitin-independent and p97-independent; NUB1 binding activates NUB1 for proteasomal docking. In vitro reconstitution, hydrogen-deuterium exchange, cryo-EM, structural modeling, site-directed mutagenesis Nature structural & molecular biology High 40217121
2020 FAT10 inhibits PDE6 cGMP hydrolyzing activity by noncovalently interacting with PDE6 GAFa and catalytic domains; FAT10 also covalently conjugates to rod PDE6 and targets it for proteasomal degradation; AIPL1 stabilizes both FAT10 monomer and the PDE6-FAT10 conjugate. In vitro PDE6 activity assay, co-immunoprecipitation, proteasome inhibitor treatment, domain interaction mapping The Journal of biological chemistry Medium 32817338
2022 FAT10 directly binds to EGFR and inhibits its ubiquitination and degradation, stabilizing EGFR expression; this stabilization upregulates PFKFB3 via the EGFR/AKT pathway, promoting glycolysis and osteosarcoma growth. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, in vitro and in vivo proliferation assays American journal of cancer research Low 32775001
2019 FAT10 directly interacts with and stabilizes the deubiquitylating enzyme USP7; FAT10-USP7 interaction mediates CHK1 upregulation, prolonging CHK1-mediated G2/M arrest in renal tubular epithelial cells exposed to hypoxia, promoting pro-fibrotic cytokine production. Co-immunoprecipitation, FAT10-/- mouse-derived cells, Western blot, cell cycle analysis Aging Low 36152057
2020 FAT10 suppresses autophagy by competing with SUMO1 at the K734 modification site of SIRT1, reducing SIRT1 nuclear translocation and activity via its C-terminal glycine residues; this reduces LC3 deacetylation and suppresses autophagosome formation, protecting the heart from ischemic injury. Co-immunoprecipitation, FAT10-knockout rat model, SIRT1 SUMOylation assay, autophagy flux assay, in vivo/in vitro ischemia models Journal of molecular and cellular cardiology Medium 33307094
2014 FAT10 promotes NF-κB activation, which upregulates CXCR4 and CXCR7 chemokine receptors; siRNA depletion of CXCR7 and CXCR4 attenuates invasion of FAT10-overexpressing cells, establishing the NF-κB-CXCR4/7 pathway as the mechanism for FAT10-induced malignant transformation. NF-κB reporter assay, siRNA knockdown, invasion assays, anchorage-independent growth, in vivo tumor formation Carcinogenesis Medium 24325913

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 FAT10, a ubiquitin-independent signal for proteasomal degradation. Molecular and cellular biology 181 15831455
2007 E1-L2 activates both ubiquitin and FAT10. Molecular cell 162 17889673
2003 Expression of the FAT10 gene is highly upregulated in hepatocellular carcinoma and other gastrointestinal and gynecological cancers. Oncogene 153 12730673
2001 The ubiquitin-like protein FAT10 forms covalent conjugates and induces apoptosis. The Journal of biological chemistry 149 11445583
1999 A MHC-encoded ubiquitin-like protein (FAT10) binds noncovalently to the spindle assembly checkpoint protein MAD2. Proceedings of the National Academy of Sciences of the United States of America 143 10200259
2008 Proinflammatory cytokines cause FAT10 upregulation in cancers of liver and colon. Oncogene 140 18574467
2014 Ubiquitin-like protein FAT10 promotes the invasion and metastasis of hepatocellular carcinoma by modifying β-catenin degradation. Cancer research 111 25056121
2006 FAT10/diubiquitin-like protein-deficient mice exhibit minimal phenotypic differences. Molecular and cellular biology 92 16782901
2004 NEDD8 ultimate buster-1L interacts with the ubiquitin-like protein FAT10 and accelerates its degradation. The Journal of biological chemistry 86 14757770
2010 USE1 is a bispecific conjugating enzyme for ubiquitin and FAT10, which FAT10ylates itself in cis. Nature communications 85 20975683
2012 The proteomic analysis of endogenous FAT10 substrates identifies p62/SQSTM1 as a substrate of FAT10ylation. Journal of cell science 81 22797925
2009 The ubiquitin-like protein FAT10 mediates NF-kappaB activation. Journal of the American Society of Nephrology : JASN 79 19959714
2006 Role of ubiquitin-like protein FAT10 in epithelial apoptosis in renal disease. Journal of the American Society of Nephrology : JASN 76 16495380
2016 The ubiquitin-like modifier FAT10 in cancer development. The international journal of biochemistry & cell biology 74 27393295
2012 FAT10 and NUB1L bind to the VWA domain of Rpn10 and Rpn1 to enable proteasome-mediated proteolysis. Nature communications 73 22434192
2006 FAT10 plays a role in the regulation of chromosomal stability. The Journal of biological chemistry 72 16495226
2009 Degradation of FAT10 by the 26S proteasome is independent of ubiquitylation but relies on NUB1L. FEBS letters 68 19166848
2008 The ubiquitin-like modifier FAT10 interacts with HDAC6 and localizes to aggresomes under proteasome inhibition. Journal of cell science 67 19033385
2016 The Ubiquitin-like Protein FAT10 Stabilizes eEF1A1 Expression to Promote Tumor Proliferation in a Complex Manner. Cancer research 65 27312528
2006 p53 negatively regulates the expression of FAT10, a gene upregulated in various cancers. Oncogene 64 16501612
2011 FAT10 mediates the effect of TNF-α in inducing chromosomal instability. Journal of cell science 61 22025632
2018 UBD modifies APOL1-induced kidney disease risk. Proceedings of the National Academy of Sciences of the United States of America 58 29531077
2014 NFκB and STAT3 synergistically activate the expression of FAT10, a gene counteracting the tumor suppressor p53. Molecular oncology 57 24518302
2014 The ubiquitin-like modifier FAT10 decorates autophagy-targeted Salmonella and contributes to Salmonella resistance in mice. Journal of cell science 56 25271057
2014 Disruption of FAT10-MAD2 binding inhibits tumor progression. Proceedings of the National Academy of Sciences of the United States of America 56 25422469
2008 Fat10 is an epigenetic marker for liver preneoplasia in a drug-primed mouse model of tumorigenesis. Experimental and molecular pathology 56 18280469
2006 FAT10, a gene up-regulated in various cancers, is cell-cycle regulated. Cell division 52 16959044
2006 UBD, a downstream element of FOXP3, allows the identification of LGALS3, a new marker of human regulatory T cells. Laboratory investigation; a journal of technical methods and pathology 50 16702978
2016 Ubiquitin-like modifier FAT10 attenuates RIG-I mediated antiviral signaling by segregating activated RIG-I from its signaling platform. Scientific reports 49 26996158
2014 Extended lifespan and reduced adiposity in mice lacking the FAT10 gene. Proceedings of the National Academy of Sciences of the United States of America 48 24706839
2013 FAT10, an ubiquitin-like protein, confers malignant properties in non-tumorigenic and tumorigenic cells. Carcinogenesis 46 24325913
2021 Parkin is an E3 ligase for the ubiquitin-like modifier FAT10, which inhibits Parkin activation and mitophagy. Cell reports 45 33730565
2009 FAT10: a novel mediator of Vpr-induced apoptosis in human immunodeficiency virus-associated nephropathy. Journal of virology 45 19726511
2011 FAT10 is a proteasomal degradation signal that is itself regulated by ubiquitination. Molecular biology of the cell 43 22072791
2018 The structure of the ubiquitin-like modifier FAT10 reveals an alternative targeting mechanism for proteasomal degradation. Nature communications 42 30127417
2009 FAT10 level in human gastric cancer and its relation with mutant p53 level, lymph node metastasis and TNM staging. World journal of gastroenterology 41 19437562
2020 The ubiquitin-like modifier FAT10 - much more than a proteasome-targeting signal. Journal of cell science 39 32719056
2010 The role of cytokines in UbD promoter regulation and Mallory-Denk body-like aggresomes. Experimental and molecular pathology 39 20433827
2012 The FAT10- and ubiquitin-dependent degradation machineries exhibit common and distinct requirements for MHC class I antigen presentation. Cellular and molecular life sciences : CMLS 38 22349260
2018 GRP78 Promotes Hepatocellular Carcinoma proliferation by increasing FAT10 expression through the NF-κB pathway. Experimental cell research 35 29458176
2016 Ubiquitin-like protein FAT10 promotes bladder cancer progression by stabilizing survivin. Oncotarget 35 27806337
2018 FAT10 attenuates hypoxia-induced cardiomyocyte apoptosis by stabilizing caveolin-3. Journal of molecular and cellular cardiology 33 29438664
2019 Attenuation of the Innate Immune Response against Viral Infection Due to ZNF598-Promoted Binding of FAT10 to RIG-I. Cell reports 31 31433974
2019 The ubiquitin-like modifier FAT10 interferes with SUMO activation. Nature communications 31 31575873
2013 FAT10 protects cardiac myocytes against apoptosis. Journal of molecular and cellular cardiology 31 23416168
2012 Mechanistic studies on activation of ubiquitin and di-ubiquitin-like protein, FAT10, by ubiquitin-like modifier activating enzyme 6, Uba6. The Journal of biological chemistry 31 22427669
2015 Structure of UBE2Z Enzyme Provides Functional Insight into Specificity in the FAT10 Protein Conjugation Machinery. The Journal of biological chemistry 30 26555268
2019 UBA6 and Its Bispecific Pathways for Ubiquitin and FAT10. International journal of molecular sciences 29 31067743
2015 The ubiquitin-like modifier FAT10 in antigen processing and antimicrobial defense. Molecular immunology 29 25983082
2022 FAT10 promotes chemotherapeutic resistance in pancreatic cancer by inducing epithelial-mesenchymal transition via stabilization of FOXM1 expression. Cell death & disease 27 35614040
2019 The ubiquitin-like modifier FAT10 stimulates the activity of deubiquitylating enzyme OTUB1. The Journal of biological chemistry 27 30718280
2020 Ubiquitin-like protein FAT10 promotes osteosarcoma glycolysis and growth by upregulating PFKFB3 via stabilization of EGFR. American journal of cancer research 26 32775001
2019 Ubiquitin-like protein FAT10 promotes osteosarcoma growth by modifying the ubiquitination and degradation of YAP1. Experimental cell research 26 31877302
2015 Conjugation of the ubiquitin activating enzyme UBE1 with the ubiquitin-like modifier FAT10 targets it for proteasomal degradation. PloS one 26 25768649
2018 FAT10 promotes the invasion and migration of breast cancer cell through stabilization of ZEB2. Biochemical and biophysical research communications 25 30361097
2015 The Ubiquitin-like Modifier FAT10 Is Selectively Expressed in Medullary Thymic Epithelial Cells and Modifies T Cell Selection. Journal of immunology (Baltimore, Md. : 1950) 25 26401002
2010 Increased expression of FAT10 in colon benign, premalignant and malignant epithelial neoplasms. Experimental and molecular pathology 25 20888811
2020 FAT10: Function and Relationship with Cancer. Current molecular pharmacology 24 31729307
2013 A proteomics strategy for the identification of FAT10-modified sites by mass spectrometry. Journal of proteome research 23 23862649
2018 Ubiquitin‑like protein FAT10 regulates DNA damage repair via modification of proliferating cell nuclear antigen. Molecular medicine reports 22 29620277
2021 Ubiquitin-Like Protein UBD Promotes Cell Proliferation in Colorectal Cancer by Facilitating p53 Degradation. Frontiers in oncology 21 34350116
2020 FAT10 promotes the progression of bladder cancer by upregulating HK2 through the EGFR/AKT pathway. Experimental cell research 21 33253711
2015 Silibinin down-regulates FAT10 and modulate TNF-α/IFN-γ-induced chromosomal instability and apoptosis sensitivity. Biology open 21 26142316
2017 The 20S immunoproteasome and constitutive proteasome bind with the same affinity to PA28αβ and equally degrade FAT10. Molecular immunology 20 29208314
2016 FAT10 Is Critical in Influenza A Virus Replication by Inhibiting Type I IFN. Journal of immunology (Baltimore, Md. : 1950) 20 27354218
2011 FAT10 protein binds to polyglutamine proteins and modulates their solubility. The Journal of biological chemistry 20 21757738
2021 FAT10 protects against ischemia-induced ventricular arrhythmia by decreasing Nedd4-2/Nav1.5 complex formation. Cell death & disease 19 33414395
2019 The ubiquitin-like modifier FAT10 is required for normal IFN-γ production by activated CD8+ T cells. Molecular immunology 19 30818228
2010 FAT10 : Activated by UBA6 and Functioning in Protein Degradation. Sub-cellular biochemistry 19 21222287
2012 FAT10 knock out mice livers fail to develop Mallory-Denk bodies in the DDC mouse model. Experimental and molecular pathology 17 22981937
2018 Different roles of FAT10, FOXO1, and ADRA2A in hepatocellular carcinoma tumorigenesis in patients with alcoholic steatohepatitis (ASH) vs non-alcoholic steatohepatitis (NASH). Experimental and molecular pathology 16 30009772
2022 Recombinant Human Proteoglycan 4 (rhPRG4) Downregulates TNFα-Stimulated NFκB Activity and FAT10 Expression in Human Corneal Epithelial Cells. International journal of molecular sciences 15 36361504
2012 The inherited blindness protein AIPL1 regulates the ubiquitin-like FAT10 pathway. PloS one 15 22347407
2012 Modification of the inflammatory mediator LRRFIP2 by the ubiquitin-like protein FAT10 inhibits its activity during cellular response to LPS. Biochemical and biophysical research communications 15 23036196
2022 Crystal structures reveal catalytic and regulatory mechanisms of the dual-specificity ubiquitin/FAT10 E1 enzyme Uba6. Nature communications 14 35986001
2021 NUB1 and FAT10 Proteins as Potential Novel Biomarkers in Cancer: A Translational Perspective. Cells 14 34571823
2020 Ubiquitin-like protein FAT10: A potential cardioprotective factor and novel therapeutic target in cancer. Clinica chimica acta; international journal of clinical chemistry 14 32946796
2019 IFNγ potentiates TNFα/TNFR1 signaling to induce FAT10 expression in macrophages. Molecular immunology 13 31759325
2020 Regulation of Interferon Induction by the Ubiquitin-Like Modifier FAT10. Biomolecules 12 32586037
2016 FAT10 is associated with the malignancy and drug resistance of non-small-cell lung cancer. OncoTargets and therapy 12 27499634
2015 FAT10 suppression stabilizes oxidized proteins in liver cells: Effects of HCV and ethanol. Experimental and molecular pathology 12 26407761
2014 Diubiquitin (Ubd) is a susceptibility gene for virus-triggered autoimmune diabetes in rats. Genes and immunity 12 24452267
2023 FAT10 Silencing Prevents Liver Fibrosis through Regulating SIRT1 Expression in Hepatic Stellate Cells. International journal of medical sciences 11 37057207
2023 The ubiquitin-like modifier FAT10 is induced in MASLD and impairs the lipid-regulatory activity of PPARα. Metabolism: clinical and experimental 11 37926201
2022 Ubiquitin-like protein FAT10 promotes renal fibrosis by stabilizing USP7 to prolong CHK1-mediated G2/M arrest in renal tubular epithelial cells. Aging 11 36152057
2019 Analysis of modification and proteolytic targeting by the ubiquitin-like modifier FAT10. Methods in enzymology 11 30850054
2018 Investigating the Promoter of FAT10 Gene in HCC Patients. Genes 11 29949944
2014 Recombinant adenovirus encoding FAT10 small interfering RNA inhibits HCC growth in vitro and in vivo. Experimental and molecular pathology 11 24440736
2012 Identification of a novel binding protein of FAT10: eukaryotic translation elongation factor 1A1. Digestive diseases and sciences 11 22569823
2024 FAT10 induces immune suppression by upregulating PD-L1 expression in hepatocellular carcinoma. Apoptosis : an international journal on programmed cell death 10 38824477
2024 Plasticity of the proteasome-targeting signal Fat10 enhances substrate degradation. eLife 10 38984715
2023 The ubiquitin-like protein FAT10 in hepatocellular carcinoma cells limits the efficacy of anti-VEGF therapy. Journal of advanced research 10 37328057
2022 IDO1, FAT10, IFI6, and GILT Are Involved in the Antiretroviral Activity of γ-Interferon and IDO1 Restricts Retrovirus Infection by Autophagy Enhancement. Cells 10 35883685
2020 The Role of FAT10 in Alcoholic Hepatitis Pathogenesis. Biomedicines 10 32630199
2020 The ubiquitin-like modifier FAT10 inhibits retinal PDE6 activity and mediates its proteasomal degradation. The Journal of biological chemistry 10 32817338
2020 Ubiquitin-like protein FAT10 suppresses SIRT1-mediated autophagy to protect against ischemic myocardial injury. Journal of molecular and cellular cardiology 10 33307094
2025 NUB1 traps unfolded FAT10 for ubiquitin-independent degradation by the 26S proteasome. Nature structural & molecular biology 9 40217121
2024 Cytokines-activated nuclear IKKα-FAT10 pathway induces breast cancer tamoxifen-resistance. Science China. Life sciences 9 38565741
2023 Ubiquitin like protein FAT10 repressed cardiac fibrosis after myocardial ischemic via mediating degradation of Smad3 dependent on FAT10-proteasome system. International journal of biological sciences 8 36778114
2023 FAT10 and NUB1L cooperate to activate the 26S proteasome. Life science alliance 8 37188463

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