| 2019 |
UFL1 is recruited to DNA double-strand breaks by the MRE11/RAD50/NBS1 (MRN) complex and monoufmylates histone H4 following DNA damage. Monoufmylated histone H4 recruits Suv39h1 and Tip60, which are required for ATM activation. ATM in turn phosphorylates UFL1 at serine 462, enhancing its E3 ligase activity in a positive feedback loop. |
Co-immunoprecipitation, in vitro ufmylation assay, site-directed mutagenesis (S462 phosphorylation site), chromatin immunoprecipitation, laser micro-irradiation/live imaging |
Nature communications |
High |
30886146
|
| 2023 |
UFL1 requires its N-terminal helix for binding to UFC1 (E2). The UFL1–DDRGK1 fusion construct was used to solve a crystal structure of this critical interaction. UFL1 and UBA5 (E1) compete for binding to UFC1, with the competition shifting in favor of UFL1 after UFM1 is charged onto UFC1, coordinating the E1→E2→E3 cascade. |
X-ray crystallography, NMR, AlphaFold2 structural modeling, biochemical binding assays, mutagenesis |
EMBO reports |
High |
37988244
|
| 2024 |
On replication stress, UFL1 localizes to stalled replication forks and catalyzes UFMylation of PTIP (a component of the MLL3/4 methyltransferase complex) at lysine 148. This promotes assembly of the PTIP–MLL3/4 complex, enrichment of H3K4me1 and H3K4me3 at stalled forks, and subsequent MRE11 nuclease recruitment to degrade nascent DNA in BRCA1/2-deficient cells. |
Proximity ligation assay, iPOND (isolation of proteins on nascent DNA), in vitro UFMylation assay, site-directed mutagenesis (K148), chromatin fractionation, fiber assay |
Nature chemical biology |
High |
38649452
|
| 2024 |
UFL1 promotes UFMylation of PD-1 in T cells, which antagonizes PD-1 ubiquitination and prevents its degradation. AMPK phosphorylates UFL1 at Thr536, disrupting PD-1 UFMylation and triggering PD-1 degradation. Loss of UFL1 in T cells reduces PD-1 stability and enhances CD8+ T cell activation. |
Conditional knockout mice, Co-immunoprecipitation, in vitro UFMylation assay, site-directed mutagenesis (T536), flow cytometry, single-cell RNA sequencing |
Molecular cell |
High |
38377992
|
| 2010 |
UFL1 (Maxer) is an ER membrane protein that interacts with CDK5RAP3, anchoring it to the ER and inhibiting CDK5RAP3's function in repressing Cyclin D1 transcription in the nucleus. Loss of Maxer leads to cell accumulation at G1 phase. |
Co-immunoprecipitation, subcellular fractionation, knockdown/overexpression with cell cycle analysis (FACS), immunofluorescence |
The EMBO journal |
Medium |
20531390
|
| 2010 |
UFL1 (NLBP) was identified as a novel LZAP-binding protein. NLBP and LZAP mutually stabilize each other by inhibiting ubiquitination of the partner protein. NLBP also inhibits NF-κB signaling and cell invasion. |
Tandem affinity purification, Co-immunoprecipitation, ubiquitination assay, invasion assay |
The Journal of biological chemistry |
Medium |
20164180
|
| 2013 |
UFL1 (NLBP) binds to the regulatory domain of p120 catenin (p120ctn), and this interaction stabilizes p120ctn by inhibiting its ubiquitination and proteasomal degradation, promoting lung adenocarcinoma cell proliferation. |
Co-immunoprecipitation, domain mapping, ubiquitination assay, overexpression proliferation assay |
Cell cycle |
Medium |
23839039
|
| 2015 |
Genetic deletion of RCAD/UFL1 in mice causes elevated ER stress, activation of UPR, blockage of autophagic degradation, increased mitochondrial mass and ROS, DNA damage response, p53 activation, and enhanced cell death in hematopoietic stem cells, establishing UFL1 as essential for HSC survival and erythroid differentiation. |
Germ-line and conditional knockout mice, Western blotting for ER stress/UPR markers, autophagy flux assays, ROS measurement, flow cytometry, p53 pathway analysis |
Cell death and differentiation |
High |
25952549
|
| 2019 |
CDK5RAP3 interacts with UFL1 in vivo, and loss of CDK5RAP3 alters the ufmylation profile in liver cells, establishing CDK5RAP3 as a substrate adaptor for UFL1-mediated UFMylation. |
Co-immunoprecipitation (in vivo interaction), conditional knockout mice, proteomics-based ufmylation profiling |
Development (Cambridge, England) |
Medium |
30635284
|
| 2018 |
Cardiac-specific knockout of Ufl1 impairs PERK (PKR-like ER-resident kinase) signaling, leading to excessive ER stress, cardiomyocyte death, and development of cardiomyopathy. Administration of the ER chaperone tauroursodeoxycholic acid alleviates ER stress and attenuates cardiac dysfunction in Ufl1-deficient mice. |
Cardiac-specific conditional knockout mice, transcriptome analysis, biochemical ER stress markers (Western blot), chemical chaperone rescue experiment |
Circulation. Heart failure |
High |
30354401
|
| 2023 |
The UFL1/UFBP1 (UFL1/CDK5RAP3) complex directly interacts with the mTOR/GβL complex and attenuates mTORC1 activity. Ablation of UFL1 or UFBP1 in hepatocytes dissociates them from the mTOR/GβL complex and activates oncogenic mTOR signaling, driving hepatocellular carcinoma development. |
Co-immunoprecipitation, hepatocyte-specific conditional knockout mice, iTRAQ proteomics, DEN/HFD liver cancer models |
Journal of experimental & clinical cancer research |
Medium |
37131258
|
| 2022 |
UFL1 inhibits TRIM29 from interacting with STING, thereby reducing STING ubiquitination at K338/K347/K370 and preventing its proteasomal degradation. This stabilizing function of UFL1 on STING is independent of its UFMylation E3 ligase activity. |
Co-immunoprecipitation, ubiquitination assay with site-specific mutants (K338/K347/K370), UFL1 ligase-dead mutant, Western blotting for protein stability |
Cell death and differentiation |
Medium |
35871231
|
| 2025 |
UFL1 promotes UFMylation of PARP1, preventing its ubiquitination and proteasomal degradation. Stabilized PARP1 enhances DNA damage repair, suppresses R-loop formation, and inhibits cGAS-STING activation, promoting tumor immune evasion in pancreatic cancer. |
Co-immunoprecipitation, UFMylation assay, R-loop detection, cGAS-STING reporter assay, conditional knockout tumor models, flow cytometry for CD8+ T cells |
Cell reports |
Medium |
41105513
|
| 2025 |
Akt phosphorylates UFL1 at T426, enhancing its interaction with ArpC4 (a core subunit of the Arp2/3 complex) and inducing ArpC4 UFMylation. UFL1-mediated ArpC4 UFMylation facilitates lamellipodia formation and promotes cell migration, invasion, and metastasis. |
Co-immunoprecipitation, in vitro UFMylation assay, site-directed mutagenesis (T426), lamellipodia formation imaging, invasion/migration assay, in vivo metastasis models |
Nature structural & molecular biology |
High |
40419786
|
| 2022 |
Skin-specific deletion of Ufl1 in mice causes epidermal thickening and hyperpigmentation. Mechanistically, Endothelin-1 (ET-1) is a UFMylation substrate; UFL1-mediated UFMylation of ET-1 regulates its stability. Loss of Ufl1 increases ET-1 expression and secretion, upregulating melanin biosynthesis genes. |
Skin-specific conditional knockout mice, RNA-Seq, in vivo UFMylation assay for ET-1, Western blotting for ET-1 stability |
Frontiers in cell and developmental biology |
Medium |
36120581
|
| 2025 |
UFL1 interacts with RNF20 and catalyzes its UFMylation, enhancing RNF20 binding to CEP192 and facilitating its centrosomal localization to support mitotic spindle assembly. Loss of UFL1 causes mitotic defects, chromosome segregation errors, and aneuploidy in prostate cancer. |
Co-immunoprecipitation, UFMylation assay, centrosome fractionation/immunofluorescence, mitotic spindle analysis, conditional knockout prostate cancer models |
Proceedings of the National Academy of Sciences of the United States of America |
Medium |
42008680
|
| 2025 |
UFL1 mediates UFMylation of IFT88 at lysine 572. This UFMylation antagonizes IFT88 ubiquitination by the E3 ligase PJA2, preventing proteasomal degradation of IFT88 and maintaining ciliary homeostasis. A K572R mutant of IFT88 (UFMylation-deficient) shows increased stability and rescues ciliary defects caused by UFL1 depletion. |
Conditional knockout mice, Co-immunoprecipitation, in vitro UFMylation and ubiquitination assays, site-directed mutagenesis (K572R), immunofluorescence of cilia, rescue experiments |
Cell death and differentiation |
High |
41272290
|
| 2026 |
UFL1 UFMylates METTL16, reducing its ubiquitination and decreasing its protein stability. Loss of UFL1 increases METTL16 stability, leading to increased m6A modification of EEF1A1 mRNA via the METTL16-IGF2BP1 axis, elevating EEF1A1 protein levels and driving enzalutamide resistance in prostate cancer. |
Co-immunoprecipitation, UFMylation assay, ubiquitination assay, m6A methylation assay, protein stability assay, xenograft models |
International journal of biological sciences |
Medium |
41608626
|
| 2025 |
WBP11 interacts with NONO and competitively inhibits UFL1-induced UFMylation of NONO at Lys198. Loss of WBP11 allows UFL1 to UFMylate NONO, reducing its stability. UFL1 overexpression suppresses HCC cell growth and metastasis via NONO degradation. |
Co-immunoprecipitation, in vitro UFMylation assay, site-directed mutagenesis (K198), competitive binding assay, xenograft models |
Oncogene |
Medium |
41184530
|
| 2024 |
LRP1 knockdown promotes binding of UFL1 to OGA (O-GlcNAcase) and accelerates ubiquitin-mediated OGA degradation. This leads to increased O-GlcNAcylation of NF-κB and inhibition of pro-apoptotic gene expression. The LRP1 β-chain stabilizes OGA by disrupting the UFL1-OGA interaction. |
Co-immunoprecipitation, ubiquitination assay, O-GlcNAcylation analysis, knockdown/overexpression, xenograft models |
Advanced science |
Medium |
39405202
|
| 2024 |
Chicken UFL1 (chUFL1) interacts with chSTING and promotes K63-linked polyubiquitination of chSTING at K308, facilitating STING dimerization and formation of the STING-TBK1-IRF7 complex for type I IFN production, independently of UFMylation. ChUFL1 also interacts with the AIV PA protein to inhibit viral polymerase activity and nuclear import of PA. |
Co-immunoprecipitation, ubiquitination assay with K63-specific analysis, site-directed mutagenesis (K308), STING dimerization assay, UFMylation-dead mutant, viral polymerase activity assay |
Journal of immunology |
Medium |
38477617
|
| 2024 |
UFL1 interacts with IRE1α and modulates the IRE1α/XBP1 pathway of the unfolded protein response in NEFA-stimulated bovine mammary epithelial cells, contributing to ER and mitochondrial homeostasis. |
Co-immunoprecipitation, Western blotting for IRE1α/XBP1 pathway markers, UFL1 knockdown/overexpression |
Free radical biology & medicine |
Low |
38821134
|
| 2026 |
UFL1 deficiency in skeletal muscle activates the PERK/eIF2α/ATF4/CHOP ER stress signaling axis, leading to myoblast apoptosis. Pharmacological inhibition of PERK (GSK2606414) reverses UFL1-deficiency-induced upregulation of p-PERK, p-eIF2α, ATF4, and CHOP and rescues the apoptotic phenotype. |
Skeletal muscle-specific knockout mice, C2C12 cells, Western blotting, PERK inhibitor rescue, apoptosis assays |
Cellular signalling |
Medium |
42019645
|
| 2025 |
ATI-1 targets VCP/p97 and disrupts its interaction with UFL1. This disruption promotes polyubiquitination and proteasomal degradation of Beclin1, inhibiting autophagy initiation. The VCP-UFL1-Beclin1 axis is identified as a regulatory node in autophagy. |
Co-immunoprecipitation (VCP-UFL1 interaction), ubiquitination assay for Beclin1, autophagy flux assays, small-molecule inhibitor (ATI-1) treatment, xenograft models |
Bioorganic chemistry |
Low |
42060985
|
| 2025 |
UFL1 interacts with multiple orthoflavivirus proteins (NS2A, NS2B-NS3, and Capsid) and promotes infectious virion production for dengue, Zika, West Nile, and yellow fever viruses. UFMylation does not regulate viral RNA translation or replication but acts at a later stage, likely viral assembly. |
Co-immunoprecipitation (UFL1 with viral proteins), infectious particle assays, siRNA depletion of UFL1/UFBP1/UBA5/UFC1/UFM1, RNA replication assays |
bioRxivpreprint |
Low |
|
| 2025 |
Intracellular Shigella bacteria become targeted by UFL1 in infected human cells. Shigella antagonizes UFL1-mediated UFMylation in two ways: LPS shields bacteria from UFL1 recruitment, and the bacterial effector IpaH9.8 prevents UFM1 decoration. Loss of UFMylation increases bacterial burden in human cells and zebrafish, and this protective role is independent of autophagy. |
Proximity biotinylation coupled to quantitative mass spectrometry, bacterial infection assays, LPS mutant bacteria, IpaH9.8 effector assays, zebrafish infection model, autophagy-independent validation |
bioRxivpreprint |
Low |
|
| 2025 |
Loss of UFMylation (via UFL1 loss) reduces phosphofructokinase (PFKAP) activity, rerouting glucose metabolism away from glycolysis toward the hexosamine biosynthesis pathway. Elevated hexosamine biosynthesis increases glycosylation of invasion-related proteins, promoting prostate cancer metastasis. PFKAP is identified as a UFMylation substrate. |
Biotin-based proximity proteomics (UFMylation substrate ID), metabolomics, UFL1 knockdown/overexpression, invasion assays, in vivo metastasis models |
bioRxivpreprint |
Low |
|