| 2015 |
USP53 contains a catalytically inactive ubiquitin-specific protease domain (as annotated at the time) and colocalizes and physically interacts with tight junction scaffolding proteins TJP1 and TJP2 in polarized epithelial cells, indicating it is part of the tight junction complex. Loss of USP53 in mambo mice causes outer hair cell degeneration and reduced endocochlear potential; hair cell loss is rescued in low-potassium cochlear organotypic cultures, indicating it is triggered by extracellular factors. |
ENU mutagenesis mouse model, co-immunoprecipitation, colocalization imaging, biotin tracer assay for tight junction barrier, cochlear organotypic culture rescue experiment |
The Journal of neuroscience |
High |
26609154
|
| 2018 |
USP53 interacts with tight junction constituent TJP2, and loss-of-function (homozygous truncating variants) causes low-GGT cholestasis and hearing loss in humans, placing USP53 functionally in the TJP2-containing tight junction pathway in bile homeostasis. |
Exome sequencing with segregation analysis; prior interaction evidence cited from mouse data |
Genetics in medicine |
Medium |
30250217
|
| 2020 |
USP53 deubiquitinates FKBP51 (identified by co-immunoprecipitation and ubiquitination assay), stabilizing it; stabilized FKBP51 then dephosphorylates AKT1, thereby inhibiting tumor growth in lung adenocarcinoma cells. |
Co-immunoprecipitation, ubiquitination assay, stable overexpression/shRNA cell lines, AKT pathway inhibitor (LY294002), in vivo xenograft |
Molecular carcinogenesis |
Medium |
32511815
|
| 2020 |
USP53 interacts with TJP2; in USP53-deficient human liver biopsies, hepatocyte–hepatocyte tight junctions are elongated by ultrastructural analysis, recapitulating TJP2 disease morphology. |
Whole-exome sequencing, transmission electron microscopy of liver biopsies, clinical phenotype correlation |
Liver international |
Medium |
32124521
|
| 2021 |
USP53 is a transcriptional target of PTH-activated NACA in osteoblasts; a NACA binding site in the Usp53 promoter was confirmed by EMSA. Usp53 knockdown in ST2 stromal cells increases osteoblastic markers and decreases adipogenic markers, and in vivo implantation of Usp53-knockdown bone marrow stromal cells increases osteoblast number and decreases adipocyte counts, indicating USP53 modulates mesenchymal lineage commitment. |
ChIP-Seq, RNA-seq, EMSA, promoter-activity luciferase assay, shRNA knockdown, in vivo implantation in immunocompromised mice |
Scientific reports |
Medium |
33875709
|
| 2022 |
USP53 physically interacts with cytochrome c (CYCS), identified by co-immunoprecipitation and mass spectrometry, and overexpression of USP53 increases CYCS protein stability following cycloheximide treatment. Overexpression of CYCS compensates for decreased apoptosis in USP53-knockdown HCC cells, demonstrating that USP53 promotes apoptosis through deubiquitination of CYCS. |
Co-immunoprecipitation, mass spectrometry, cycloheximide chase, shRNA knockdown, overexpression rescue assay |
Oncogenesis |
Medium |
35654790
|
| 2022 |
H3K27 acetylation activates USP53 transcription by binding to the USP53 promoter region, as shown by ChIP assay. USP53 suppresses glycolysis, oxidative metabolism, and mitochondrial dynamics, and its knockdown is reversed by AMPK inhibitor, placing USP53 upstream of the AMPK signaling pathway in esophageal carcinoma. |
ChIP assay, AMPK inhibitor treatment, shRNA knockdown, in vitro and in vivo growth assays, metabolic assays |
Carcinogenesis |
Medium |
34919659
|
| 2023 |
USP53 regulates RANKL (Rankl) expression by enhancing the interaction between VDR and SMAD3 in osteoblasts and bone marrow adipocytes. Usp53 null mice show low bone mass, increased osteoclast numbers, and elevated serum RANKL. |
Usp53 knockout mice, microCT, histomorphometry, ELISA for RANKL, co-immunoprecipitation of VDR-SMAD3 complex |
Journal of bone and mineral research |
Medium |
36726200
|
| 2023 |
USP53 directly binds CRKL and deubiquitinates it, preventing proteasomal degradation and stabilizing CRKL protein, thereby promoting tumor growth, metastasis, and chemoresistance in triple-negative breast cancer. |
Co-immunoprecipitation, ubiquitination assay, overexpression and knockdown functional assays |
Cancers |
Low |
37894400
|
| 2023 |
USP53 colocalizes in hippocampal CA1-3 and granular dentate neurons with GRIA2/GluA2 and GRIP2, and all three proteins co-immunoprecipitate, placing USP53 within the AMPA receptor interactome in brain tissue. |
Immunofluorescence colocalization, co-immunoprecipitation |
Genes |
Low |
37895270
|
| 2024 |
USP53 binds SR-A via its USP domain and cysteine at position 41, removes K48-linked ubiquitin chains from SR-A, and prevents its proteasomal degradation, thereby mediating foam cell formation in smooth muscle cells downstream of endothelial DKK1 signaling. DKK1 regulates USP53 transcription by facilitating CREB binding to the USP53 promoter. |
Co-immunoprecipitation, ChIP, RNA-seq, endothelium-specific DKK1 KO and overexpression mice, AAV-mediated SMC-specific USP53 overexpression, parallel-plate co-culture flow system |
International journal of biological sciences |
Medium |
38904030
|
| 2024 |
USP53 interacts with ZMYND11, catalyzes its deubiquitination and stabilization. The Cys-box domain (aa 33–50) is key for USP53 enzymatic activity but not required for binding to ZMYND11. Rescue experiments show USP53's anti-tumor effect in breast cancer is at least partially mediated through ZMYND11. |
Co-immunoprecipitation, ubiquitination assay, domain deletion/mutation analysis, rescue overexpression experiments, xenograft |
Biological procedures online |
Medium |
39044157
|
| 2024 |
USP53 interacts with and deubiquitinates MYO5B via its IQ domain. Loss of USP53 causes increased ubiquitination of MYO5B and impairs endosomal recruitment of MYO5B, resulting in BSEP accumulation in MYO5B/RAB11A-positive recycling endosomes and failure of BSEP trafficking to the plasma membrane. The recurrent PFIC-associated MYO5B p.(Arg824Cys) variant (in the IQ domain) fails to interact with USP53. |
Co-immunoprecipitation, CRISPR-KO, surface protein biotinylation, confocal immunofluorescence, live cell imaging, FRAP, site-directed mutagenesis, immunohistochemistry of patient tissue |
Hepatology |
High |
40828662
|
| 2024 |
USP53 interacts with and deubiquitinates USP53 interacts with TJP2 in hepatocytes, demonstrated by co-immunoprecipitation and immunofluorescence. Usp53 liver-specific KO mice show upregulation of Tjp2 and longer hepatocellular tight junctions, and are protected from DDC-induced liver injury, suggesting USP53 and TJP2 share mechanistic pathways in bile homeostasis. |
Liver-specific Cre-lox knockout mice, immunofluorescence, co-immunoprecipitation, dietary challenge models, RT-qPCR, histopathology, electron microscopy |
Biochimica et biophysica acta. Molecular basis of disease |
Medium |
39705897
|
| 2025 |
USP53 is active against K63-linked polyubiquitin chains (not catalytically inactive as previously annotated). USP53 patient mutations abrogate catalytic activity. USP53 deubiquitinates substrates in a K63-linkage-dependent manner, and depletion of USP53 increases K63-linked ubiquitination of tricellular junction components. Structural analysis reveals K63-specific S2-ubiquitin-binding sites within the catalytic domain. |
Biochemical DUB activity assays with defined ubiquitin chain linkages, structural analysis, patient mutation functional testing, substrate-bound polyubiquitin assays, depletion experiments with K63-ubiquitination readout |
bioRxiv (preprint)preprint |
High |
bio_10.1101_2024.07.07.602376
|
| 2025 |
USP53 interacts with RIPK1 (via its intermediate domain) and removes K63-linked ubiquitination at lysine-377 (K377) of RIPK1, facilitating RIPK1 autophosphorylation and triggering apoptotic and necroptotic pathways in cardiomyocytes. Ethanol induces USP53 expression via transcription factor EGR1. Cardiomyocyte-specific USP53 knockout mice show improved survival and less cardiomyocyte death in an alcoholic cardiomyopathy model. |
Co-immunoprecipitation combined with LC-MS/MS, site-specific ubiquitination mapping (K377), cardiomyocyte-specific KO mouse model, in vivo/in vitro ethanol exposure models |
Research (Washington, D.C.) |
Medium |
40822127
|
| 2025 |
USP53 interacts with NOTCH2 and its knockdown prevents Aβ-induced deubiquitination of NOTCH2 in microglia. USP53 knockdown reduces Aβ-induced neuroinflammatory mediators (IL-1β, TNF-α) and represses IKKβ/NFκB signaling pathway activation. USP53 knockout in 5XFAD mice improves learning and memory and reduces Tau accumulation. |
Co-immunoprecipitation, USP53 knockout in 5XFAD AD mouse model, Morris Water Maze, Western blot, immunofluorescence, qRT-PCR, primary human microglia knockdown |
Neurochemistry international |
Medium |
41482165
|
| 2025 |
USP53 binds MORF4L1 and deubiquitinates it, with K249 and K227 of MORF4L1 identified as key ubiquitination sites. USP53 overexpression prevents MORF4L1 ubiquitination and degradation, and suppresses colorectal cancer cell growth; this effect is abrogated by MORF4L1 silencing. |
Co-immunoprecipitation combined with LC-MS/MS (IP-LC/MS), ubiquitylome analysis, site-directed mutagenesis of MORF4L1 ubiquitination sites, in vitro and in vivo gain/loss-of-function, rescue experiments |
Biochimica et biophysica acta. Molecular basis of disease |
Medium |
41061828
|
| 2025 |
ATF3 transcriptionally represses USP53 by binding the USP53 promoter (validated by ChIP and luciferase reporter assay). USP53 upregulation promotes adipogenesis and activates the RhoA/ROCK pathway; USP53 overexpression partially rescues the inhibitory effect of ATF3 overexpression on adipogenesis. |
ChIP assay, luciferase reporter assay, Oil Red O staining, triglyceride measurement, Western blot, RT-qPCR, 3T3-L1 adipocyte differentiation model |
Journal of molecular endocrinology |
Medium |
39641389
|
| 2025 |
USP53 deubiquitinates SMAD5, stabilizing its protein expression; the EIF4A3 RNA-binding protein stabilizes USP53 mRNA. Knockdown of USP53 inhibits BMSC viability, invasion, and osteogenic differentiation, effects rescued by SMAD5 overexpression, establishing the EIF4A3–USP53–SMAD5 axis in BMSC osteogenic differentiation. |
Co-immunoprecipitation, ubiquitination assay, shRNA knockdown, overexpression rescue, ALP activity assay, Alizarin Red S staining, RT-qPCR, Western blot |
Scientific reports |
Low |
40481141
|
| 2025 |
USP53 deubiquitinates MLKL and GSDMD, promoting their stability; FOS transcriptionally activates USP53 expression by directly binding the USP53 promoter (validated by ChIP-qPCR). Reduced FOS (by juglone treatment) lowers USP53, promoting ubiquitination and degradation of MLKL and GSDMD, thereby inhibiting necroptosis and pyroptosis in injured neurons. |
ChIP-qPCR, immunoprecipitation, Western blot, RNA-seq, qRT-PCR, in vitro OGD/R and in vivo SCI models |
Phytomedicine |
Low |
41045624
|