Affinage

USP45

Ubiquitin carboxyl-terminal hydrolase 45 · UniProt Q70EL2

Length
814 aa
Mass
91.7 kDa
Annotated
2026-06-11
17 papers in source corpus 10 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

USP45 is a catalytically active deubiquitylase that controls the stability and localization of diverse substrates by removing ubiquitin chains, with linkage preferences (K48, K63, K6) that vary by target (PMID:25538220, PMID:30258100, PMID:40788071). In genome maintenance, USP45 associates with ERCC1 through an acidic motif outside its catalytic domain and directly deubiquitylates ERCC1; loss of USP45 elevates ubiquitylated ERCC1, impairs ERCC1 recruitment to DNA damage foci, and sensitizes cells to UV and interstrand cross-links, while USP45 itself localizes to damage sites in an activity-dependent manner (PMID:25538220). Biallelic loss-of-function mutations in USP45 cause Leber congenital amaurosis, consistent with its enrichment in photoreceptor inner segments and the retinal phenotypes produced by zebrafish knockdown (rescued by wild-type mRNA) and mouse knockout (PMID:30573563). Beyond these roles, USP45 acts broadly as a substrate-stabilizing DUB: it deubiquitylates Coronin 1B to restrain F-actin/V-ATPase-driven lysosomal acidification and autophagy (PMID:40067150), stabilizes Spindly to support cell migration (PMID:30258100), and stabilizes oncogenic and signaling substrates including MYC, Snail, the RTCB-DDX1 axis, and MRGPRF, and removes ubiquitin from HIV-1 Tat as an interferon-stimulated gene (PMID:36765885, PMID:36929633, PMID:41468936, PMID:40788071, PMID:41668887).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2014 High

    Established USP45 as a bona fide deubiquitylase with a defined substrate (ERCC1) and a concrete role in nucleotide excision/cross-link repair, answering whether USP45 has enzymatic function and a biological context.

    Evidence In vitro deubiquitylation, Co-IP, catalytic-dead and binding-deficient mutants, knockout cells with UV/ICL sensitivity and foci imaging

    PMID:25538220

    Open questions at the time
    • Linkage specificity of ERCC1 chains not defined
    • Mechanism of USP45 recruitment to damage sites independent of ERCC1-XPF unresolved
  2. 2016 Medium

    Provided the first in vivo developmental role for USP45, showing it is required for vertebrate retinal differentiation.

    Evidence Morpholino knockdown in zebrafish with retinal morphology analysis

    PMID:27613029

    Open questions at the time
    • No molecular substrate linked to the retinal phenotype
    • Morpholino specificity not controlled by rescue in this report
  3. 2018 Medium

    Connected USP45 to cytoskeletal/migration biology by identifying Spindly as a catalytic-activity-dependent substrate and defining linkage preference (K48, possibly K6).

    Evidence Mass spectrometry interactome, Co-IP, in vitro deubiquitylation with catalytic-dead mutant, migration assay on knockdown

    PMID:30258100

    Open questions at the time
    • Functional consequence of Spindly mono-ubiquitin removal on its known roles not mapped
    • Single-lab finding
  4. 2018 High

    Established USP45 as a human disease gene, demonstrating that biallelic loss-of-function causes Leber congenital amaurosis with cross-species replication.

    Evidence Whole-exome sequencing, IHC localization, zebrafish knockdown with mRNA rescue, mouse knockout with ERG

    PMID:30573563

    Open questions at the time
    • Relevant substrate(s) in photoreceptors unidentified
    • Mechanism linking DUB activity to photoreceptor maintenance unknown
  5. 2023 Medium

    Implicated USP45 in oncogenesis by showing it stabilizes MYC to drive stemness and drug resistance, and identified a small-molecule inhibitor.

    Evidence Co-IP/GST pulldown, in vitro deubiquitination, overexpression/knockdown, MYC epistasis, xenograft, α-mangostin binding

    PMID:36765885

    Open questions at the time
    • Ubiquitin linkage on MYC not defined
    • Inhibitor selectivity beyond reported binding not fully characterized
  6. 2023 Medium

    Defined a recruitment mechanism for USP45 onto a substrate, showing MYH9/MYH10 deliver USP45 to deubiquitylate and stabilize Snail, promoting EMT and chemoresistance.

    Evidence Co-IP, GST pulldown, confocal co-localization, MYH10 knockdown in vitro/in vivo, epistasis

    PMID:36929633

    Open questions at the time
    • Direct vs adaptor-mediated USP45-Snail contact not separated
    • Generality of myosin-mediated recruitment to other substrates unknown
  7. 2025 High

    Linked USP45 to lysosomal and autophagy regulation via Coronin 1B, establishing an actin/V-ATPase mechanistic axis conserved across species.

    Evidence Co-IP, in vitro deubiquitination, KO/KD, F-actin and V-ATPase imaging, lysosomal acidification and autophagy flux assays in Drosophila and mammalian cells

    PMID:40067150

    Open questions at the time
    • Ubiquitin linkage type on Coro1B not specified
    • How USP45 activity is regulated in this pathway unknown
  8. 2025 Medium

    Revealed an asymmetric multi-substrate regulatory hierarchy in which USP45 stabilizes RTCB and DDX1, with DDX1 deubiquitination requiring RTCB.

    Evidence Co-IP, co-localization, in vitro deubiquitination, RTCB/DDX1 knockdown epistasis, xenograft

    PMID:41468936

    Open questions at the time
    • Structural basis of the RTCB-dependent hierarchy unresolved
    • Single-lab finding
  9. 2025 Medium

    Identified a tumor-suppressive context for USP45, showing its catalytic domain binds and stabilizes MRGPRF by removing K63 chains to inhibit melanoma malignancy.

    Evidence Screen of 40 USPs, Co-IP, in vitro deubiquitination with K63 specificity, domain mapping, MRGPRF KD/OE epistasis, xenograft

    PMID:40788071

    Open questions at the time
    • Reconciliation of pro- and anti-tumor roles across cancer types not addressed
    • Upstream control of USP45 in melanoma unknown
  10. 2026 Medium

    Extended USP45 into antiviral innate immunity, showing it is interferon-induced and deubiquitylates HIV-1 Tat at K19 to suppress viral transcription.

    Evidence NanoBRET DUB screen, Co-IP, site-specific (K19) in vitro deubiquitination, transcription and viral production assays, digital PCR in latent cells, interferon stimulation

    PMID:41668887

    Open questions at the time
    • Effect of Tat deubiquitination on Tat function mechanistically incomplete
    • In vivo antiviral relevance not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How USP45 selects among its many substrates and switches linkage preferences (K48/K63/K6) in different cellular contexts, and how its activity is regulated, remain unresolved.
  • No structural model of substrate engagement
  • Determinants of linkage specificity unknown
  • Regulation of USP45 catalytic activity uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 8 GO:0016787 hydrolase activity 3
Localization
GO:0000228 nuclear chromosome 1 GO:0005634 nucleus 1
Pathway
R-HSA-392499 Metabolism of proteins 6 R-HSA-73894 DNA Repair 1 R-HSA-9612973 Autophagy 1
Partners
CORO1BDDX1ERCC1MRGPRFMYCRTCBSNAI1SPDL1

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 USP45 associates with ERCC1 (a subunit of the XPF-ERCC1 DNA repair endonuclease) via a short acidic motif outside the USP45 catalytic domain, and directly deubiquitylates ERCC1 in vitro. USP45 knockout cells show markedly elevated ubiquitylated ERCC1 and are hypersensitive to UV irradiation and DNA interstrand cross-links, similar to ERCC1-deficient cells. ERCC1 translocation to DNA damage-induced subnuclear foci is impaired in USP45 knockout cells. USP45 itself localizes to sites of DNA damage in a manner dependent on its deubiquitylase activity but independent of ERCC1-XPF binding. In vitro deubiquitylation assay, Co-IP, mutant analysis (catalytic-dead and ERCC1-binding-deficient USP45), knockout cell lines, UV/ICL sensitivity assays, immunofluorescence of subnuclear foci The EMBO journal High 25538220
2018 USP45 forms a complex with Spindly (identified by mass spectrometry), and this interaction depends on the catalytic activity of USP45. USP45 preferentially cleaves K48-linked ubiquitin chains and potentially K6-linked chains. Spindly is mono-ubiquitylated, and this modification is specifically removed by catalytically active but not catalytic-inactive USP45. Loss of USP45 impairs cell migration, similar to loss of Spindly. Mass spectrometry-based interactome, Co-IP, in vitro deubiquitylation assay with catalytic-dead mutant, cell migration assay (knockdown) Scientific reports Medium 30258100
2016 Morpholino-mediated knockdown of usp45 in zebrafish causes abnormal retinal development with defective formation of retinal structures, establishing a functional role for USP45 in vertebrate retina differentiation. Morpholino knockdown in zebrafish embryos, phenotypic analysis of retinal morphology Methods in molecular biology (Clifton, N.J.) Medium 27613029
2018 Biallelic loss-of-function mutations in USP45 cause Leber congenital amaurosis. USP45 protein is enriched in the inner segments of photoreceptors (human and zebrafish retina). usp45 morpholino knockdown in zebrafish causes abnormal retinal development rescued by wild-type usp45 mRNA. Targeted knockout of Usp45 in mice produces abnormal electroretinography responses consistent with LCA. Whole-exome sequencing, immunohistochemistry for localization, zebrafish morpholino knockdown with mRNA rescue, mouse knockout with ERG functional readout Journal of medical genetics High 30573563
2023 USP45 directly binds MYC and deubiquitinates/stabilizes it, preventing its proteasomal degradation. USP45 overexpression upregulates MYC and enhances cancer cell stemness and drug resistance. The natural small molecule α-mangostin specifically binds and inhibits USP45, suppressing USP45-induced stemness and drug resistance in vitro and in a cervical cancer xenograft model. Co-IP/GST pulldown, in vitro deubiquitination assay, USP45 overexpression/shRNA knockdown, MYC shRNA epistasis, xenograft mouse model, binding assay with α-mangostin Cancers Medium 36765885
2023 MYH10 combines with MYH9 to recruit USP45, which then deubiquitinates Snail, preventing its degradation and promoting EMT, tumorigenesis, and cisplatin resistance in serous ovarian cancer. Interaction was established by Co-IP and GST pulldown. Co-IP, GST pulldown, confocal co-localization, knockdown of MYH10 in vitro and in vivo, MYH10/MYH9/Snail epistasis Advanced science (Weinheim, Baden-Wurttemberg, Germany) Medium 36929633
2025 USP45 interacts with and deubiquitinates Coronin 1B (Coro1B), stabilizing Coro1B protein levels. Loss of USP45 or Coro1B promotes formation of F-actin patches and translocation of V-ATPase to lysosomes in an N-WASP-dependent manner, leading to increased lysosomal acidification, enhanced lysosomal function, and autophagy activation. This pathway was demonstrated in both Drosophila and mammalian cells. Co-IP, in vitro deubiquitination assay, USP45/Coro1B KO/KD, F-actin imaging, V-ATPase localization assay, lysosomal acidification assay, autophagy flux assay in Drosophila and mammalian cells The Journal of cell biology High 40067150
2025 USP45 directly interacts with and deubiquitinates both RTCB and DDX1, removing polyubiquitin chains and stabilizing these proteins. USP45-mediated DDX1 deubiquitination requires RTCB (asymmetric regulatory hierarchy), whereas RTCB deubiquitination is DDX1-independent. This USP45-RTCB-DDX1 axis promotes cell proliferation and chemoresistance in cellular and murine models. Co-IP, co-localization, in vitro deubiquitination assay, epistasis using RTCB/DDX1 knockdown, xenograft mouse model International journal of biological macromolecules Medium 41468936
2025 USP45's catalytic domain directly binds the N-terminus of MRGPRF and stabilizes MRGPRF, specifically by removing K63-linked ubiquitination from MRGPRF in melanoma cells. USP45 overexpression inhibits melanoma cell malignancy via MRGPRF, and MRGPRF depletion mitigates USP45's anti-melanoma effects; MRGPRF overexpression rescues the enhanced malignancy caused by USP45 deficiency. Screening of 40 USPs, Co-IP, in vitro deubiquitination assay (K63-chain specificity), domain mapping, epistasis via MRGPRF KD/OE, xenograft mouse model Advanced science (Weinheim, Baden-Wurttemberg, Germany) Medium 40788071
2026 USP45 specifically deubiquitinates HIV-1 Tat at lysine 19, targeting both K48-linked and K63-linked ubiquitin chains. USP45 overexpression suppresses Tat-dependent HIV-1 transcriptional activation and viral particle production, while USP45 knockdown enhances both. USP45 primarily inhibits the initial stages of viral transcription in latently infected cells. USP45 expression is induced by interferons, identifying it as an interferon-stimulated gene. NanoBRET-based DUB screening, Co-IP, in vitro deubiquitination assay with site-specific mapping (K19), USP45 overexpression/knockdown, HIV-1 transcription assay, digital PCR in latently infected cells, interferon stimulation Frontiers in microbiology Medium 41668887

Source papers

Stage 0 corpus · 17 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1990 Cloning of usp45, a gene encoding a secreted protein from Lactococcus lactis subsp. lactis MG1363. Gene 185 2123812
1993 Functional analysis of the Lactococcus lactis usp45 secretion signal in the secretion of a homologous proteinase and a heterologous alpha-amylase. Molecular & general genetics : MGG 76 8413193
2014 USP45 deubiquitylase controls ERCC1-XPF endonuclease-mediated DNA damage responses. The EMBO journal 51 25538220
2010 Use of the usp45 lactococcal secretion signal sequence to drive the secretion and functional expression of enterococcal bacteriocins in Lactococcus lactis. Applied microbiology and biotechnology 32 20842358
2023 MYH10 Combines with MYH9 to Recruit USP45 by Deubiquitinating Snail and Promotes Serous Ovarian Cancer Carcinogenesis, Progression, and Cisplatin Resistance. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 28 36929633
2018 Biallelic mutations in USP45, encoding a deubiquitinating enzyme, are associated with Leber congenital amaurosis. Journal of medical genetics 19 30573563
2023 Suppression of Cancer Cell Stemness and Drug Resistance via MYC Destabilization by Deubiquitinase USP45 Inhibition with a Natural Small Molecule. Cancers 15 36765885
2018 USP45 and Spindly are part of the same complex implicated in cell migration. Scientific reports 15 30258100
2016 Combining Zebrafish and Mouse Models to Test the Function of Deubiquitinating Enzyme (Dubs) Genes in Development: Role of USP45 in the Retina. Methods in molecular biology (Clifton, N.J.) 15 27613029
2020 Another Breaker of the Wall: the Biological Function of the Usp45 Protein of Lactococcus lactis. Applied and environmental microbiology 14 32532874
2022 Comprehensive Analysis Reveals USP45 as a Novel Putative Oncogene in Pan-Cancer. Frontiers in molecular biosciences 11 35836933
2020 Secretion of recombinant xylanase in Lactococcus lactis using signal peptides Usp45 and Spk1. Biotechnology letters 7 32335791
2025 The deubiquitinase USP45 inhibits autophagy through actin regulation by Coronin 1B. The Journal of cell biology 3 40067150
2025 USP45 Represses Melanoma Development by Deubiquitinating and Stabilizing Tumor Suppressor MRGPRF. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 3 40788071
2025 Deubiquitinase USP45 stabilizes RTCB and DDX1, promoting tumorigenesis and chemoresistance. International journal of biological macromolecules 1 41468936
2026 USP45-mediated deubiquitination of HIV-1 Tat regulates viral transcription and latency. Frontiers in microbiology 0 41668887
2024 Production of recombinant glycosidases fused with Usp45 and SpaX to avoid the purification and immobilization stages. Enzyme and microbial technology 0 38581868

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