Affinage

TMUB1

Transmembrane and ubiquitin-like domain-containing protein 1 · UniProt Q9BVT8

Length
246 aa
Mass
26.3 kDa
Annotated
2026-06-10
21 papers in source corpus 18 papers cited in narrative 18 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TMUB1 (HOPS) is an endoplasmic reticulum-resident transmembrane ubiquitin-like protein that operates at the interface of protein quality control, apoptosis, and inflammatory signalling (PMID:35961308, PMID:31867855). In the ER membrane it functions as a transmembrane-domain escortase: it engages the exposed hydrophobic TMDs of client proteins undergoing ERAD retrotranslocation, shielding ~10–14 residues through its transmembrane and cytosolic regions, and uses its ubiquitin-like domain to recruit the p97 ATPase that extracts clients into the cytosol for proteasomal degradation (PMID:35961308). Acting on specific ER substrates, it competes with the E3 ligase HUWE1 to protect PD-L1 from K281 polyubiquitination while recruiting STT3A to promote PD-L1 N-glycosylation and maturation, thereby supporting tumour immune evasion (PMID:36376293), and it is organized within ER ERLIN1/2 SPFH-domain scaffolds that mediate its association with RNF170, an interaction linked to hereditary spastic paraplegia (PMID:38782601). TMUB1 also governs apoptosis through p53: it binds cytoplasmic p53, blocks importin-α-mediated nuclear import to raise cytoplasmic p53, inhibits p53 proteasomal turnover, and directs p53 to mitochondria to trigger intrinsic apoptosis, with Hops-null and haploinsufficient mice showing blunted chemotherapy- and DNA-damage-induced apoptosis (PMID:31867855, PMID:34281239). It additionally regulates NF-κB signalling by binding and destabilising the E3 ligase TRAF6 to enhance IKK activation and p65 transcriptional output (PMID:33060567), and as a synaptic factor it complexes with GluR2 and GRIP to promote AMPA-receptor recycling to the neuronal surface (PMID:18665261). In hepatocytes it acts as a proliferation suppressor, interacting with CAML via its TM1 domain to disrupt the CAML–cyclophilin B interaction and reduce Ca²⁺ influx, and inhibiting STAT3 phosphorylation within a STAT3-driven negative feedback loop (PMID:29967478, PMID:30610893).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2008 High

    Established the first molecular function for TMUB1 outside the ER, showing it acts as a trafficking adaptor that controls synaptic receptor availability.

    Evidence Co-IP of a Tmub1–GluR2–GRIP complex from mouse brain with RNAi/overexpression, electrophysiology, and surface recycling assays

    PMID:18665261

    Open questions at the time
    • Does not define which TMUB1 domain mediates GluR2/GRIP binding
    • Relationship to TMUB1's ER escortase role not addressed
  2. 2010 High

    Identified CAMLG as a TMUB1 partner and linked the protein to organismal physiology, opening a Ca2+-related signalling axis.

    Evidence Yeast two-hybrid screen confirmed by reciprocal Co-IP and co-localization in HEK cells, plus Tmub1 knockout mouse EEG/locomotor recordings

    PMID:20582322

    Open questions at the time
    • Mechanism connecting CAML binding to the behavioral phenotype unresolved
    • No downstream Ca2+ effector defined here
  3. 2012 Medium

    Connected the TMUB1–CAML interaction to a cellular outcome, showing TMUB1 negatively controls hepatocyte proliferation.

    Evidence Co-IP, confocal co-localization, shRNA knockdown, Ca2+ influx and thymidine incorporation assays in hepatocytes

    PMID:22426572

    Open questions at the time
    • Single lab
    • Domain requirement for CAML binding not yet mapped
    • Molecular link from CAML to proliferation incomplete
  4. 2018 High

    Mapped the structural basis of TMUB1's anti-proliferative effect to its TM1 domain and a defined biochemical mechanism.

    Evidence Co-IP with TM1 deletion mutant, Ca2+ imaging, and proliferation assays in BRL-3A cells showing TMUB1 disrupts CAML–cyclophilin B

    PMID:29967478

    Open questions at the time
    • Does not show how reduced Ca2+ influx mechanistically halts the cell cycle
    • In vivo relevance in liver regeneration not tested here
  5. 2019 High

    Defined a major apoptotic function for TMUB1 by showing it stabilizes and relocalizes p53 to mitochondria, with in vivo confirmation.

    Evidence Reciprocal Co-IP (HOPS–p53, HOPS–importin α), mitochondrial fractionation, apoptosis assays, and Hops-/- mouse

    PMID:31867855

    Open questions at the time
    • Does not resolve how a transmembrane ER protein accesses cytoplasmic p53
    • Whether p53 stabilization is direct or via blocked degradation not fully separated
  6. 2019 High

    Established TMUB1 as a STAT3-pathway regulator embedded in a transcriptional negative-feedback loop in hepatocytes.

    Evidence Co-IP (Tmub1–STAT3), loss/gain-of-function in Lo2 cells, partial hepatectomy model, ChIP and luciferase reporter assays

    PMID:30610893

    Open questions at the time
    • Does not show how TMUB1 binding inhibits STAT3 phosphorylation mechanistically
    • Relationship to the CAML/Ca2+ proliferation axis unclear
  7. 2019 Low

    Proposed a STAT1/CCND1 transcriptional axis for TMUB1's growth-suppressive role in hepatocellular carcinoma.

    Evidence Loss/gain-of-function in HCC cell lines with qPCR, western blot, proliferation assays, and tissue correlation

    PMID:31827061

    Open questions at the time
    • No direct TMUB1–STAT1 binding demonstrated; only expression correlation
    • Pathway placement relative to STAT3 regulation unresolved
  8. 2020 High

    Revealed that TMUB1 amplifies NF-κB inflammatory signalling by destabilizing the E3 ligase TRAF6.

    Evidence Co-IP (HOPS–TRAF6), Hops-/- cells, IκBα stability, NF-κB reporter assays, and cytokine measurements

    PMID:33060567

    Open questions at the time
    • Mechanism of TRAF6 destabilization (ligase recruitment vs sequestration) not defined
    • Reconciliation with TMUB1's pro-apoptotic role left open
  9. 2020 High

    Extended TMUB1's pro-apoptotic activity in HCC by showing it drives ubiquitin-dependent degradation of ΔNp63 isoforms.

    Evidence Co-IP (Tmub1–ΔNp63), ubiquitination assay, loss/gain-of-function, xenograft, and ΔNp63 rescue experiments

    PMID:32671188

    Open questions at the time
    • E3 ligase that TMUB1 recruits to ΔNp63 not identified
    • Link to the p53 axis not directly tested
  10. 2022 High

    Provided the defining biochemical mechanism of TMUB1 as an ER escortase coupling client TMD shielding to p97-driven retrotranslocation in ERAD.

    Evidence In vitro reconstitution, retrotranslocation intermediate trapping, domain mutagenesis, and Co-IP with p97

    PMID:35961308

    Open questions at the time
    • Full client repertoire not enumerated
    • Selectivity rules for which TMDs are escorted not defined
  11. 2022 High

    Demonstrated a substrate-protective ER role for TMUB1, shielding PD-L1 from ubiquitination while promoting its glycosylation to enable immune evasion.

    Evidence Reciprocal Co-IP, K281 mutagenesis, competition binding, glycosylation assays, and in vivo tumor models with competing peptide

    PMID:36376293

    Open questions at the time
    • How TMUB1 reconciles substrate protection here with escortase-mediated degradation elsewhere unresolved
    • STT3A recruitment mechanism not structurally defined
  12. 2021 Medium

    Confirmed gene-dosage dependence of TMUB1's p53-apoptosis function via haploinsufficiency.

    Evidence Hops heterozygous mice and MEFs with etoposide, p53 quantification, apoptosis and p53-target profiling

    PMID:34281239

    Open questions at the time
    • Single lab
    • Does not address tissue specificity of haploinsufficiency
  13. 2021 Low

    Described cell-cycle-dependent nucleocytoplasmic shuttling and crystallin association of TMUB1 in lens, hinting at a UPS role in differentiation.

    Evidence Immunofluorescence localization in mouse lens across cell cycle and differentiation zones

    PMID:33543240

    Open questions at the time
    • Descriptive localization without functional perturbation
    • Crystallin association not validated biochemically
  14. 2023 Medium

    Showed TMUB1 is required for IKK/NF-κB activation and inflammation in trophoblasts, consistent with its TRAF6/NF-κB role.

    Evidence TMUB1 knockdown in trophoblast cells, LPS abortion model, IKKα/β phosphorylation and p65 translocation assays

    PMID:37249279

    Open questions at the time
    • Single lab
    • Does not confirm TRAF6 dependence in this cell type
  15. 2024 Medium

    Placed TMUB1 in an oncogenic m6A-regulated AKT ubiquitination circuit in colorectal cancer, contrasting with its tumor-suppressive liver roles.

    Evidence MeRIP-seq, Co-IP (TMUB1–AMFR–AKT), K63-ubiquitination assay, and in vivo/in vitro functional assays

    PMID:38341886

    Open questions at the time
    • Single lab with limited orthogonal validation of K63-AKT ubiquitination
    • Reconciliation with growth-suppressive functions unclear
  16. 2024 Medium

    Defined the ER ERLIN1/2 scaffold and N-terminal luminal region that organize TMUB1–RNF170 assembly, linking the complex to hereditary spastic paraplegia.

    Evidence Co-IP, domain deletion/mutation, 3D structural modelling, proteomics, and ERLIN double-knockout phenotyping in HeLa

    PMID:38782601

    Open questions at the time
    • Functional consequences shown in ERLIN KO rather than direct TMUB1 KO
    • Disease causality from TMUB1 mutation not directly demonstrated
  17. 2024 Medium

    Extended TMUB1's apoptotic function to mutant p53 forms, indicating context-dependent regulation through TP63 pathways.

    Evidence IP (HOPS–mutant p53 R175H/R248W/R273H), apoptosis assays, and MYC/TP63 expression analysis

    PMID:38731819

    Open questions at the time
    • Single lab
    • Determinants of gain- vs loss-of-function context not defined
  18. 2025 Medium

    Identified PBX1 as an upstream repressor of TMUB1 transcription controlling its inflammatory/apoptotic output.

    Evidence Luciferase reporter for PBX1 binding to the TMUB1 promoter, PBX1 overexpression, and TMUB1 rescue in LPS-treated trophoblasts

    PMID:39961876

    Open questions at the time
    • Single lab
    • Direct PBX1 promoter occupancy by ChIP not shown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TMUB1's single biochemical identity as an ER transmembrane Ub-like escortase mechanistically gives rise to its diverse cytoplasmic, mitochondrial, synaptic, and transcription-coupled functions remains unresolved.
  • No structural model unifying the escortase, p53, and TRAF6 roles
  • Topology allowing an ER protein to act on cytosolic/mitochondrial p53 unexplained
  • Determinants of context-dependent tumor-suppressive vs oncogenic behavior unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005783 endoplasmic reticulum 3 GO:0005829 cytosol 3 GO:0005739 mitochondrion 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-392499 Metabolism of proteins 2
Partners
CAMLGERLIN1HUWE1P97/VCPSTAT3STT3ATP53TRAF6
Complex memberships
ERLIN1/2-RNF170 ER scaffold complexGluR2-GRIP AMPA receptor recycling complex

Evidence

Reading pass · 18 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2022 TMUB1 competes with the E3 ubiquitin ligase HUWE1 to interact with PD-L1 at the endoplasmic reticulum, inhibiting PD-L1 polyubiquitination at K281, while also recruiting STT3A to enhance PD-L1 N-glycosylation and stability, thereby promoting PD-L1 maturation and tumor immune evasion. Co-immunoprecipitation, site-directed mutagenesis (K281), competition binding assays, glycosylation assays, in vivo tumor models with synthetic competing peptide Nature communications High 36376293
2022 TMUB1 is an ER-resident escortase that interacts with transmembrane domains (TMDs) of client proteins undergoing ERAD retrotranslocation, shielding ~10–14 hydrophobic residues exposed out of the membrane via its transmembrane and cytosolic regions, and recruits p97 via its ubiquitin-like domain to pull client TMDs into the cytosol for proteasomal degradation. In vitro reconstitution, biochemical retrotranslocation assays, domain mutagenesis, trapping of retrotranslocation intermediates, co-immunoprecipitation with p97 Molecular cell High 35961308
2019 HOPS/TMUB1 binds p53 in the cytoplasm, inhibits its proteasomal degradation, interferes with importin α to increase cytoplasmic p53 levels, and promotes p53 recruitment to mitochondria to induce the intrinsic apoptosis pathway; Hops−/− mice show significantly reduced apoptosis after chemotherapy. Co-immunoprecipitation (HOPS–p53 and HOPS–importin α), Hops knockout mouse model, apoptosis assays, mitochondrial fractionation EMBO reports High 31867855
2008 Tmub1/HOPS facilitates recycling of GluR2-containing AMPA receptors to the synaptic surface by forming a complex with GluR2 and GRIP; RNAi knockdown of Tmub1 reduces AMPAR currents and synaptic surface GluR2, while overexpression increases surface GluR2. Co-immunoprecipitation from mouse brain (Tmub1–GluR2–GRIP complex), RNAi knockdown in neurons, electrophysiology (AMPAR current), surface recycling assay, EGFP-Tmub1 overexpression PloS one High 18665261
2020 HOPS/TMUB1 directly binds the E3 ubiquitin ligase TRAF6, reducing TRAF6 stability and thereby increasing IKK complex activation, which destabilizes IκBα and enhances NF-κB (p65/RelA) transcriptional activity; Hops−/− cells show impaired pro-inflammatory responses. Co-immunoprecipitation (HOPS–TRAF6), Hops knockout cells, IκBα stability assays, NF-κB transcriptional reporter assays, inflammatory cytokine measurements Cell death & disease High 33060567
2010 Tmub1 binds to CAMLG (calcium-modulating cyclophilin ligand) as confirmed by yeast two-hybrid screen and co-immunoprecipitation in HEK cells; the two proteins co-localize in the cytoplasm; Tmub1 knockout mice exhibit increased wakefulness and locomotor activity during the dark phase. Yeast two-hybrid screen, co-immunoprecipitation in HEK cells, co-localization (fluorescence microscopy), Tmub1 knockout mouse with EEG/telemetric locomotor recording PloS one High 20582322
2019 Tmub1 inhibits STAT3 phosphorylation and STAT3 signaling in hepatocytes; co-immunoprecipitation demonstrates direct interaction between Tmub1 and STAT3; chromatin immunoprecipitation and luciferase assays show STAT3 binds the Tmub1 promoter, suggesting a negative feedback loop. Co-immunoprecipitation (Tmub1–STAT3), loss- and gain-of-function in Lo2 cells, partial hepatectomy mouse model, chromatin immunoprecipitation, luciferase reporter assay Cellular signalling High 30610893
2020 Tmub1 forms a protein complex with ΔNp63 isoforms (ΔNp63α, β, γ) and promotes their ubiquitination and proteasomal degradation, thereby inducing apoptosis in hepatocellular carcinoma cells. Co-immunoprecipitation (Tmub1–ΔNp63), ubiquitination assay, loss- and gain-of-function (Hep3B and MHCC-LM3 cells), xenograft growth assay, rescue experiments with ΔNp63 overexpression Molecular therapy oncolytics High 32671188
2018 TMUB1 interacts with CAML via its TM1 hydrophobic domain; overexpression of TMUB1 abolishes the interaction between CAML and cyclophilin B, reducing intracellular Ca2+ influx and inhibiting hepatocyte proliferation; deletion of TM1 abolishes these effects. Co-immunoprecipitation in BRL-3A cells, TM1 domain deletion mutant, Ca2+ influx assay (fluorescence microscopy), hepatocyte proliferation assay Scientific reports High 29967478
2024 ERLIN1/2 scaffolds mediate the interaction between the full-length isoform of TMUB1 and RNF170; a luminal N-terminal conserved region in TMUB1 (and RNF170) is required for binding to the SPFH domain of adjacent ERLIN subunits; disruption of this interaction is linked to hereditary spastic paraplegia. Co-immunoprecipitation, domain deletion/mutation analysis, 3D structural modelling, proteomics (omics-based), HeLa ERLIN double-knockout phenotypic characterization Life science alliance Medium 38782601
2012 Tmub1 co-localizes with CAML in the hepatocellular cytoplasm; Tmub1 knockdown upregulates CAML protein expression and alters Ca2+ influx; Tmub1 plays a negative role in IL-6-induced hepatocyte proliferation through its interaction with CAML. Co-immunoprecipitation, laser scanning confocal microscopy (co-localization), shRNA knockdown, Ca2+ influx assay, [3H]-thymidine incorporation proliferation assay International journal of molecular medicine Medium 22426572
2024 NNK promotes TMUB1 upregulation via METTL14/YTHDF2-mediated m6A modification; elevated TMUB1 interacts with AMFR to promote K63-linked ubiquitination of AKT, leading to malignant proliferation and metastasis in colorectal cancer cells. Methylated RNA immunoprecipitation sequencing, co-immunoprecipitation (TMUB1–AMFR–AKT), ubiquitination assay (K63-linkage), in vivo and in vitro functional assays Journal of hazardous materials Medium 38341886
2019 TMUB1 promotes STAT1 expression in hepatocellular carcinoma cells and suppresses CCND1, negatively regulating HCC cell proliferation; TMUB1 expression is positively correlated with STAT1 in HCC tissues. Loss- and gain-of-function in HCC cell lines, qPCR, western blotting, CCK-8 and EdU proliferation assays Medical science monitor Low 31827061
2021 HOPS/TMUB1 shuttles between nucleus and cytoplasm during the cell cycle in lens cells; it localizes mainly to the nucleus of central epithelial cells and moves to cytoplasm during mitosis, returning to nucleus post-mitosis; in differentiating fiber cells it associates with crystallin proteins, possibly acting in the ubiquitin-proteasome system. Immunofluorescence localization in mouse lens tissue across cell cycle stages and differentiation zones Bioscience reports Low 33543240
2021 Hops heterozygous mice and mouse embryonic fibroblasts show impaired apoptotic response to etoposide-induced DNA damage, with reduced p53 protein levels and reduced percentage of apoptotic cells, demonstrating haploinsufficiency of HOPS in supporting p53-dependent DNA damage responses. Hops heterozygous mouse model, etoposide treatment, p53 protein quantification (western blot), apoptosis assay, p53-target gene expression profiling International journal of molecular sciences Medium 34281239
2023 TMUB1 deficiency in LPS-stimulated trophoblast cells suppresses phosphorylation of IKKα/β and blocks cytoplasmic-to-nuclear translocation of NF-κB p65, inhibiting apoptosis and NF-κB-mediated inflammation. TMUB1 knockdown in human chorionic trophoblast cells, LPS-induced mouse abortion model, IKKα/β phosphorylation assay, NF-κB p65 nuclear translocation (immunofluorescence), apoptosis assay Immunity, inflammation and disease Medium 37249279
2024 HOPS/TMUB1 binds mutant p53 forms (R175H, R248W, R273H) by immunoprecipitation and promotes apoptosis in p53-mutant cancer cells; the interaction with p53-mutants modulates apoptosis in a context-dependent gain- or loss-of-function manner involving TP63-dependent pathways. Immunoprecipitation (HOPS–mutant p53), apoptosis assays in SKBR3/MIA PaCa2/H1975 cells, gene expression analysis (MYC, TP63) International journal of molecular sciences Medium 38731819
2025 PBX1 transcription factor binds the TMUB1 promoter and represses TMUB1 transcription; restoration of TMUB1 expression abolishes PBX1-mediated suppression of apoptosis, inflammation, and NF-κB signaling in LPS-treated trophoblast cells. Luciferase reporter assay (PBX1 binding to TMUB1 promoter), PBX1 overexpression, exogenous TMUB1 rescue experiment, NF-κB pathway assays Journal of molecular histology Medium 39961876

Source papers

Stage 0 corpus · 21 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2022 Promoting anti-tumor immunity by targeting TMUB1 to modulate PD-L1 polyubiquitination and glycosylation. Nature communications 82 36376293
2019 HOPS/TMUB1 retains p53 in the cytoplasm and sustains p53-dependent mitochondrial apoptosis. EMBO reports 29 31867855
2008 Transmembrane and ubiquitin-like domain-containing protein 1 (Tmub1/HOPS) facilitates surface expression of GluR2-containing AMPA receptors. PloS one 24 18665261
2022 TMUB1 is an endoplasmic reticulum-resident escortase that promotes the p97-mediated extraction of membrane proteins for degradation. Molecular cell 20 35961308
2012 IL-6 induction of hepatocyte proliferation through the Tmub1-regulated gene pathway. International journal of molecular medicine 18 22426572
2010 Transmembrane and ubiquitin-like domain containing 1 (Tmub1) regulates locomotor activity and wakefulness in mice and interacts with CAMLG. PloS one 17 20582322
2020 HOPS/Tmub1 involvement in the NF-kB-mediated inflammatory response through the modulation of TRAF6. Cell death & disease 16 33060567
2024 Nicotine-derived NNK promotes CRC progression through activating TMUB1/AKT pathway in METTL14/YTHDF2-mediated m6A manner. Journal of hazardous materials 15 38341886
2019 Tmub1 negatively regulates liver regeneration via inhibiting STAT3 phosphorylation. Cellular signalling 14 30610893
2019 Transmembrane and Ubiquitin-Like Domain Containing 1 Protein (TMUB1) Negatively Regulates Hepatocellular Carcinoma Proliferation via Regulating Signal Transducer and Activator of Transcription 1 (STAT1). Medical science monitor : international medical journal of experimental and clinical research 14 31827061
2023 Inhibition of TMUB1 blocks apoptosis and NF-κB pathway-mediated inflammation in recurrent spontaneous abortion. Immunity, inflammation and disease 13 37249279
2020 Tmub1 Suppresses Hepatocellular Carcinoma by Promoting the Ubiquitination of ΔNp63 Isoforms. Molecular therapy oncolytics 12 32671188
2020 The Ins and Outs of HOPS/TMUB1 in biology and pathology. The FEBS journal 12 32860479
2018 MiR-27a/b Regulates Liver Regeneration by Posttranscriptional Modification of Tmub1. Digestive diseases and sciences 12 29777440
2024 ERLIN1/2 scaffolds bridge TMUB1 and RNF170 and restrict cholesterol esterification to regulate the secretory pathway. Life science alliance 6 38782601
2021 Hops/Tmub1 Heterozygous Mouse Shows Haploinsufficiency Effect in Influencing p53-Mediated Apoptosis. International journal of molecular sciences 5 34281239
2018 TMUB1 Inhibits BRL-3A Hepatocyte Proliferation by Interfering with the Binding of CAML to Cyclophilin B through its TM1 Hydrophobic Domain. Scientific reports 4 29967478
2024 HOPS/TMUB1 Enhances Apoptosis in TP53 Mutation-Independent Setting in Human Cancers. International journal of molecular sciences 2 38731819
2025 PBX1 attenuates inflammation and apoptosis of trophoblast cells induced by LPS through downregulating the transcription of TMUB1: PBX1 ameliorates RSA development. Journal of molecular histology 1 39961876
2026 Exploration of the diagnostic and therapeutic potential of the nucleocytoplasmic shuttling protein TMUB1 by inducing G0/G1 cell cycle arrest in ovarian cancer. Molecular & cellular oncology 0 41923894
2021 Functional expression and localisation of HOPS/TMUB1 in mouse lens. Bioscience reports 0 33543240

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