Affinage

TRIM36

E3 ubiquitin-protein ligase TRIM36 · UniProt Q9NQ86

Length
728 aa
Mass
83.0 kDa
Annotated
2026-06-10
24 papers in source corpus 15 papers cited in narrative 15 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

TRIM36 is a microtubule-associated RING-finger/RBCC-family E3 ubiquitin ligase that controls cytoskeletal organization, cell cycle progression, and developmental patterning, and that acts as a substrate-selective degradation factor across multiple signaling pathways (PMID:19232519, PMID:19675128). It possesses E3 ligase activity, colocalizes with alpha-tubulin and the kinetochore protein CENP-H, and its overexpression slows cell cycle progression, consistent with a role in chromosome segregation and microtubule-dependent processes (PMID:19232519). In early Xenopus development its ligase activity drives vegetal microtubule polymerization and cortical rotation required for dorsoventral axis formation, acting upstream of Wnt/beta-catenin signaling, and it is also required for somitogenesis (PMID:19675128, PMID:19032936). As a degradative ligase, TRIM36 directs K48-linked polyubiquitination and proteasomal turnover of a series of substrates — FOXA2 (linking it to NRF2/GPX4-dependent ferroptosis), phospho-AKT1, DDX3X, GRB7, RAD51, and cyclin E — and promotes ubiquitination of beta-catenin, thereby suppressing Wnt/beta-catenin and MAPK/ERK signaling and acting as a tumor suppressor in prostate, esophageal, hepatocellular, lung, and colorectal cancers (PMID:29449534, PMID:35768649, PMID:36058131, PMID:36062277, PMID:37875418, PMID:41323265, PMID:39803720, PMID:41553545). In the germline, TRIM36 (Haprin) localizes to the sperm acrosomal region and is required for the acrosome reaction and fertilization competence: antibody inhibition blocks acrosomal exocytosis and knockout mice produce morphologically abnormal, poorly motile sperm that fail in IVF (PMID:12917430, PMID:15955891, PMID:32311190). A homozygous B30.2/SPRY-domain missense mutation (p.Pro508Thr) causes autosomal recessive anencephaly, destabilizing the protein and disrupting microtubule and spindle organization (PMID:28087737).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2003 Medium

    Established TRIM36/Haprin as a germ-cell RBCC protein with a direct functional role in sperm, answering whether this RING-finger protein participates in acrosomal exocytosis.

    Evidence Western blot and IHC localization to the acrosomal region plus antibody inhibition of the acrosome reaction in permeabilized mouse sperm

    PMID:12917430

    Open questions at the time
    • Did not identify ubiquitination substrates in sperm
    • Mechanism linking the RING domain to exocytosis not defined
  2. 2005 Medium

    Showed the sperm acrosomal role is conserved in human, testing whether mouse findings generalize across species.

    Evidence Western blot and immunocytochemistry in human testis and sperm, with loss of signal after the acrosome reaction

    PMID:15955891

    Open questions at the time
    • Functional perturbation in human sperm not performed
    • No substrate identified
  3. 2009 Medium

    Defined TRIM36 as an active E3 ligase associated with microtubules and the kinetochore, addressing its molecular activity and cell-division role beyond the germline.

    Evidence Yeast two-hybrid identifying CENP-H interaction, immunofluorescence colocalization with alpha-tubulin, and overexpression cell cycle/growth assays

    PMID:19232519

    Open questions at the time
    • No in vitro reconstitution of ligase activity on CENP-H
    • CENP-H not shown to be a degradation substrate
  4. 2008 Medium

    Implicated Trim36 in somitogenesis, extending its developmental requirement beyond axis formation.

    Evidence Morpholino knockdown in Xenopus laevis with in situ/RT-PCR expression analysis

    PMID:19032936

    Open questions at the time
    • Pathway connecting TRIM36 to somite formation undefined
    • Single functional readout
  5. 2009 High

    Placed Trim36 ligase activity upstream of Wnt/beta-catenin in vertebrate dorsoventral patterning by showing it drives the cytoskeletal events of cortical rotation, the strongest mechanistic anchor for its developmental function.

    Evidence Maternal antisense loss-of-function, wnt11 mRNA and egg-tipping rescue, and ligase-dead mutant analysis in Xenopus

    PMID:19675128

    Open questions at the time
    • The ubiquitination substrate linking ligase activity to microtubule polymerization not identified
    • Direct biochemical target in cortical rotation unknown
  6. 2017 High

    Linked TRIM36 to human disease and to spindle/microtubule integrity, establishing a Mendelian phenotype and a cell-division function for the protein.

    Evidence Whole-exome sequencing identifying p.Pro508Thr in the B30.2/SPRY domain, stability assays, and transfection of mutant vs WT in HeLa/LN229 with spindle, proliferation and apoptosis readouts

    PMID:28087737

    Open questions at the time
    • How the SPRY-domain mutation impairs substrate recognition not resolved
    • Causal substrate underlying spindle defects unidentified
  7. 2018 Medium

    Identified TRIM36 as a tumor suppressor acting through MAPK/ERK, beginning the cancer-pathway phase of its characterization.

    Evidence Gain/loss-of-function in prostate cancer lines, phospho-ERK western blot, proliferation/cell cycle assays, and xenografts

    PMID:29449534

    Open questions at the time
    • Direct ubiquitination substrate in the ERK axis not defined
    • Mechanism of ERK suppression unclear
  8. 2022 Medium

    Established TRIM36 as a substrate-selective K48-ligase across several oncogenic effectors, defining its degradative mechanism for beta-catenin, RAD51, and cyclin E.

    Evidence Co-IP and ubiquitination assays for beta-catenin (ESCC), RAD51 (LUAD radiosensitivity), and cyclin E (HCC, downstream of miR-494-3p), with overexpression/knockdown and xenografts

    PMID:35768649 PMID:36058131 PMID:36062277

    Open questions at the time
    • Ubiquitination linkage type not specified for all substrates
    • Substrate recognition determinants not mapped
    • Single-lab reports per substrate
  9. 2023 Medium

    Extended the K48-degradation mechanism to FOXA2 and connected it to ferroptosis, showing TRIM36 controls the NRF2/GPX4 antioxidant axis.

    Evidence Co-IP, K48-linkage-specific ubiquitination assay, and NRF2/GPX4 western blot with ferroptosis assays in colorectal cancer cells

    PMID:37875418

    Open questions at the time
    • Direct enzymatic reconstitution absent
    • In vivo contribution to ferroptosis not tested
  10. 2025 Medium

    Broadened the substrate repertoire to phospho-AKT1 and GRB7, linking TRIM36 to AKT signaling in fibrosis and to autophagy-dependent tumor suppression in vivo.

    Evidence Co-IP and K48-ubiquitination assays for phospho-AKT1 (bleomycin pulmonary fibrosis) and GRB7 (AOM/DSS colorectal model in TRIM36-KO mice)

    PMID:39803720 PMID:41323265

    Open questions at the time
    • Selectivity for phospho-AKT1 over unphosphorylated AKT1 not mechanistically explained
    • Each substrate validated by single lab
  11. 2026 Medium

    Connected TRIM36-mediated DDX3X degradation to macrophage polarization, extending its degradative role into immune phenotype control.

    Evidence Co-IP, K48-linkage ubiquitination assay, overexpression in BMDMs, and an in vivo rat tubal factor infertility model

    PMID:41553545

    Open questions at the time
    • Mechanism linking DDX3X loss to M1-to-M2 switch not fully defined
    • Single-model validation

Open questions

Synthesis pass · forward-looking unresolved questions
  • A unifying biochemical picture of how TRIM36 selects its diverse substrates and how its microtubule/developmental functions relate to its degradative oncosuppressive functions remains unresolved.
  • No structural model of substrate recognition by the B30.2/SPRY domain
  • No reconstituted in vitro ligase assay defining minimal E2/substrate requirements
  • Whether the developmental microtubule role and the cancer substrate-degradation roles share a common molecular mechanism is untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016874 ligase activity 7 GO:0016740 transferase activity 5 GO:0140096 catalytic activity, acting on a protein 5 GO:0008092 cytoskeletal protein binding 3
Localization
GO:0005856 cytoskeleton 3 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-392499 Metabolism of proteins 5 R-HSA-162582 Signal Transduction 3 R-HSA-1266738 Developmental Biology 2 R-HSA-1474165 Reproduction 2 R-HSA-1640170 Cell Cycle 2
Partners
AKT1CENP-HCTNNB1DDX3XFOXA2GRB7RAD51

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 Haprin (TRIM36) is a haploid germ cell-specific RING finger / RBCC motif protein localized to the acrosomal region of elongated spermatids and mature sperm; a specific antibody against its RING finger domain inhibited the acrosome reaction in permeabilized sperm, establishing a direct role in acrosomal exocytosis. Western blot, immunohistochemistry, antibody inhibition of acrosome reaction in permeabilized sperm The Journal of biological chemistry Medium 12917430
2005 Human HAPRIN (TRIM36) is expressed exclusively in testes, localizes to the acrosomal region of sperm, and disappears after the acrosome reaction, indicating functional conservation of its role in the acrosome reaction between mouse and human. Western blot, immunocytochemistry in human testis and sperm Journal of andrology Medium 15955891
2009 TRIM36 has E3 ubiquitin ligase activity and interacts with the kinetochore protein CENP-H, co-localizes with alpha-tubulin (microtubules), and its overexpression decelerates cell cycle progression and attenuates cell growth, suggesting a role in chromosome segregation. Yeast two-hybrid screening (TRIM36–CENP-H interaction), immunofluorescence (colocalization with alpha-tubulin), cell growth/cycle assays upon overexpression Biochemical and biophysical research communications Medium 19232519
2009 In Xenopus, maternal trim36 mRNA is localized to the vegetal cortex/germ plasm and encodes a ubiquitin ligase required for cortical rotation and dorsoventral axis formation; depletion causes ventralized embryos rescued by wnt11 mRNA injection, placing Trim36 upstream of Wnt/beta-catenin activation. Ubiquitin ligase activity of Trim36 is required for vegetal microtubule polymerization and cortical rotation. Antisense oligonucleotide maternal loss-of-function, wnt11 mRNA rescue, egg tipping rescue, ubiquitin ligase-dead mutant analysis Development (Cambridge, England) High 19675128
2008 Morpholino-mediated knockdown of Trim36/Haprin in Xenopus laevis specifically inhibits somite formation, establishing a role for this E3 ligase in somitogenesis during early embryogenesis. Morpholino antisense knockdown, temporal and spatial expression analysis (in situ hybridization, RT-PCR) Biochemical and biophysical research communications Medium 19032936
2017 A homozygous missense mutation (p.Pro508Thr) in the B30.2/SPRY domain of TRIM36 causes autosomal recessive anencephaly; the mutant protein is less stable, and its transient expression in HeLa and LN229 cells disrupts microtubule organization, causes disorganized spindles, multiple spindles, abnormal cytokinesis, reduced proliferation, and increased apoptosis compared to wild-type TRIM36. Whole-exome sequencing, in silico conservation analysis, in vitro stability assay, transient transfection of mutant vs WT in HeLa/LN229 cells, immunofluorescence of microtubules/spindles, proliferation and apoptosis assays, siRNA knockdown Human molecular genetics High 28087737
2018 TRIM36 inhibits prostate cancer cell cycle progression and cell proliferation in vitro and in vivo via inhibition of MAPK/ERK phosphorylation; restoring TRIM36 expression during anti-androgen therapy improves drug efficacy. Overexpression and knockdown in prostate cancer cell lines, cell cycle and proliferation assays, in vivo xenograft, phospho-ERK western blot Cell death & disease Medium 29449534
2020 Haprin (TRIM36)-deficient mice generated by homologous knockout show normal spermatogenesis but reduced sperm morphology and motility, and spermatozoa fail to fertilize oocytes under standard IVF conditions, demonstrating that Haprin is required for spermiogenesis and in vitro fertilization competence. Knockout mouse generation, spermatogenesis histology, sperm morphology and motility analysis, in vitro fertilization assay Molecular reproduction and development High 32311190
2022 TRIM36 promotes ubiquitination of beta-catenin, leading to its inactivation, thereby inhibiting Wnt/beta-catenin signaling and suppressing esophageal squamous cell carcinoma (ESCC) tumor growth in vitro and in vivo. Lentivirus-mediated overexpression/knockdown, ubiquitination assay of beta-catenin, flow cytometry (cell cycle, apoptosis), xenograft mouse model Human cell Medium 35768649
2022 TRIM36 forms a complex with RAD51 and promotes its ubiquitination and degradation, thereby enhancing radiosensitivity in lung adenocarcinoma (LUAD) cells. Co-immunoprecipitation (TRIM36–RAD51 complex), ubiquitination assay, overexpression/knockdown with radiation treatment, proliferation and apoptosis assays Biochemical and biophysical research communications Medium 36058131
2022 TRIM36 is a direct target of miR-494-3p; TRIM36 promotes ubiquitination of cyclin E, reducing its levels and inhibiting HCC cell cycle progression and proliferation. Luciferase reporter assay (miR-494-3p targeting TRIM36 3'UTR), Co-IP and ubiquitination assay (TRIM36–cyclin E), overexpression/knockdown experiments, xenograft model Journal of clinical and translational hepatology Medium 36062277
2023 TRIM36 directly interacts with FOXA2 and induces its K48-linked polyubiquitination, leading to FOXA2 protein degradation; loss of FOXA2 weakens NRF2 pathway activation and decreases GPX4 levels, inducing ferroptosis in colorectal cancer cells. Co-immunoprecipitation (TRIM36–FOXA2 interaction), ubiquitination assay (K48-linkage), overexpression/knockdown with NRF2/GPX4 western blot, ferroptosis assays Advanced science (Weinheim, Baden-Wurttemberg, Germany) Medium 37875418
2025 TRIM36 mediates K48-linked polyubiquitination of phospho-AKT1 (at T308/S473), leading to its proteasomal degradation and inhibition of AKT signaling, thereby suppressing lung fibroblast activation and pulmonary fibrosis; TRIM36 overexpression ameliorates bleomycin-induced pulmonary fibrosis in mice. Co-immunoprecipitation, K48-linked ubiquitination assay (phospho-AKT1 substrate), overexpression in fibroblasts, bleomycin mouse model iScience Medium 41323265
2025 TRIM36 directly binds GRB7 and promotes its ubiquitination and degradation; TRIM36 knockout in mice promotes AOM/DSS-induced colorectal carcinogenesis and inhibits autophagy, and this tumor-suppressive role is mediated through GRB7 degradation. Co-immunoprecipitation (TRIM36–GRB7), ubiquitination assay, TRIM36 knockout mice (AOM/DSS model), overexpression/knockdown in CRC cell lines Molecular carcinogenesis Medium 39803720
2026 TRIM36 promotes K48-linked polyubiquitination and proteasomal degradation of DDX3X, shifting macrophage polarization from M1 to M2 phenotype and ameliorating tubal factor infertility in a rat model. Co-immunoprecipitation (TRIM36–DDX3X), ubiquitination assay (K48-linkage), TRIM36 overexpression in BMDMs, in vivo rat TFI model with oe-TRIM36 therapy Cell biology and toxicology Medium 41553545

Source papers

Stage 0 corpus · 24 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2023 FOXA2 Suppression by TRIM36 Exerts Anti-Tumor Role in Colorectal Cancer Via Inducing NRF2/GPX4-Regulated Ferroptosis. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 62 37875418
2003 Haprin, a novel haploid germ cell-specific RING finger protein involved in the acrosome reaction. The Journal of biological chemistry 48 12917430
2018 TRIM36, a novel androgen-responsive gene, enhances anti-androgen efficacy against prostate cancer by inhibiting MAPK/ERK signaling pathways. Cell death & disease 46 29449534
2009 TRIM36 interacts with the kinetochore protein CENP-H and delays cell cycle progression. Biochemical and biophysical research communications 41 19232519
2009 Vegetally localized Xenopus trim36 regulates cortical rotation and dorsal axis formation. Development (Cambridge, England) 39 19675128
2004 Cloning and characterisation of the RBCC728/TRIM36 zinc-binding protein from the tumor suppressor gene region at chromosome 5q22.3. Gene 30 15145053
2017 A homozygous mutation in TRIM36 causes autosomal recessive anencephaly in an Indian family. Human molecular genetics 28 28087737
2008 Trim36/Haprin plays a critical role in the arrangement of somites during Xenopus embryogenesis. Biochemical and biophysical research communications 21 19032936
2022 TRIM36 inhibits tumorigenesis through the Wnt/β-catenin pathway and promotes caspase-dependent apoptosis in hepatocellular carcinoma. Cancer cell international 19 36068629
2017 TRIM36 hypermethylation is involved in polycyclic aromatic hydrocarbons-induced cell transformation. Environmental pollution (Barking, Essex : 1987) 19 28359976
2022 TRIM36 suppresses cell growth and promotes apoptosis in human esophageal squamous cell carcinoma cells by inhibiting Wnt/β-catenin signaling pathway. Human cell 16 35768649
2005 Identification of human HAPRIN potentially involved in the acrosome reaction. Journal of andrology 14 15955891
2022 Microtubular TRIM36 E3 Ubiquitin Ligase in Embryonic Development and Spermatogenesis. Cells 13 35053362
2022 TRIM36 enhances lung adenocarcinoma radiosensitivity and inhibits tumorigenesis through promoting RAD51 ubiquitination and antagonizing hsa-miR-376a-5p. Biochemical and biophysical research communications 12 36058131
2022 Extracellular Polysaccharide from Rhizopus nigricans Inhibits Hepatocellular Carcinoma via miR-494-3p/TRIM36 Axis and Cyclin E Ubiquitination. Journal of clinical and translational hepatology 11 36062277
2020 Haprin-deficient spermatozoa are incapable of in vitro fertilization. Molecular reproduction and development 8 32311190
2019 High expression of TRIM36 is associated with radiosensitivity in gastric cancer. Oncology letters 8 30944633
2005 The RING-finger protein haprin: domains and function in the acrosome reaction. Current protein & peptide science 8 16381605
2025 TRIM36 Inhibits the Development of AOM/DSS-Induced Colitis-Associated Colorectal Cancer by Promoting the Ubiquitination and Degradation of GRB7. Molecular carcinogenesis 5 39803720
2023 Genome-wide association study reveals HSF2, GJA1 and TRIM36 as susceptibility genes for preeclampsia: a community-based population study in Tianjin, China. Hypertension in pregnancy 3 37735976
2025 TRIM36 inhibits lung fibroblast activation and pulmonary fibrosis through the degradation of phospho-AKT1. iScience 1 41323265
2026 E3 ubiquitin ligase trim36 targets ddx3x for degradation to reprogram macrophage polarization and ameliorate tubal factor infertility in rats. Cell biology and toxicology 0 41553545
2026 TRIM36 and CAMK2N2 regulate ferroptosis and antigen presentation in small cell lung cancer. iScience 0 41940332
1990 [Organelle-specific activity of enzymes of different rat organs as one of the criteria in the hygienic evaluation of haprin]. Voprosy pitaniia 0 2275125

Missed literature

Know a paper Affinage missed for TRIM36? Flag it for the maintainers and the community.

No submissions yet.