Affinage

TRIM28

Transcription intermediary factor 1-beta · UniProt Q13263

Length
835 aa
Mass
88.5 kDa
Annotated
2026-06-10
100 papers in source corpus 44 papers cited in narrative 44 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TRIM28 (KAP1/TIF1beta) is a multifunctional nuclear scaffold that couples sequence-specific transcription factor recruitment to heterochromatin assembly, RNA Pol II control, and post-translational modification of diverse substrates (PMID:23293284, PMID:32402252, PMID:36341546). Its RBCC/TRIM domain forms antiparallel dimers that present a coiled-coil interface—pinned by Leu301—for binding the KRAB domains of zinc-finger proteins, and structure-guided disruption of this interface abolishes transcriptional silencing and genome-wide H3K9me3 deposition at thousands of KAP1/KRAB-ZFP loci (PMID:31289231, PMID:36341546, PMID:36173157). Recruited by KRAB-ZFPs, TRIM28 acts downstream of these factors and upstream of the SETDB1/ESET methyltransferase to install stable H3K9me3 and de novo DNA methylation that silence endogenous retroviruses and transposable elements (PMID:23293284, PMID:30061100), with HP1 binding contributing to repressive complex assembly (PMID:31427381). Its tandem PHD finger–bromodomain functions as an intramolecular SUMO E3 ligase whose auto-SUMOylation is required for co-repressor activity (PMID:18488044, PMID:31427381). Beyond silencing, a chromatin reader cassette binds hypo-acetylated histone H4 at promoters, stabilizes paused Pol II, and recruits CDK9/P-TEFb and SMAD2 to drive pause release upon TGF-beta signaling (PMID:25173174, PMID:32402252). TRIM28 additionally serves as an E3 ubiquitin and SUMO ligase for an extensive substrate set—targeting MAVS, RIPK1, TBK1, NLRP3, BCL2A1, ACSL4, TFE3, PD-L1, BRD7, and p27 for ubiquitination or SUMOylation—thereby controlling innate immune signaling, inflammasome activation, ferroptosis, cell-cycle progression, and antitumor immunity (PMID:30042493, PMID:34373456, PMID:37357254, PMID:37865804, PMID:37119745, PMID:39875520, PMID:38495890). TRIM28 also stabilizes p53-degrading MDM2 complexes and Oct4 to govern p53 turnover and pluripotency (PMID:16107876, PMID:32895487). All of these activities are gated by a phosphorylation–SUMOylation cross-talk switch: ATM phosphorylation of Ser824 reduces SUMOylation to de-repress damage-response genes, while PKCdelta/mTORC1/PKR phosphorylation of Ser473 reconfigures partner interactions across the cell cycle, DNA replication, and stress responses (PMID:17942393, PMID:18590578, PMID:29955894, PMID:33783327, PMID:34518220).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2005 High

    Established TRIM28 as a positive regulator of p53 turnover, linking it to oncogenic signaling before its silencing roles were fully appreciated.

    Evidence Reciprocal Co-IP, RNAi, ubiquitination and competition assays mapping the KAP1 coiled-coil to the MDM2 acidic domain

    PMID:16107876

    Open questions at the time
    • Did not address whether SUMOylation or phosphorylation gates the MDM2 interaction
    • Physiological contexts where ARF competition dominates unresolved
  2. 2007 High

    Defined the central phosphorylation–SUMOylation switch by showing ATM phosphorylation of Ser824 antagonizes SUMOylation to de-repress damage-response genes.

    Evidence S824A/S824D mutagenesis, ATM kinase and SUMOylation assays, reporter assays, ChIP

    PMID:17942393

    Open questions at the time
    • Which SUMO sites are coupled to S824 not pinpointed
    • Genome-wide scope of the switch not assessed
  3. 2008 High

    Resolved how TRIM28 generates its own activating modification and how a second phospho-site tunes HP1 binding, mechanizing the PTM-controlled co-repressor.

    Evidence NMR structure of the PHD–bromodomain SUMO ligase; S473 mutagenesis with ChIP and Co-IP showing PKCdelta disrupts HP1beta binding

    PMID:18488044 PMID:18590578

    Open questions at the time
    • Intramolecular vs intermolecular SUMO transfer in vivo not fully delineated
    • S473 kinase repertoire beyond PKCdelta unknown at this stage
  4. 2011 High

    Showed KAP1 recruitment is bipartite—RBCC/KRAB-ZFP-dependent at zinc-finger gene bodies but KRAB-independent at promoters—revealing more than one targeting mode.

    Evidence ChIP-seq with RBCC-deletion mutants and knockdown

    PMID:21343339

    Open questions at the time
    • Identity of the KRAB-independent promoter recruiter not determined
  5. 2013 High

    Placed KAP1 epistatically between KRAB-ZFPs and SETDB1 in establishing stable DNA methylation at ERVs, ordering the silencing pathway.

    Evidence KAP1 KO in early embryos, ERV reporter assays, bisulfite sequencing in ES cells

    PMID:23293284

    Open questions at the time
    • Mechanism linking H3K9me3 to de novo DNA methyltransferase recruitment not resolved
  6. 2014 High

    Expanded TRIM28 function beyond silencing to direct control of Pol II promoter-proximal pausing genome-wide.

    Evidence In vitro pausing assay, Pol II ChIP-seq, RNAi knockdown

    PMID:25173174

    Open questions at the time
    • Chromatin features directing TRIM28 to paused genes not yet defined
  7. 2015 Medium

    Identified TRIM28 partners that retune its DNA-repair and stem-cell roles, showing context-dependent regulation of chromatin retention.

    Evidence Co-IP and HR repair assays for SET; reciprocal Co-IP/MS, ChIP and mammosphere assays for an EZH2/SWI/SNF activating complex

    PMID:25818296 PMID:28068325

    Open questions at the time
    • SET-KAP1 interaction shown by single-lab Co-IP without reciprocal structural mapping
    • How TRIM28 switches between PRC2-independent activation and repression unclear
  8. 2016 Medium

    Defined a URI-KAP1-PP2A complex that dephosphorylates KAP1 to sustain retrotransposon repression, mechanizing phosphatase control of the switch.

    Evidence Co-IP/MS, URI knockdown, transposon microarray, phosphorylation assay

    PMID:27780869

    Open questions at the time
    • Single-lab; specific KAP1 phospho-sites targeted by PP2A not mapped
  9. 2018 High

    Catalogued TRIM28 as a substrate-specific E3 ligase and replication-coupled heterochromatin factor, broadening its enzymatic and cell-cycle roles.

    Evidence Co-IP and ubiquitination assays for BCL2A1 (TRIM17-antagonized) and TRIM24 (anti-SPOP); S473-promoted Co-IP with PCNA/MCM3/MCM6 and Suv39h1 during S phase

    PMID:29955894 PMID:30042493 PMID:30479348

    Open questions at the time
    • Whether E3 activity requires RING dimerization not addressed here
    • Direct vs scaffolded ubiquitin transfer to each substrate not always distinguished
  10. 2019 High

    Provided high-resolution structural and biophysical definition of the TRIM28 dimer, KRAB-binding interface, and asymmetric HP1 stoichiometry.

    Evidence Crystal structure, SAXS/SEC-MALS, single-molecule and SUMOylation assays; CDK9 SUMOylation by SUMO-MS and mutagenesis for HIV latency

    PMID:30652970 PMID:31289231 PMID:31427381

    Open questions at the time
    • Functional role of higher-order oligomerization beyond silencing unclear
    • How asymmetry is read out by partners not resolved
  11. 2020 High

    Mechanized the chromatin-reading-to-elongation coupling, showing TRIM28 reads hypo-acetylated H4 and recruits SMAD2/CDK9 for ligand-responsive pause release; also stabilizes Oct4.

    Evidence ChIP-seq, reader-domain characterization, Co-IP, CDK9-dependent pause-release assay; AP-MS/Co-IP and K133R mutagenesis showing KAP1 blocks Itch ubiquitination of Oct4

    PMID:32402252 PMID:32895487

    Open questions at the time
    • How the same protein switches between Pol II stabilization and release at a given gene not fully defined
  12. 2021 High

    Established TRIM28 as a master post-translational regulator of innate immunity and inflammasome stability, with antitumor-immunity consequences.

    Evidence Co-IP, SUMOylation/ubiquitination assays and conditional KO for NLRP3 stabilization; CRISPR screen and cGAS-STING readouts for SETDB1-TRIM28 immune suppression; PKR-S473-driven CTIF interaction for aggresome/viral control; mTORC1-driven mutant TERT activation

    PMID:33514850 PMID:33589597 PMID:33783327 PMID:34373456 PMID:34518220 PMID:34848497

    Open questions at the time
    • Direct vs indirect SUMO transfer to NLRP3 across cell types not fully resolved
    • How distinct phospho-sites partition immune versus chromatin functions unclear
  13. 2022 High

    Confirmed the KRAB-binding interface by crystallography and AlphaFold2, and extended SUMO-ligase control to cell-fate maintenance and X-inactivation choice.

    Evidence Crystal structure of TRIM/ZNF93-KRAB with mutagenesis and H3K9me3 ChIP-seq; AlphaFold2 Leu301 'pin' model; granulosa-cell conditional KO with SUMO profiling; allele-specific ChIP at Xist

    PMID:34786738 PMID:35906245 PMID:36173157 PMID:36341546

    Open questions at the time
    • AlphaFold2 interface lacks independent X-ray/cryo-EM confirmation
    • How SUMOylation enforces lineage-specific gene sets mechanistically incomplete
  14. 2023 High

    Mapped TRIM28's substrate-specific ubiquitin/SUMO ligase activities onto immune checkpoint, RLR signaling, ferroptosis, EMT, and reproductive programs, with RING residues C65/C68 as the catalytic determinant.

    Evidence CRISPR screens, Co-IP, ubiquitination and SUMOylation assays, RING mutagenesis, in vivo tumor and SCI models, RIME for ERalpha/PR; substrates PD-L1, RIPK1, MAVS, ACSL4, TFE3, SARS2-NP

    PMID:36935008 PMID:37119745 PMID:37357254 PMID:37528140 PMID:37748077 PMID:37865804 PMID:38172120 PMID:39875520

    Open questions at the time
    • Opposing ubiquitin- vs SUMO-promoting outcomes on shared substrates not unified into a single rule
    • How substrate selection is encoded in TRIM28 not defined
  15. 2024 Medium

    Extended the E3 ligase substrate repertoire (BRD7, TBK1) and clarified that TRIM28 can both activate and degrade innate signaling components depending on chain linkage.

    Evidence Co-IP/MS, K21 and chain-type-specific ubiquitination assays, CRISPR KO, xenograft and infection models

    PMID:38495890 PMID:39222175

    Open questions at the time
    • Reconciliation of TRIM28 promoting (K63-TBK1) versus degrading (K48-MAVS) innate signaling not mechanistically integrated
    • TBK1 result single-lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single scaffold partitions its silencing, Pol II-elongation, and dozens of distinct ubiquitin/SUMO substrate activities—and whether the phospho-SUMO switch alone encodes this selectivity—remains unresolved.
  • No unified model linking specific phospho-states to specific substrate or chromatin outputs
  • Determinants of ubiquitin-chain-linkage choice (K48 vs K63) versus SUMO modification on substrates undefined
  • Stoichiometry/competition among the many named partners in cells not measured

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 8 GO:0016874 ligase activity 6 GO:0140110 transcription regulator activity 4 GO:0060090 molecular adaptor activity 3 GO:0003677 DNA binding 2 GO:0042393 histone binding 2
Localization
GO:0000228 nuclear chromosome 4 GO:0005634 nucleus 4 GO:0005739 mitochondrion 1
Pathway
R-HSA-168256 Immune System 6 R-HSA-392499 Metabolism of proteins 6 R-HSA-4839726 Chromatin organization 5 R-HSA-1640170 Cell Cycle 3 R-HSA-73894 DNA Repair 3 R-HSA-74160 Gene expression (Transcription) 3
Partners
CDK9EZH2HP1MDM2OCT4SETDB1SMAD2TRIM24
Complex memberships
KAP1-SETDB1 heterochromatin complexTRIM28-EZH2-SWI/SNF complexURI-KAP1-PP2A complex

Evidence

Reading pass · 44 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 MDM2 interacts with KAP1/TRIM28 via the N-terminal coiled-coil domain of KAP1 and the central acidic domain of MDM2; this interaction stimulates formation of a p53-HDAC1 complex, inhibits p53 acetylation, and promotes p53 ubiquitination and degradation. ARF competes with KAP1 for MDM2 binding, reducing KAP1-MDM2 interaction. Co-immunoprecipitation, RNAi knockdown, ubiquitination assay, competition binding assay The EMBO journal High 16107876
2007 ATM-dependent phosphorylation of KAP1 at Ser-824 in response to genotoxic stress reduces KAP1 sumoylation, leading to de-repression of p21WAF1/CIP1 and Gadd45alpha. Conversely, a phospho-mimetic S824D mutation decreases sumoylation and stimulates p21 transcription, while S824A increases sumoylation and maintains repression. SENP1 deSUMOylase is involved in regulating basal KAP1 Ser-824 phosphorylation. Site-directed mutagenesis (S824A, S824D), ATM kinase assay, sumoylation assay, reporter gene assay, ChIP The Journal of biological chemistry High 17942393
2008 The tandem PHD finger-bromodomain of KAP1 forms a unified structural scaffold in which the PHD finger and bromodomain cooperate as an intramolecular SUMO E3 ligase, facilitating lysine SUMOylation that is required for KAP1 co-repressor activity in gene silencing. Structure-function mutagenesis correlating UBC9 binding, SUMOylation, and transcriptional repression confirmed this. NMR solution structure determination, mutation-based structure-function analysis, SUMOylation assay, transcriptional repression assay, UBC9 binding assay Nature structural & molecular biology High 18488044
2008 Phosphorylation of TIF1beta/KAP1 at Ser473 by PKCdelta disrupts its interaction with HP1beta (at the PXVXL HP1-box), reducing co-repressor function and permitting expression of cell cycle genes (cyclin A2, Cdc2, Cdc25A). Unphosphorylated KAP1 allows HP1beta co-occupancy at target promoters and transcriptional repression; Ser473 phosphorylation coincides with S-phase. Site-directed mutagenesis (S473A, S473E), ChIP, co-immunoprecipitation, reporter assays, PKCdelta inhibitor treatment BMC molecular biology High 18590578
2011 KAP1 genomic recruitment requires its RBCC domain for binding to 3' coding exons of zinc finger genes (via KRAB-ZNF interaction), but RBCC deletion does not abolish KAP1 binding to promoter regions, indicating a second, KRAB-ZNF-independent recruitment mechanism for promoter-bound KAP1. ChIP-seq, stable cell lines expressing tagged wild-type and RBCC-deletion mutant KAP1, KAP1 knockdown Molecular and cellular biology High 21343339
2013 De novo DNA methylation of endogenous retroviruses (ERVs) in embryonic stem cells requires a KRAB-ZFP that recognizes the specific ERV sequence, plus both KAP1 and ESET (SETDB1). KAP1 knockout in early embryos reduces methylation of ERVs. KAP1 thus acts downstream of KRAB-ZFPs and upstream of ESET to install stable DNA methylation marks at ERV loci. Genetic knockout (KAP1 KO in early embryos), reporter assay with introduced ERV sequences, bisulfite sequencing, ES cell differentiation model Development (Cambridge, England) High 23293284
2014 TRIM28 stabilizes paused RNA Pol II at promoter-proximal regions of many genes and regulates Pol II pause release in a transcription-coupled phosphorylation-dependent manner. TRIM28 depletion triggers de novo expression of genes regulated by paused Pol II genome-wide. In vitro Pol II pausing assay, RNAi knockdown, genome-wide ChIP-seq of Pol II occupancy, gene expression analysis Nature structural & molecular biology High 25173174
2015 The nuclear oncogene SET interacts with KAP1 and its overexpression causes sustained retention of KAP1 and HP1 on chromatin at double-strand breaks, leading to inhibition of DNA end resection and homologous recombination-mediated DNA repair. Co-immunoprecipitation, overexpression and depletion studies, chromatin fractionation, HR repair assay (I-SceI system) Cell reports Medium 25818296
2016 URI (unconventional prefoldin RPB5 interactor) forms a nuclear complex with KAP1 and PP2A phosphatase; PP2A recruited by URI decreases KAP1 phosphorylation. This URI-KAP1-PP2A complex mediates retrotransposon (LINE-1, L1PA2) repression, functionally overlapping with the KAP1-SETDB1 silencing complex. Co-immunoprecipitation, mass spectrometry, URI knockdown, microarray of transposon expression, phosphorylation assay The Journal of biological chemistry Medium 27780869
2017 TRIM28 forms a complex with EZH2 and SWI/SNF (distinct from PRC2) to activate, rather than repress, a set of stem cell maintenance genes in breast cancer cells. TRIM28 depletion represses EZH2 recruitment to chromatin and reduces mammosphere formation; rescue by EZH2 requires intact TRIM28 interaction (pre-SET domain). Co-immunoprecipitation, mass spectrometry, ChIP, siRNA knockdown, mammosphere formation assay, EZH2 mutant rescue experiment Oncogene High 28068325
2018 TRIM28 acts as an E3 ubiquitin ligase for BCL2A1 at the mitochondria; endogenous TRIM28 and BCL2A1 physically interact and TRIM28 knockdown decreases BCL2A1 ubiquitination. TRIM17 antagonizes TRIM28 by blocking its binding to BCL2A1, stabilizing BCL2A1 and promoting chemoresistance. Co-immunoprecipitation, ubiquitination assay, TRIM28 knockdown, TRIM17 overexpression and knockout Cell death and differentiation High 30042493
2018 TRIM28 physically interacts with TRIM24 and prevents TRIM24 ubiquitination and SPOP-mediated degradation; TRIM28 also facilitates TRIM24 chromatin occupancy and augments AR signaling in prostate cancer. Co-immunoprecipitation, ubiquitination assay, ChIP, knockdown and overexpression in cell lines and xenograft models Nature communications High 30479348
2018 KAP1 associates with DNA replication factors PCNA, MCM3, and MCM6; these interactions are promoted by KAP1 phosphorylation at serine 473 during S phase. KAP1 forms a complex with PCNA and Suv39h1 histone methyltransferase to reinstate H3K9 methylation-dependent heterochromatin after DNA replication. Co-immunoprecipitation, phosphorylation-specific analysis (S473), ChIP, cell fractionation during S phase Nucleic acids research High 29955894
2019 TRIM28 promotes HIV-1 latency by SUMOylating CDK9 (catalytic subunit of P-TEFb) at lysines K44, K56, and K68 with SUMO4. This SUMOylation inhibits CDK9 kinase activity and/or prevents P-TEFb assembly by blocking CDK9-Cyclin T1 interaction, thereby suppressing HIV-1 transcriptional elongation. Global site-specific SUMO-MS, serial SUMOylation assays, site-directed mutagenesis of CDK9 residues, Co-immunoprecipitation, kinase activity assay eLife High 30652970
2019 The KAP1 TRIM domain forms antiparallel dimers that further assemble into tetramers and higher-order oligomers. Crystal structure identifies the KRAB domain binding site in the coiled-coil domain near the dimer dyad; mutations at this site abolish KRAB binding and retrotransposon silencing activity. B-box 1 mutations that prevent higher-order oligomerization do not significantly impair silencing. Crystal structure determination, biophysical analysis (SAXS, SEC-MALS), site-directed mutagenesis, retrotransposon silencing assay Proceedings of the National Academy of Sciences of the United States of America High 31289231
2019 KAP1 is an elongated antiparallel dimer with functional asymmetry at the C-terminal domains. The RING domain contributes to KAP1 auto-SUMOylation. HP1 occupies only one of the two putative HP1 binding sites on the KAP1 dimer, resulting in an unexpected stoichiometry. Solution scattering (SAXS), integrative modeling, single-molecule experiments, biochemical assays Life science alliance High 31427381
2020 KAP1/TRIM28 uses a chromatin reader cassette to bind hypo-acetylated histone H4 tails at promoters, then associates with RNA Pol II and recruits SMAD2 upon TGF-beta signaling to enable CDK9-dependent Pol II pause release. This couples chromatin reading to both Pol II pausing and pause release for transcriptional elongation. ChIP-seq, chromatin reader domain characterization, Co-immunoprecipitation, CDK9-dependent pause release assay, SMAD2 recruitment assay Molecular cell High 32402252
2021 TRIM28 acts as an E3 SUMO ligase that binds NLRP3, promotes SUMO1/2/3 modification of NLRP3, and thereby inhibits NLRP3 ubiquitination and proteasomal degradation, stabilizing NLRP3 protein levels to facilitate inflammasome assembly and activation. Trim28 deficiency attenuates NLRP3 inflammasome activation in vitro and in vivo. Co-immunoprecipitation, SUMOylation assay, ubiquitination assay, Trim28 conditional knockout, NLRP3 inflammasome activation assays (IL-1β secretion, caspase-1 cleavage) Nature communications High 34373456
2021 KAP1/TRIM28 represses HIV-1 expression in myeloid cells by interacting with and colocalizing with the viral transactivator Tat, promoting Tat's degradation via the proteasome. KAP1 is also bound to the latent HIV-1 promoter and cooperates with CTIP2, an epigenetic silencer; Tat and CTIP2 compete for KAP1 binding. Co-immunoprecipitation, colocalization (confocal microscopy), proteasome inhibitor treatment, KAP1 depletion, ChIP, myeloid HIV-1 latency model reactivation Scientific reports Medium 33514850
2021 UBE2S interacts with TRIM28 in the nucleus; together they enhance ubiquitination of p27 to facilitate its proteasomal degradation and promote G1/S cell cycle progression in hepatocellular carcinoma cells. Co-immunoprecipitation, ubiquitination assay, cell cycle analysis, siRNA knockdown Signal transduction and targeted therapy Medium 33589597
2021 The SETDB1-TRIM28 complex suppresses antitumor immunity; inhibition of this complex upregulates PD-L1 and activates the cGAS-STING innate immune pathway by promoting micronuclei formation in the cytoplasm, increasing CD8+ T cell infiltration. CRISPR-Cas9 epigenetic screen, flow cytometry, cGAS-STING pathway activation assay, syngeneic mouse tumor model, SETDB1 KO Cancer immunology research Medium 34848497
2021 TRIM28 acts as a negative regulator of aggresome formation through direct interaction with CTIF; this interaction leads to inefficient aggresomal targeting of misfolded polypeptides. TRIM28 phosphorylation at S473 by double-stranded RNA-activated protein kinase (PKR) promotes TRIM28-CTIF association, inhibits aggresome formation, and suppresses viral proliferation. Co-immunoprecipitation, proximity ligation assay, phosphorylation analysis (S473), aggresome formation assay, influenza A virus infection model Autophagy High 33783327
2021 TRIM28 is a transcriptional activator of the mutant TERT promoter. TRIM28 is recruited to the mutant hTERT promoter and interacts with TRIM24, which inhibits TRIM28 activity. Phosphorylation of TRIM28 via mTORC1 releases it from TRIM24 and induces hTERT transcription; mTORC1 inhibition suppresses TRIM28 phosphorylation and hTERT expression. CRISPR-Cas9 kinome knockout screen (FACS-based), ChIP, Co-immunoprecipitation, mTORC1 inhibition (rapamycin analog), phosphorylation assays Proceedings of the National Academy of Sciences of the United States of America High 34518220
2022 Crystal structure of the KAP1 TRIM in complex with the KRAB domain of ZNF93 identifies the KAP1-KRAB binding interface. Structure-guided mutations in this interface abolish repressive activity in a transcriptional silencing assay and eliminate genome-wide H3K9me3 deposition at thousands of KAP1/KRAB-ZFP target loci. Crystal structure determination, site-directed mutagenesis, epigenetic transcriptional silencing assay, ChIP-seq (H3K9me3 genome-wide) The EMBO journal High 36341546
2022 TRIM28-dependent SUMOylation is required to maintain the adult ovarian cell fate by repressing testicular-specific genes. TRIM28 is recruited to chromatin near FOXL2 binding sites, and its E3-SUMO ligase activity regulates the sex-specific SUMOylation profile of ovarian-specific genes. Loss of Trim28 in granulosa cells leads to their transdifferentiation into Sertoli cells. Conditional knockout (Trim28 deletion in granulosa cells), ChIP, SUMOylation profiling, histology/lineage tracing Nature communications High 35906245
2022 KAP1 and the KRAB domain residues forming the molecular interface were structurally mapped using AlphaFold2; leucine 301 on each chain of the TRIM28 coiled-coil acts as a 'pin' inserting into a hydrophobic pocket on the KRAB domain. Site-directed mutations at this interface abolish KRAB domain binding. AlphaFold2 modeling, site-directed mutagenesis, binding assays Protein science Medium 36173157
2023 TRIM28 directly binds and stabilizes PD-L1 by inhibiting PD-L1 ubiquitination and promoting PD-L1 SUMOylation. Additionally, TRIM28 facilitates K63 polyubiquitination of TBK1, activating TBK1-IRF1 and TBK1-mTOR pathways to enhance PD-L1 transcription. CRISPR-Cas9 genome-wide screen, Co-immunoprecipitation, ubiquitination assay, SUMOylation assay, in vivo mouse tumor model, TBK1 pathway inhibitor studies Signal transduction and targeted therapy High 37357254
2023 TRIM28 promotes ubiquitination and proteasome-mediated degradation of TFE3 transcription factor in renal cancer cells, thereby suppressing TFE3-driven autophagic gene expression and cell proliferation. This defines a TRIM28-TFE3-KDM6A signaling axis in kidney cancer. Co-immunoprecipitation, ubiquitination assay, TRIM28 knockdown, ChIP, autophagy assays, cell proliferation assays The Journal of biological chemistry Medium 36935008
2023 TRIM28 physically interacts with RIPK1 and promotes K63-linked ubiquitination of RIPK1, sustaining NF-κB pathway activation and upregulation of CXCL1, which recruits MDSCs. Mutagenesis of the TRIM28 RING/E3 ligase domain (C65, C68) abrogates NF-κB activation. Co-immunoprecipitation, K63-ubiquitination assay, RING domain mutagenesis, NF-κB reporter, CXCL1 ELISA, syngeneic mouse tumor models Journal of experimental & clinical cancer research High 37865804
2023 TRIM28 acts as the E3 SUMO ligase responsible for SUMOylation of the SARS-CoV-2 nucleocapsid protein (SARS2-NP) at lysine K65, which mediates NP homo-oligomerization, RNA association, liquid-liquid phase separation, and suppression of innate antiviral immunity. An interfering peptide targeting the TRIM28-SARS2-NP interaction blocks NP SUMOylation and LLPS. SUMOylation assay, site-directed mutagenesis (K65), LLPS assay, Co-immunoprecipitation, antiviral immune assay, interfering peptide screen Nature communications High 38172120
2023 TRIM28 negatively regulates the RLR signaling pathway by targeting MAVS for K48-linked polyubiquitination and proteasome-mediated degradation. The RING domain of TRIM28 (specifically C65 and C68 residues) is critical for this activity; ubiquitin chains are transferred to K7, K10, K371, K420, and K500 of MAVS. Ubiquitination assay, proteasome inhibitor treatment, RING domain mutagenesis, Co-immunoprecipitation, type I interferon production assay The Journal of biological chemistry High 37119745
2023 TIAM1 interacts with TRIM28 in the nucleus of NSCLC cells and the TIAM1-TRIM28 complex promotes H3K9me3-induced silencing of protocadherins and decreases E-cadherin expression, driving epithelial-to-mesenchymal transition and cell migration. Co-immunoprecipitation, ChIP (H3K9me3), siRNA knockdown, migration/invasion assay, rescue by protocadherin depletion Proceedings of the National Academy of Sciences of the United States of America Medium 37748077
2023 TRIM28 binds ACSL4 and promotes SUMO3 modification at ACSL4 lysine K532, inhibiting K63-linked ACSL4 ubiquitination and thereby suppressing OPTN-dependent autophagic degradation of ACSL4, promoting neuronal ferroptosis. SENP3 acts as the opposing deSUMOylation enzyme. Co-immunoprecipitation, SUMOylation assay, ubiquitination assay, mutagenesis (K532), autophagic degradation assay, Trim28 genetic deletion, in vivo SCI mouse model Cell death and differentiation High 39875520
2024 TRIM28 facilitates type I interferon activation by interacting with TBK1 and mediating K63-linked ubiquitination of TBK1, augmenting TBK1 signal transmission; TRIM28 KO cells display defective TBK1 phosphorylation and impaired complex assembly with IRF3. CRISPR-Cas9 TRIM28 knockout, Co-immunoprecipitation, K63-ubiquitination assay, TBK1 phosphorylation assay, virus infection susceptibility assay Frontiers in immunology Medium 38495890
2024 TRIM28 acts as an E3 ubiquitin ligase for BRD7; the coiled-coil region of TRIM28 binds the N-terminal domain of BRD7 and mediates BRD7 ubiquitination at K21, promoting its proteasomal degradation. This promotes breast cancer malignant progression. Co-immunoprecipitation with mass spectrometry, ubiquitination assay, domain deletion/mutagenesis (K21), xenograft mouse model Cellular oncology (Dordrecht, Netherlands) High 39222175
2012 KAP1 directly interacts with IRF5 via IRF5's N-terminus (DNA-binding domain and disordered region); KAP1 knockdown potentiates IRF5-mediated TNF and M1 macrophage marker expression. This inhibitory effect is linked to SETDB1 methyltransferase activity (H3K9me3 deposition) at the TNF locus. Affinity purification with mass spectrometry (IRF5 interactome), Co-immunoprecipitation, domain mapping, KAP1 siRNA knockdown, ChIP (H3K9me3) Immunobiology Medium 22995936
2007 KAP1 physically associates with endogenous STAT3 in cells; KAP1 knockdown enhances IL-6-induced STAT3-dependent transcription and causes marked accumulation of STAT3 phosphorylated on Ser727 in the nucleus, indicating KAP1 acts as a transcriptional repressor of the IL-6/STAT3 signaling pathway. Yeast two-hybrid screen, endogenous Co-immunoprecipitation, siRNA knockdown, reporter gene assay, phospho-STAT3 analysis Oncogene Medium 18037959
2020 Kap1 interacts with Oct4 and inhibits Itch-mediated ubiquitination of Oct4 at lysine K133, thereby stabilizing Oct4 protein in embryonic stem cells and promoting self-renewal and cellular reprogramming. Affinity purification with mass spectrometry, Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (K133R), Kap1 knockdown and overexpression, reprogramming assay Cell death and differentiation High 32895487
2012 KAP1-dependent H3K9me3 repressive chromatin is established at T-cell-specific cis-regulatory elements enriched in Ikaros/NuRD complexes; KAP1 directly controls FoxO1 expression and TCR/cytokine signaling genes. T-cell-specific Kap1 deletion causes expansion of immature thymocytes and altered CD4+/CD8+ ratios. T-cell-specific conditional Kap1 KO (Cre-lox), ChIP/ChIP-seq, transcriptome analysis FASEB journal Medium 22872677
2023 TRIM28 modulates uterine function by complexing with estrogen receptor α (ERα) and progesterone receptor (PR); TRIM28 ablation suppresses PR and ERα chromatin binding in uterine epithelium and stroma, impairing implantation and early pregnancy. RIME (rapid immunoprecipitation mass spectrometry), Co-immunoprecipitation, conditional knockout, ChIP Nature communications High 37528140
2012 MAGE-C2 binds KAP1 and increases co-precipitation of KAP1 with ATM kinase; MAGE-C2 binding to KAP1 is required for enhanced ATM-dependent phosphorylation of KAP1-Ser824, which facilitates heterochromatin relaxation and DNA double-strand break repair. Co-immunoprecipitation, KAP1 S824 phosphorylation assay, I-SceI endonuclease DSB repair assay, MAGE-C2 knockdown/overexpression The Journal of investigative dermatology Medium 23096706
2015 CCAR2/DBC1 is required for Chk2-dependent KAP1 phosphorylation at Ser824; loss of CCAR2 impairs Chk2 activation and reduces KAP1 S824 phosphorylation, leading to defective heterochromatin relaxation and impaired repair of heterochromatic DSBs. CCAR2 knockout, Chk2 activation assay, KAP1 S824 phosphorylation assay, DNA damage foci resolution (late time-point), HP1β depletion rescue Oncotarget Medium 26158765
2022 At the onset of X chromosome inactivation, KAP1 is recruited to the Xist promoter allele that will upregulate Xist and is required for the increase in Tsix levels preceding cell fate choice. RIF1 and KAP1 show mutual exclusion at the Xist promoters, establishing an asymmetric self-sustaining loop for X chromosome choice. mESC differentiation, allele-specific ChIP, KAP1 and RIF1 depletion, Tsix/Xist RNA FISH The EMBO journal Medium 34786738
2018 KAP1 interacts with KAP1 regulates ERV (including HERV-T, HERV-S) and ZNF gene expression in adult differentiated human cells including peripheral blood mononuclear cells, requiring H3K9me3. KAP1 depletion leads to decreased H3K9me3 at ERVs and ZNF loci and activates an RNA-sensing response mediated through MAVS signaling. KAP1 knockout, RNA-seq, ChIP-seq (H3K9me3, KAP1), MAVS signaling assay, interferon response measurement EMBO reports Medium 30061100

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 KAP1 protein: an enigmatic master regulator of the genome. The Journal of biological chemistry 298 21652716
2005 MDM2 interaction with nuclear corepressor KAP1 contributes to p53 inactivation. The EMBO journal 211 16107876
2017 The complexity of TRIM28 contribution to cancer. Journal of biomedical science 193 28851455
2016 Trim28 Haploinsufficiency Triggers Bi-stable Epigenetic Obesity. Cell 154 26824653
2007 Role for KAP1 serine 824 phosphorylation and sumoylation/desumoylation switch in regulating KAP1-mediated transcriptional repression. The Journal of biological chemistry 148 17942393
2013 De novo DNA methylation of endogenous retroviruses is shaped by KRAB-ZFPs/KAP1 and ESET. Development (Cambridge, England) 146 23293284
2021 TRIM28 SUMOylates and stabilizes NLRP3 to facilitate inflammasome activation. Nature communications 135 34373456
2014 TRIM28 regulates RNA polymerase II promoter-proximal pausing and pause release. Nature structural & molecular biology 123 25173174
2008 Structural insights into human KAP1 PHD finger-bromodomain and its role in gene silencing. Nature structural & molecular biology 111 18488044
2009 KAP1 is associated with peritoneal carcinomatosis in gastric cancer. Annals of surgical oncology 103 19898899
2018 TRIM28 protects TRIM24 from SPOP-mediated degradation and promotes prostate cancer progression. Nature communications 100 30479348
2016 TRIM28 regulates the nuclear accumulation and toxicity of both alpha-synuclein and tau. eLife 99 27779468
2019 TRIM28 promotes HIV-1 latency by SUMOylating CDK9 and inhibiting P-TEFb. eLife 95 30652970
2011 Functional analysis of KAP1 genomic recruitment. Molecular and cellular biology 94 21343339
2014 KAP1 promotes proliferation and metastatic progression of breast cancer cells. Cancer research 93 25421577
2018 KAP1 regulates endogenous retroviruses in adult human cells and contributes to innate immune control. EMBO reports 88 30061100
2014 KAPtain in charge of multiple missions: Emerging roles of KAP1. World journal of biological chemistry 85 25225599
2015 The nuclear oncogene SET controls DNA repair by KAP1 and HP1 retention to chromatin. Cell reports 79 25818296
2023 TRIM28 promotes the escape of gastric cancer cells from immune surveillance by increasing PD-L1 abundance. Signal transduction and targeted therapy 77 37357254
2021 UBE2S interacting with TRIM28 in the nucleus accelerates cell cycle by ubiquitination of p27 to promote hepatocellular carcinoma development. Signal transduction and targeted therapy 77 33589597
2006 KAP1 dictates p53 response induced by chemotherapeutic agents via Mdm2 interaction. Biochemical and biophysical research communications 70 17056014
2017 TRIM28 interacts with EZH2 and SWI/SNF to activate genes that promote mammosphere formation. Oncogene 67 28068325
2019 Structure of KAP1 tripartite motif identifies molecular interfaces required for retroelement silencing. Proceedings of the National Academy of Sciences of the United States of America 65 31289231
2007 Physical and functional interactions between STAT3 and KAP1. Oncogene 65 18037959
2021 The SETDB1-TRIM28 Complex Suppresses Antitumor Immunity. Cancer immunology research 64 34848497
2012 KAP1/TRIM28: an inhibitor of IRF5 function in inflammatory macrophages. Immunobiology 62 22995936
2022 KAP1/TRIM28: Transcriptional Activator and/or Repressor of Viral and Cellular Programs? Frontiers in cellular and infection microbiology 57 35281453
2012 MAGE-C2 promotes growth and tumorigenicity of melanoma cells, phosphorylation of KAP1, and DNA damage repair. The Journal of investigative dermatology 54 23096706
2008 Phosphorylation at Ser473 regulates heterochromatin protein 1 binding and corepressor function of TIF1beta/KAP1. BMC molecular biology 54 18590578
2023 N6-methyladenosine hypomethylation of circGPATCH2L regulates DNA damage and apoptosis through TRIM28 in intervertebral disc degeneration. Cell death and differentiation 53 37438603
2017 TRIM28 multi-domain protein regulates cancer stem cell population in breast tumor development. Oncotarget 53 27845900
2015 TRIM28 as a novel transcriptional elongation factor. BMC molecular biology 51 26293668
2014 Inhibition of KAP1 enhances hypoxia-induced Kaposi's sarcoma-associated herpesvirus reactivation through RBP-Jκ. Journal of virology 51 24696491
2021 TRIM28 is a transcriptional activator of the mutant TERT promoter in human bladder cancer. Proceedings of the National Academy of Sciences of the United States of America 50 34518220
2018 TRIM17 and TRIM28 antagonistically regulate the ubiquitination and anti-apoptotic activity of BCL2A1. Cell death and differentiation 50 30042493
2018 The long non-coding RNA Paupar promotes KAP1-dependent chromatin changes and regulates olfactory bulb neurogenesis. The EMBO journal 48 29661885
2014 High levels of KAP1 expression are associated with aggressive clinical features in ovarian cancer. International journal of molecular sciences 48 25548895
2019 TRIM28 haploinsufficiency predisposes to Wilms tumor. International journal of cancer 45 30694527
2020 KAP1 Is a Chromatin Reader that Couples Steps of RNA Polymerase II Transcription to Sustain Oncogenic Programs. Molecular cell 44 32402252
2012 KAP1 regulates gene networks controlling T-cell development and responsiveness. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 44 22872677
2019 Hdac3, Setdb1, and Kap1 mark H3K9me3/H3K14ac bivalent regions in young and aged liver. Aging cell 43 31858687
2016 KAP1 is overexpressed in hepatocellular carcinoma and its clinical significance. International journal of clinical oncology 43 27095111
2024 TRIM28-mediated nucleocapsid protein SUMOylation enhances SARS-CoV-2 virulence. Nature communications 42 38172120
2018 Germline mutations and somatic inactivation of TRIM28 in Wilms tumour. PLoS genetics 41 29912901
2023 E3 ligase TRIM28 promotes anti-PD-1 resistance in non-small cell lung cancer by enhancing the recruitment of myeloid-derived suppressor cells. Journal of experimental & clinical cancer research : CR 39 37865804
2012 KAP1 regulates gene networks controlling mouse B-lymphoid cell differentiation and function. Blood 38 22452978
2022 Structure and functional mapping of the KRAB-KAP1 repressor complex. The EMBO journal 37 36341546
2019 TRIM28 activates autophagy and promotes cell proliferation in glioblastoma. OncoTargets and therapy 37 30655676
2018 KAP1 facilitates reinstatement of heterochromatin after DNA replication. Nucleic acids research 37 29955894
2018 TRIM28 and the control of transposable elements in the brain. Brain research 35 29522722
2022 TRIM28-dependent SUMOylation protects the adult ovary from activation of the testicular pathway. Nature communications 34 35906245
2021 Inhibition of HIV-1 gene transcription by KAP1 in myeloid lineage. Scientific reports 31 33514850
2025 Redox regulation of TRIM28 facilitates neuronal ferroptosis by promoting SUMOylation and inhibiting OPTN-selective autophagic degradation of ACSL4. Cell death and differentiation 30 39875520
2018 KAP1 Regulates Regulatory T Cell Function and Proliferation in Both Foxp3-Dependent and -Independent Manners. Cell reports 30 29669285
1998 The Crithidia fasciculata KAP1 gene encodes a highly basic protein associated with kinetoplast DNA. Molecular and biochemical parasitology 27 9719509
2022 IFI16 Partners with KAP1 to Maintain Epstein-Barr Virus Latency. Journal of virology 26 35969079
2021 TRIM28 Selective Nanobody Reduces Glioblastoma Stem Cell Invasion. Molecules (Basel, Switzerland) 26 34500575
2016 URI Regulates KAP1 Phosphorylation and Transcriptional Repression via PP2A Phosphatase in Prostate Cancer Cells. The Journal of biological chemistry 26 27780869
2023 TRIM28 represses renal cell carcinoma cell proliferation by inhibiting TFE3/KDM6A-regulated autophagy. The Journal of biological chemistry 24 36935008
2021 TRIM28 Expression on Dendritic Cells Prevents Excessive T Cell Priming by Silencing Endogenous Retrovirus. Journal of immunology (Baltimore, Md. : 1950) 24 33619215
2018 TRIM28 promotes cervical cancer growth through the mTOR signaling pathway. Oncology reports 24 29393469
2010 Interactions of ErbB4 and Kap1 connect the growth factor and DNA damage response pathways. Molecular cancer research : MCR 24 20858735
2024 TRIM28 in cancer and cancer therapy. Frontiers in genetics 23 39100077
2015 CCAR2/DBC1 is required for Chk2-dependent KAP1 phosphorylation and repair of DNA damage. Oncotarget 23 26158765
2007 Polymorphism of the KAP1.1, KAP1.3 and K33 genes in Merino sheep. Molecular and cellular probes 23 17532184
2021 TRIM28 variants and Wilms' tumour predisposition. The Journal of pathology 22 33565090
2019 KAP1 is an antiparallel dimer with a functional asymmetry. Life science alliance 22 31427381
2021 TRIM28 regulates SARS-CoV-2 cell entry by targeting ACE2. Cellular signalling 21 34146659
2020 Merkel Cell Polyomavirus DNA Replication Induces Senescence in Human Dermal Fibroblasts in a Kap1/Trim28-Dependent Manner. mBio 21 32156811
2020 TRIM28 regulates sprouting angiogenesis through VEGFR-DLL4-Notch signaling circuit. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 21 32918765
2011 Identification of the ovine keratin-associated protein KAP1-2 gene (KRTAP1-2). Experimental dermatology 20 21771088
2023 TRIM28 negatively regulates the RLR signaling pathway by targeting MAVS for degradation via K48-linked polyubiquitination. The Journal of biological chemistry 19 37119745
2023 TRIM28 modulates nuclear receptor signaling to regulate uterine function. Nature communications 19 37528140
2015 Expression of KAP1 in epithelial ovarian cancer and its correlation with drug-resistance. International journal of clinical and experimental medicine 19 26770323
2023 A TIAM1-TRIM28 complex mediates epigenetic silencing of protocadherins to promote migration of lung cancer cells. Proceedings of the National Academy of Sciences of the United States of America 18 37748077
2024 TRIM28 Fosters Microglia Ferroptosis via Autophagy Modulation to Enhance Neuropathic Pain and Neuroinflammation. Molecular neurobiology 17 38647647
2023 The Host E3-Ubiquitin Ligase TRIM28 Impedes Viral Protein GP4 Ubiquitination and Promotes PRRSV Replication. International journal of molecular sciences 17 37446143
2020 Infertility-Causing Haploinsufficiency Reveals TRIM28/KAP1 Requirement in Spermatogonia. Stem cell reports 17 32302554
2014 TRIM28/KAP1 regulates senescence. Immunology letters 17 25160591
2021 TRIM28 functions as a negative regulator of aggresome formation. Autophagy 16 33783327
2020 TRIM28 Regulates Dlk1 Expression in Adipogenesis. International journal of molecular sciences 16 33008113
2024 Multifaceted role of TRIM28 in health and disease. MedComm 15 39534556
2022 Mapping the interaction between Trim28 and the KRAB domain at the center of Trim28 silencing of endogenous retroviruses. Protein science : a publication of the Protein Society 15 36173157
2021 Acute myeloid leukemia cell-derived extracellular vesicles carrying microRNA-548ac regulate hematopoietic function via the TRIM28/STAT3 pathway. Cancer gene therapy 15 34453123
2018 KAP1 inhibits the Raf-MEK-ERK pathway to promote tumorigenesis in A549 lung cancer cells. Molecular carcinogenesis 15 29917268
2024 TRIM28 promotes tumor growth and metastasis in breast cancer by targeting the BRD7 protein for ubiquitination and degradation. Cellular oncology (Dordrecht, Netherlands) 14 39222175
2023 Co-option of endogenous retroviruses through genetic escape from TRIM28 repression. Cell reports 14 37294634
2022 Enhanced Expression of Human Endogenous Retroviruses, TRIM28 and SETDB1 in Autism Spectrum Disorder. International journal of molecular sciences 14 35682642
2020 KAP1-associated transcriptional inhibitory complex regulates C2C12 myoblasts differentiation and mitochondrial biogenesis via miR-133a repression. Cell death & disease 14 32908124
2018 TRIM28 is overexpressed in glioma and associated with tumor progression. OncoTargets and therapy 14 30349292
2020 Kap1 regulates the self-renewal of embryonic stem cells and cellular reprogramming by modulating Oct4 protein stability. Cell death and differentiation 13 32895487
2018 Expression of TRIM28 correlates with proliferation and Bortezomib-induced apoptosis in B-cell non-Hodgkin lymphoma. Leukemia & lymphoma 13 29569972
2024 TRIM28 facilitates type I interferon activation by targeting TBK1. Frontiers in immunology 12 38495890
2023 TRIM28 promotes luminal cell plasticity in a mouse model of prostate cancer. Oncogene 11 36882525
2023 ATM, KAP1 and the Epstein-Barr virus polymerase processivity factor direct traffic at the intersection of transcription and replication. Nucleic acids research 11 37852757
2022 KAP1 phosphorylation promotes the survival of neural stem cells after ischemia/reperfusion by maintaining the stability of PCNA. Stem cell research & therapy 11 35799276
2021 KAP1-Mediated Epigenetic Suppression in Anti-RNA Viral Responses by Direct Targeting RIG-I and MDA5. Journal of immunology (Baltimore, Md. : 1950) 11 34497149
2021 RIF1 and KAP1 differentially regulate the choice of inactive versus active X chromosomes. The EMBO journal 11 34786738
2016 Genome-wide analysis of KAP1, the 7SK snRNP complex, and RNA polymerase II. Genomics data 11 26981421
2023 TRIM28 inactivation in epithelial nephroblastoma is frequent and often associated with predisposing TRIM28 germline variants. The Journal of pathology 10 37792584

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