Affinage · Toxoplasma gondii

TEEGR

E2F4-associated EZH2-inducing gene regulator TEEGR · UniProt S8F4W1

Annotated
2026-09-11
10 papers in source corpus 7 papers cited in narrative 7 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TEEGR (also called HCE1) is a Toxoplasma gondii dense granule effector that manipulates host cell transcription and immune signalling to promote parasite persistence (PMID:31036909). After secretion, it is exported from the parasitophorous vacuole into the host nucleus in a MYR1-dependent manner, where it binds the host cyclin E regulatory complex components E2F3, E2F4, and DP1 and is both necessary and sufficient to upregulate cyclin E and E2F target genes, driving the host G1-to-S cell cycle transition; parasites lacking TEEGR show a substantial growth defect (PMID:31036909, PMID:31040242, PMID:35587658). In parallel, TEEGR promotes EZH2 upregulation to epigenetically silence a subset of NF-κB-regulated cytokines, and it counter-regulates GRA15-driven NF-κB responses — suppressing CCR7-mediated macrophage hypermigration and the CCL5/CCR5 axis used for CNS dissemination in an MYR-translocon-dependent manner (PMID:31036909, PMID:39207098, PMID:41528135). TEEGR also contributes, additively with seven other MYR1-dependent effectors, to activation of the non-canonical NF-κB (RelB/p52) pathway, though no single effector accounts for this phenotype (PMID:42663465).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2019 High

    Established that TEEGR/HCE1 is a nuclear-targeted dense granule effector that rewires host transcription and dampens NF-κB immunity, defining it as a parasite persistence factor.

    Evidence Dense granule localization, host nuclear export, reciprocal Co-IP with E2F3/E2F4, EZH2 pathway assays, and in vivo mouse persistence model

    PMID:31036909

    Open questions at the time
    • Direct binding site of TEEGR on E2F factors not mapped
    • Mechanism by which TEEGR drives EZH2 upregulation not resolved
  2. 2022 Medium

    Resolved which host cell cycle events depend on TEEGR versus host context, attributing the G1-to-S transition to TEEGR but the subsequent S-phase block to host cell type and contact inhibition.

    Evidence FUCCI live-cell cell cycle reporter with TEEGR knockout parasites across multiple host cell lines

    PMID:35587658

    Open questions at the time
    • Molecular basis of the host-context-dependent S-phase block unidentified
    • Single lab
  3. 2024 Medium

    Positioned TEEGR as a counter-regulator of GRA15/GRA24-driven macrophage chemotaxis, showing it opposes NF-κB-induced CCR7-mediated hypermigration.

    Evidence Individual effector knockouts, macrophage chemotaxis/migration assays, and NF-κB readouts

    PMID:39207098

    Open questions at the time
    • Whether TEEGR acts directly on the CCR7 axis or via its transcriptional/EZH2 activity not distinguished
    • Single lab
  4. 2026 Medium

    Extended TEEGR's immune-suppressive role to CNS dissemination, showing it suppresses GRA15-driven NF-κB-dependent CCL5 induction via the MYR translocon in brain endothelial cells and dendritic cells.

    Evidence GRA15 and TEEGR knockouts, MYR-translocon dependency assay, CCL5 secretion measurement, NF-κB readouts in primary brain endothelial cells and DCs

    PMID:41528135

    Open questions at the time
    • In vivo relevance to CNS dissemination not directly tested
    • Single lab
  5. 2026 Medium

    Placed TEEGR within a cooperative effector network activating non-canonical NF-κB, showing it acts additively with seven other MYR1-dependent effectors rather than alone.

    Evidence Combinatorial effector knockout panel, RelB/p52 nuclear accumulation assays, TRAF3/NIK western blotting, MYR1-dependency epistasis

    PMID:42663465

    Open questions at the time
    • The specific molecular contribution of TEEGR to TRAF3 depletion/NIK stabilization not isolated
    • Single lab

Mechanism profile

Synthesis pass · controlled-vocabulary classification
Partners
DP1 (HOST)E2F3 (HOST)E2F4 (HOST)EZH2 (HOST, UPREGULATED)MYR1 (PARASITE TRANSLOCON, REQUIRED FOR EXPORT)
Complex memberships
Host cyclin E regulatory complex (E2F3/E2F4/DP1)

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2019 TEEGR (also called HCE1) is a dense granule-resident effector exported into the host cell nucleus where it complexes with host transcription factors E2F3 and E2F4 to induce gene expression, and also promotes EZH2 upregulation, which epigenetically silences a subset of NF-κB-regulated cytokines, counteracting NF-κB signalling and promoting parasite persistence in mice. Dense granule localization, host cell nuclear export assay, co-immunoprecipitation with E2F3/E2F4, EZH2 pathway functional assays, in vivo mouse persistence model Nature microbiology High 31036909
2022 HCE1/TEEGR drives host cell cycle G1-to-S transition as shown by FUCCI reporter kinetics; however, a subsequent S-phase block in DNA synthesis is not caused by HCE1/TEEGR or additional dense granule effectors but depends on host cell type and contact inhibition status. FUCCI fluorescence cell cycle reporter, HCE1/TEEGR knockout parasites, multiple host cell lines mSphere Medium 35587658
2024 TEEGR counter-regulates GRA15/GRA24-driven CCR7-mediated macrophage chemotaxis (hypermigration) in parasitized macrophages, acting downstream or in opposition to NF-κB signalling induced by GRA15. Genetic knockout of individual effectors including TEEGR, macrophage chemotaxis and migration assays, NF-κB signalling readouts mBio Medium 39207098
2026 TEEGR counteracts GRA15-driven NF-κB-dependent CCL5 induction in brain endothelial cells and dendritic cells in an MYR-translocon-dependent manner, establishing TEEGR as a suppressor of the CCL5/CCR5 axis used by GRA15 for Toxoplasma CNS dissemination. GRA15 and TEEGR effector knockouts, MYR-translocon dependency assay, CCL5 secretion measurement, NF-κB signalling readouts in primary brain endothelial cells and DCs mBio Medium 41528135
2026 HCE1/TEEGR is one of eight MYR1-dependent dense granule effectors that cooperatively and additively activate the non-canonical NF-κB pathway (RelB/p52) by driving TRAF3 depletion, NIK stabilization, p100 phosphorylation, and p52 processing; no single effector including HCE1/TEEGR is solely responsible for this phenotype. Combinatorial knockout panel of effectors, nuclear accumulation assays for RelB/p52, TRAF3/NIK western blotting, MYR1-dependency epistasis mBio Medium 42663465
2019 HCE1/TEEGR is exported from the parasitophorous vacuole in a MYR1-dependent manner and localizes to the host nucleus, where it binds the cyclin E regulatory complex components DP1, E2F3, and E2F4, and is necessary and sufficient to upregulate cyclin E and E2F transcription factor target genes; parasites lacking HCE1/TEEGR exhibit a substantial growth defect. MYR1 knockout epistasis, immunoprecipitation of HCE1 from infected host cells, ectopic expression in Neospora caninum and uninfected HFFs, loss-of-function growth assay mBio High 31040242
2024 MYR1-dependent export of effectors (including HCE1/TEEGR) is required for early host S-phase arrest and double-strand DNA break induction within 15 min post-infection; deletion of HCE1 alone did not replicate this phenotype, indicating cyclin E1 upregulation is not the mechanism for this early DNA damage. TgΔmyr1 and TgΔhce1 knockout parasites, flow cytometry cell cycle analysis, γH2AX DNA damage foci imaging, kinetic time-course up to 3 h p.i. Communications biology Medium 39681694

Source papers

Stage 0 corpus · 10 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 The Toxoplasma effector TEEGR promotes parasite persistence by modulating NF-κB signalling via EZH2. Nature microbiology 81 31036909
2019 Toxoplasma Controls Host Cyclin E Expression through the Use of a Novel MYR1-Dependent Effector Protein, HCE1. mBio 51 31040242
2024 Hypermigration of macrophages through the concerted action of GRA effectors on NF-κB/p38 signaling and host chromatin accessibility potentiates Toxoplasma dissemination. mBio 13 39207098
2022 Disruption of Toxoplasma gondii-Induced Host Cell DNA Replication Is Dependent on Contact Inhibition and Host Cell Type. mSphere 5 35587658
2024 Toxoplasma gondii infection induces early host cell cycle arrest and DNA damage in primary human host cells by a MYR1-dependent mechanism. Communications biology 3 39681694
2025 Proteome changes during in vitro culture adaptation of Toxoplasma gondii archetypal II and III field isolates. Frontiers in cellular and infection microbiology 1 41036225
2024 Hypermigration of macrophages through the concerted action of GRA effectors on NF-κB/p38 signaling and host chromatin accessibility potentiates Toxoplasma dissemination. bioRxiv : the preprint server for biology 1 38370679
2026 Toxoplasma effector GRA15-driven CCL5 secretion enhances brain parasite load through microvascular sequestration of phagocytes. mBio 0 41528135
2026 A suite of eight Toxoplasma gondii effectors cooperates to activate the non-canonical NF-κB pathway. mBio 0 42663465
2026 A Suite of Eight Toxoplasma gondii Effectors Cooperates to Activate the Non-canonical NF-κB Pathway. bioRxiv : the preprint server for biology 0 41959509