Affinage · Toxoplasma gondii

HSP90

heat shock protein HSP90 · UniProt A0A125YVB7

Annotated
2026-09-08
23 papers in source corpus 8 papers cited in narrative 8 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TgHsp90 is an essential, developmentally regulated cytosolic molecular chaperone in Toxoplasma gondii required for host-cell invasion, intracellular replication, and stage interconversion (PMID:28627357, PMID:15967463). Genetic knockout abolishes invasion and proliferation in vitro and long-term parasite survival in mice, with defects reversed by complementation, establishing that TgHsp90 is essential for the lytic cycle and in vivo viability (PMID:28627357). TgHsp90 is a cytoplasmic protein secreted from extracellular tachyzoites, and its pharmacological inhibition by geldanamycin disturbs host-cell entry and intracellular growth without affecting secretion, placing its function at the level of invasion and replication rather than release (PMID:14623321). Its transcript and protein levels rise under stress and bradyzoite differentiation conditions, and the protein redistributes from a cytosolic pool in tachyzoites to both nucleus and cytosol in mature bradyzoites; geldanamycin blocks both directions of tachyzoite-bradyzoite interconversion, implicating TgHsp90 in developmental stage switching (PMID:15967463). Mechanistically, TgHsp90 acts within a cytosolic chaperone complex, co-immunoprecipitating with TgHsp70 and the Hsp40/J-domain co-chaperone TgSis1 (PMID:22209934), and contributes to folding of the class XIVa myosin TgMyoA through the UCS co-chaperone TgUNC, whose TPR domain is dispensable for recruitment (PMID:25231988).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2003 Medium

    Establishing whether TgHsp90 activity is needed for the parasite lytic cycle, this work showed the chaperone is a secreted cytoplasmic protein whose function, not its secretion, is required for host entry and replication.

    Evidence Monoclonal antibody characterization, cDNA cloning, and geldanamycin inhibition with invasion and growth assays in T. gondii

    PMID:14623321

    Open questions at the time
    • Pharmacological inhibition does not exclude off-target effects
    • Substrates mediating the invasion/growth requirement not identified
    • No genetic confirmation of essentiality at this stage
  2. 2005 Medium

    Addressing whether TgHsp90 has a role in developmental stage transitions, this study linked its stress-induced upregulation and nuclear/cytosolic redistribution to an essential function in bidirectional tachyzoite-bradyzoite interconversion.

    Evidence Fluorescence microscopy, Western blot, and geldanamycin inhibition in RH ΔUPRT, ME49, and PK strains

    PMID:15967463

    Open questions at the time
    • Geldanamycin is not fully Hsp90-specific in vivo
    • Molecular basis of nuclear redistribution unknown
    • Client proteins driving stage switching not defined
  3. 2011 Medium

    To define the chaperone machinery TgHsp90 operates within, this work placed it in a cytosolic complex with TgHsp70 and the co-chaperone TgSis1.

    Evidence Co-immunoprecipitation and immunofluorescence localization in T. gondii

    PMID:22209934

    Open questions at the time
    • Co-IP without reciprocal validation or functional mutagenesis
    • Stoichiometry and dynamics of the complex unknown
    • Client specificity of the complex not addressed
  4. 2014 Medium

    Identifying a client and folding route for TgHsp90, this study showed the chaperone contributes to functional TgMyoA folding via the UCS co-chaperone TgUNC, with its TPR domain dispensable, implying alternative Hsp90 recruitment mechanisms.

    Evidence Baculovirus/Sf9 heterologous expression with TgUNC co-expression, in vitro actin motility assay, and domain deletion analysis

    PMID:25231988

    Open questions at the time
    • Direct TgHsp90-TgMyoA interaction not demonstrated in the parasite
    • TPR-independent recruitment mechanism undefined
    • Other myosin/motility clients not surveyed
  5. 2017 High

    Providing definitive genetic proof of essentiality, this work showed that TgHsp90 knockout blocks invasion, proliferation, and in vivo survival, with complementation rescuing all defects.

    Evidence Gene knockout (ΔHsp90), complementation, in vitro invasion/proliferation assays, and a mouse survival model

    PMID:28627357

    Open questions at the time
    • Molecular clients responsible for the phenotypes not mapped
    • Stage-specific contributions not dissected genetically
    • Structural determinants of essential function unknown
  6. 1998 Low

    Early pharmacological evidence implicating heat shock proteins in bradyzoite development showed that quercetin, which inhibits Hsp90/Hsp70/Hsp27 synthesis, suppresses bradyzoite induction.

    Evidence Quercetin inhibition with bradyzoite-specific immunofluorescence, Western blot, and RT-PCR in T. gondii

    PMID:9632598

    Open questions at the time
    • Inhibitor not specific to Hsp90 (also targets Hsp70 and Hsp27)
    • No genetic confirmation of Hsp90's specific contribution
    • Mechanism of differentiation blockade unresolved
  7. 2024 Low

    Positioning TgHsp90 within a broader stress-response network, this study found HSP90 transcription is upregulated alongside other HSPs and BFD1 in a bag1 knockout background that partially rescues bradyzoite differentiation.

    Evidence ME49Δbag1 knockout with qPCR of HSP-family transcripts, Western blot, and cyst formation assays

    PMID:39080770

    Open questions at the time
    • Transcriptional readout only, no direct functional test on Hsp90
    • Compensatory role inferred, not demonstrated
    • Regulatory link between Hsp90 and BFD1 unestablished
  8. 2026 Low

    In ocular toxoplasmosis pathology, HDAC6 inhibition modulated the HDAC6-Hsp90 pathway with reduced VEGF and HSF1, placing an Hsp90 pathway downstream of HDAC6 in retinal infection.

    Evidence Intravitreal Tubastatin A (HDAC6 inhibitor) with immunofluorescence, cytokine measurement, and histopathology in a murine ocular toxoplasmosis model

    PMID:41533437

    Open questions at the time
    • Does not distinguish host from parasite Hsp90
    • Pathway placement is correlative
    • Direct Hsp90 involvement not demonstrated

Open questions

Synthesis pass · forward-looking unresolved questions
  • The specific client proteins through which TgHsp90 drives invasion, replication, and stage switching, and the structural/regulatory basis of its nuclear redistribution in bradyzoites, remain undefined.
  • Full client repertoire beyond TgMyoA unknown
  • Mechanism of tachyzoite-to-bradyzoite redistribution uncharacterized
  • Direct role in stage switching not genetically dissected from chaperone function

Mechanism profile

Synthesis pass · controlled-vocabulary classification
Partners
TGHSP70 [#3]TGMYOA (CLASS XIVA MYOSIN CLIENT) [#4]TGSIS1 (HSP40/J-DOMAIN CO-CHAPERONE) [#3]TGUNC (UCS-FAMILY MYOSIN CO-CHAPERONE) [#4]
Complex memberships
Cytosolic chaperone complex with TgHsp70 and the Hsp40/J-domain co-chaperone TgSis1 [#3]

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 TgHsp90 transcript and protein levels increase under stress or bradyzoite differentiation conditions. Fluorescence microscopy revealed that Hsp90 is cytosolic in tachyzoites but present in both nucleus and cytosol in mature bradyzoites, indicating developmentally regulated subcellular redistribution. Geldanamycin (a benzoquinone ansamycin that binds and disrupts Hsp90 function) blocked conversion both from tachyzoite to bradyzoite and bradyzoite to tachyzoite stages, establishing an essential role for Hsp90 in stage interconversion. Fluorescence microscopy, Western blot, geldanamycin pharmacological inhibition in RH ΔUPRT and ME49/PK strains Journal of molecular biology Medium 15967463
2003 TgHsp90 (82 kDa) is a cytoplasmic protein secreted from extracellular tachyzoites but not released into the parasitophorous vacuole after invasion. Geldanamycin treatment did not affect TgHsp90 secretion from extracellular tachyzoites but significantly disturbed host cell entry and intracellular parasite growth, indicating TgHsp90 function is required for invasion and intracellular replication. Monoclonal antibody characterization, cDNA cloning and sequencing, geldanamycin pharmacological inhibition, invasion and growth assays Biochemical and biophysical research communications Medium 14623321
2017 Genetic knockout of TgHsp90 (ΔHsp90) resulted in defective host-cell invasion, failure to proliferate in vitro in Vero cells, and loss of long-term survival in mice in vivo. These defects were rescued by complementation with TgHsp90, establishing that TgHsp90 is essential for invasion, replication, and parasite viability in vivo. Gene knockout (ΔHsp90), complementation strain, in vitro invasion and proliferation assays, mouse survival model Parasite (Paris, France) High 28627357
2011 TgSis1 (a Hsp40/J-domain protein) co-immunoprecipitated with both TgHsp70 and TgHsp90, indicating that TgHsp90 participates in a cytosolic chaperone complex with TgHsp70 and TgSis1. Co-immunoprecipitation, immunofluorescence localization International journal of biological macromolecules Medium 22209934
2014 TgUNC (a UCS-family myosin co-chaperone) enables functional expression of TgMyoA (class XIVa myosin) in Sf9 cells; its tetratricopeptide repeat (TPR) domain was not essential for obtaining functional myosin, implying alternative mechanisms exist for Hsp90 recruitment to TgMyoA during folding. Baculovirus/Sf9 heterologous expression, co-expression with TgUNC, in vitro actin motility assay, domain deletion analysis The Journal of biological chemistry Medium 25231988
1998 Quercetin, a bioflavonoid that inhibits synthesis of Hsp90, Hsp70, and Hsp27, suppresses induction of bradyzoite development in vitro, implicating heat shock proteins including Hsp90 in the process of bradyzoite differentiation. Quercetin pharmacological inhibition, immunofluorescence with bradyzoite-specific antibodies, Western blot, RT-PCR Infection and immunity Low 9632598
2024 Following bag1 (HSP30) knockout in ME49, transcription of HSP90 (along with HSP20, HSP21, HSP40, HSP60, HSP70, and BFD1) was significantly upregulated, indicating that TgHsp90 participates in a compensatory stress-response network that partially rescues bradyzoite differentiation in the absence of BAG1. Gene knockout (ME49Δbag1), qPCR for HSP family transcript levels, Western blot, cyst formation assay Parasites & vectors Low 39080770
2026 In a murine ocular toxoplasmosis model, HDAC6 inhibition by Tubastatin A regulated the HDAC6-Hsp90 pathway, leading to decreased VEGF and HSF1 expression. This places TgHsp90 (or the host Hsp90 pathway) downstream of HDAC6 in the context of retinal infection pathology. Intravitreal injection of Tubastatin A (HDAC6 inhibitor), immunofluorescence, cytokine measurement, histopathology in murine OT model ACS infectious diseases Low 41533437

Source papers

Stage 0 corpus · 23 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 Bradyzoite development in Toxoplasma gondii and the hsp70 stress response. Infection and immunity 104 9632598
2011 Intracellular protozoan parasites of humans: the role of molecular chaperones in development and pathogenesis. Protein and peptide letters 90 20955165
2005 Toxoplasma gondii Hsp90 is a potential drug target whose expression and subcellular localization are developmentally regulated. Journal of molecular biology 83 15967463
2013 Identification of differentially expressed proteins in sulfadiazine resistant and sensitive strains of Toxoplasma gondii using difference-gel electrophoresis (DIGE). International journal for parasitology. Drugs and drug resistance 42 24533291
2003 Molecular cloning of the 82-kDa heat shock protein (HSP90) of Toxoplasma gondii associated with the entry into and growth in host cells. Biochemical and biophysical research communications 40 14623321
2014 A Toxoplasma gondii class XIV myosin, expressed in Sf9 cells with a parasite co-chaperone, requires two light chains for fast motility. The Journal of biological chemistry 36 25231988
2017 The heat shock protein 90 of Toxoplasma gondii is essential for invasion of host cells and tachyzoite growth. Parasite (Paris, France) 26 28627357
2015 Heat Shock Protein 90 regulates encystation in Entamoeba. Frontiers in microbiology 21 26528271
2013 A review of recent patents on the protozoan parasite HSP90 as a drug target. Recent patents on biotechnology 21 23002958
2012 Toxoplasma gondii antigens recognized by IgG antibodies differ between mice with and without active proliferation of tachyzoites in the brain during the chronic stage of infection. Infection and immunity 21 22851753
2011 Toxoplasma gondii Sis1-like J-domain protein is a cytosolic chaperone associated to HSP90/HSP70 complex. International journal of biological macromolecules 15 22209934
2014 Toxoplasma gondii Hsp90: potential roles in essential cellular processes of the parasite. Parasitology 13 24560345
2019 Plant Hsp90 is a novel adjuvant that elicits a strong humoral and cellular immune response against B- and T-cell epitopes of a Toxoplasma gondii SAG1 peptide. Parasites & vectors 12 30909938
2021 Oral Immunization With a Plant HSP90-SAG1 Fusion Protein Produced in Tobacco Elicits Strong Immune Responses and Reduces Cyst Number and Clinical Signs of Toxoplasmosis in Mice. Frontiers in plant science 11 34675949
2000 Expression of a cDNA encoding a Toxoplasma gondii protein belonging to the heat-shock 90 family and analysis of its antigenicity. FEMS microbiology letters 11 11034281
2025 Immunization with plant-based vaccine expressing Toxoplasma gondii SAG1 fused to plant HSP90 elicits protective immune response in lambs. Acta tropica 6 39894243
2017 Suppressors for Human Epidermal Growth Factor Receptor 2/4 (HER2/4): A New Family of Anti-Toxoplasmic Agents in ARPE-19 Cells. The Korean journal of parasitology 6 29103264
2024 Mechanisms of adaptation and evolution in Toxoplasma gondii. Molecular and biochemical parasitology 4 38354788
2024 Toxoplasma gondii bradyzoite-specific BAG1 is nonessential for cyst formation due to compensation by other heat-shock proteins. Parasites & vectors 3 39080770
2019 Heat treatment alleviates the growth and photosynthetic impairment of transplastomic plants expressing Leishmania infantum Hsp83-Toxoplasma gondii SAG1 fusion protein. Plant science : an international journal of experimental plant biology 2 31084864
2026 Intravitreal Administration of a Selective HDAC6 Inhibitor Prevents Retinal Damage Progression in the Acute Ocular Toxoplasmosis Model. ACS infectious diseases 0 41533437
2025 Identification of a New Pentafluorosulfanyl-Substituted Chalcone with Activity Against Hepatoma and Human Parasites. Pharmaceuticals (Basel, Switzerland) 0 39861113
2024 Molecular Mimicry between Toxoplasma gondii B-Cell Epitopes and Neurodevelopmental Proteins: An Immunoinformatic Approach. Biomolecules 0 39199321