Histone variant H2B.Z acetylation is necessary for maintenance of Toxoplasma gondii biological fitness

Vanagas, Laura; Muñoz, Daniela; Cristaldi, Constanza; Ganuza, Agustina; Nájera, Rosario; Bonardi, Mabel C.; Turowski, Valeria R.; Guzmán, Fanny; Deng, Bin; Kim, Kami; Sullivan, William J.; Angel, Sérgio O.

doi:10.1016/j.bbagrm.2023.194943

Cited by 6 publications

(8 citation statements)

References 82 publications

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“…Another study using an H2BK120 ubiquitin-specific antibody detected reactivity with T. gondii H2B and H2B.Z supporting the presence of ubiquitin-histone conjugates in T. gondii chromatin that could have conserved functions [135]. Histone H2B.Z is unique to apicomplexan parasites and has been described to conform to a double variant nucleosome (DVN), hyperacetylated in the N-terminal tail and associated with transcriptional activation (Figure 4C) [39,142,[144][145][146][147]. Recent research has examined acetylations in the H2B.Z N-terminal tail lysines and their significance in various biological processes in T. gondii [39].…”

Section: Histonesmentioning

confidence: 68%

“…PTMs such as phosphorylation [37], glycosylation [38], and acetylation [39,40] play crucial roles in regulating various cellular processes in apicomplexan parasites, including T. gondii. These modifications affect protein activity, localization, and interactions, and contribute to the complexity of the proteome, thereby likely influencing developmental transitions, biology, and pathogenesis of these parasites.…”

Section: Post-translational Modifications (Ptms)mentioning

confidence: 99%

“…Histone H2B.Z is unique to apicomplexan parasites and has been described to conform to a double variant nucleosome (DVN), hyperacetylated in the N-terminal tail and associated with transcriptional activation (Figure 4C) [39,142,[144][145][146][147]. Recent research has examined acetylations in the H2B.Z N-terminal tail lysines and their significance in various biological processes in T. gondii [39]. This study revealed that the inability to regulate this N-tail positive charge patch when no acetylation is possible, produced a reduced in vitro replication, a heightened differentiation rate, an increased sensitivity to DNA damage, and, in an in vivo model, a complete loss of T. gondii virulence [39].…”

Section: Histonesmentioning

confidence: 99%

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Proteomics Applications in Toxoplasma gondii: Unveiling the Host–Parasite Interactions and Therapeutic Target Discovery

Deng,

Vanagas,

Alonso

et al. 2023

Pathogens

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Toxoplasma gondii, a protozoan parasite with the ability to infect various warm-blooded vertebrates, including humans, is the causative agent of toxoplasmosis. This infection poses significant risks, leading to severe complications in immunocompromised individuals and potentially affecting the fetus through congenital transmission. A comprehensive understanding of the intricate molecular interactions between T. gondii and its host is pivotal for the development of effective therapeutic strategies. This review emphasizes the crucial role of proteomics in T. gondii research, with a specific focus on host–parasite interactions, post-translational modifications (PTMs), PTM crosstalk, and ongoing efforts in drug discovery. Additionally, we provide an overview of recent advancements in proteomics techniques, encompassing interactome sample preparation methods such as BioID (BirA*-mediated proximity-dependent biotin identification), APEX (ascorbate peroxidase-mediated proximity labeling), and Y2H (yeast two hybrid), as well as various proteomics approaches, including single-cell analysis, DIA (data-independent acquisition), targeted, top-down, and plasma proteomics. Furthermore, we discuss bioinformatics and the integration of proteomics with other omics technologies, highlighting its potential in unraveling the intricate mechanisms of T. gondii pathogenesis and identifying novel therapeutic targets.

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Section: Histonesmentioning

confidence: 68%

Section: Post-translational Modifications (Ptms)mentioning

confidence: 99%

Section: Histonesmentioning

confidence: 99%

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Proteomics Applications in Toxoplasma gondii: Unveiling the Host–Parasite Interactions and Therapeutic Target Discovery

Deng,

Vanagas,

Alonso

et al. 2023

Pathogens

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“…Similarly, TgH2A.Z/TgH2B.Z dimer localizes with activate mark H3K4me3 in promoter/transcriptional start site regions of active genes and the gene bodies of silent genes ( 62 ). Two recent reports showed that PfH2A.Z was colocalized with PfARP4a and its knockdown resulted in the depletion of PfH2A.Z and reduced H3K9ac at the upstream regions of genes ( 63 ) and five mutations of N-terminal lysines of TgH2B.Z to arginines led to defects of parasite growth and virulence, more sensitive to DNA damage, and increase of differentiation to bradyzoites ( 64 ). The SWR1 complex in these parasites might be specifically involved in the regulation of the abovementioned processes.…”

Section: Discussionmentioning

confidence: 99%

MYST regulates DNA repair and forms a NuA4-like complex in the malaria parasite Plasmodium falciparum

Kalamuddin,

Shakri,

Wang

et al. 2024

mSphere

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Histone lysine acetyltransferase MYST-associated NuA4 complex is conserved from yeast to humans and plays key roles in cell cycle regulation, gene transcription, and DNA replication/repair. Here, we identified a Plasmodium falciparum MYST-associated complex, PfNuA4, which contains 11 of the 13 conserved NuA4 subunits. Reciprocal pulldowns using PfEAF2, a shared component between the NuA4 and SWR1 complexes, not only confirmed the PfNuA4 complex but also identified the PfSWR1 complex, a histone remodeling complex, although their identities are low compared to the homologs in yeast or humans. Notably, both H2A.Z/H2B.Z were associated with the PfSWR1 complex, indicating that this complex is involved in the deposition of H2A.Z/H2B.Z, the variant histone pair that is enriched in the activated promoters. Overexpression of PfMYST resulted in earlier expression of genes involved in cell cycle regulation, DNA replication, and merozoite invasion, and upregulation of the genes related to antigenic variation and DNA repair. Consistently, PfMYST overexpression led to high basal phosphorylated PfH2A (γ-PfH2A), the mark of DNA double-strand breaks, and conferred protection against genotoxic agent methyl methanesulfonate (MMS), X-rays, and artemisinin, the first-line antimalarial drug. In contrast, the knockdown of PfMYST caused a delayed parasite recovery upon MMS treatment. MMS induced the gradual disappearance of PfMYST in the cytoplasm and concomitant accumulation of PfMYST in the nucleus, suggesting cytoplasm-nucleus shuttling of PfMYST. Meanwhile, PfMYST colocalized with the γ-PfH2A, indicating PfMYST was recruited to the DNA damage sites. Collectively, PfMYST plays critical roles in cell cycle regulation, gene transcription, and DNA replication/DNA repair in this low-branching parasitic protist. IMPORTANCE Understanding gene regulation and DNA repair in malaria parasites is critical for identifying targets for antimalarials. This study found PfNuA4, a PfMYST-associated, histone modifier complex, and PfSWR1, a chromatin remodeling complex in malaria parasite Plasmodium falciparum . These complexes are divergent due to the low identities compared to their homologs from yeast and humans. Furthermore, overexpression of PfMYST resulted in substantial transcriptomic changes, indicating that PfMYST is involved in regulating the cell cycle, antigenic variation, and DNA replication/repair. Consistently, PfMYST was found to protect against DNA damage caused by the genotoxic agent methyl methanesulfonate, X-rays, and artemisinin, the first-line antimalarial drug. Additionally, DNA damage led to the relocation of cytoplasmic PfMYST to the nucleus and colocalization of PfMYST with γ-PfH2A, the mark of DNA damage. In summary, this study demonstrated that the PfMYST complex has critical functions in regulating cell cycle, antigenic variation, and DNA replication/DNA repair in P. falciparum .

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“…Co-IP assays were performed as described in Vanagas et al [21] with minor modifications. Protease inhibitor cocktail (Sigma) was added in every step.…”

Section: Co-immunoprecipitation (Co-ip)mentioning

confidence: 99%

Safe plant Hsp90 adjuvants elicit an effective immune response against SARS-CoV2 derived RBD antigen

Ramos-Duarte,

Orlowski,

Jaquenod de Giusti

et al. 2023

Preprint

Self Cite

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To better understand the role of pHsp90 adjuvant in immune response modulation, we proposed the use of the Receptor Binding Domain (RBD) of the Spike protein of SARS-CoV2, the principal candidate in the design of subunit vaccines. We evaluated the humoral and cellular immune responses against RBD through the strategy “protein mixture” (Adjuvant + Antigen). The rRBD adjuvanted with rAtHsp81.2 group showed a higher increase of the anti-rRBD IgG1, while the rRBD adjuvanted with rNbHsp90.3 group showed a significant increase of anti-rRBD IgG2b/2a. These results were consistent with the cellular immune response analysis. Spleen cell cultures from rRBD+rNbHsp90.3-immunized mice showed significantly increased IFN-γ production. In contrast, spleen cell cultures from rRBD+rAtHsp81.2-immunized mice showed significant increased IL-4 levels. Finally, vaccines adjuvanted with rNbHsp90.3 induced higher neutralizing antibody responses compared to those adjuvanted with rAtHsp81.2. To know whether both chaperones must form complexes to generate an effective immune response, we performed co-immunoprecipitation (co-IP) assays. The results indicated that the greater neutralizing capacity observed in the rRBD adjuvanted with rNbHsp90.3 group would be given by the rRBD-rNbHsp90.3 interaction rather than by the quality of the immune response triggered by the adjuvants. These results, together with our previous results, provide a comparative benchmark of these two novel and safe vaccine adjuvants for their capacity to stimulate immunity to a subunit vaccine, demonstrating the capacity of adjuvanted SARS-CoV2 subunit vaccines. Furthermore, these results revealed differences in the ability to modulate the immune response between these two pHsp90s, highlighting the importance of adjuvant selection for future rational vaccine and adjuvant design.

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Histone variant H2B.Z acetylation is necessary for maintenance of Toxoplasma gondii biological fitness

Cited by 6 publications

References 82 publications

Proteomics Applications in Toxoplasma gondii: Unveiling the Host–Parasite Interactions and Therapeutic Target Discovery

Proteomics Applications in Toxoplasma gondii: Unveiling the Host–Parasite Interactions and Therapeutic Target Discovery

MYST regulates DNA repair and forms a NuA4-like complex in the malaria parasite Plasmodium falciparum

Safe plant Hsp90 adjuvants elicit an effective immune response against SARS-CoV2 derived RBD antigen

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