Nuclear phosphatase PfNIF2 governs erythrocyte invasion and genome integrity through invasion-related proteins and SR1 dephosphorylation
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ABSTRACT:
PROVIDER: PRJNA1285694 | ENA |
REPOSITORIES: ENA
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Project description:PfNIF2 is a nuclear protein phosphatase belonging to the NIF family in Plasmodium falciparum. It is characterized by a conserved ‘DLDET’ motif, which is essential for its catalytic activity. PfNIF2 primarily localizes to the perinuclear or nuclear compartment and shows peak expression during the schizont stage of the parasite's lifecycle. Genetic disruption of the pfnif2 gene significantly impaired the efficiency of merozoite invasion, resulting in a 1.65-fold reduction (P < 0.05). It also increased susceptibility to artemisinin derivatives, with the IC50 of dihydroartemisinin decreasing from 12.5 nM to 7.9 nM (P < 0.001), although the asexual development of the parasites remained viable. Site-directed mutagenesis confirmed that aspartate 65 within the ‘D63LD65ET’ motif is critical for enzymatic function and invasion competence. Transcriptomic profiling revealed extensive dysregulation of invasion-related genes, including RON4 and MSP1, in schizont-stage PfNIF2Del parasites. Integrated co-immunoprecipitation, LC-MS/MS, and phosphoproteomic analyses demonstrated that PfNIF2 interacts with DNA repair machinery, such as SR1, SUN2, and MSH2-1. It plays a role in dephosphorylating RNA-binding proteins and invasion effectors. Notably, the expression of a phosphoablative variant of serine/arginine-rich splicing factor 1 (SR1-S205A/S208A) in PfNIF2Del parasites substantially rescued defects in DNA damage repair, alternative splicing fidelity, artemisinin sensitivity, and erythrocyte invasion. These findings establish PfNIF2 as a multifunctional regulator that bridges nuclear RNA processing, genome integrity maintenance, and host cell invasion in malaria parasites.
2025-08-13 | GSE301593 | GEO
Project description:Efforts to improve the clinical outcome of highly aggressive triplenegative breast cancer (TNBC) have been hindered by the lack of effective targeted therapies. Hence, it is important to identify the specific gene targets/pathways driving the invasive phenotype to develop more effective therapeutics. Here we show that UBASH3B (ubiquitin associated and SH3 domain containing B), a protein tyrosine phosphatase, is overexpressed in TNBC, where it supports malignant growth, invasion and metastasis in large through modulating EGFR. We also show that UBASH3B is a functional target of anti-invasive miR-200a that is downregulated in TNBC. Importantly, the oncogenic potential of UBASH3B is dependent on its tyrosine phosphatase activity, which targets CBL ubiquitin ligase for dephosphorylation and inactivation, leading to EGFR upregulation. Thus, UBASH3B may function as a crucial node in bridging multiple invasion-promoting pathways, thus providing a potential new therapeutic target for TNBC. Breast cancer tissues and breast cancer cell lines
2013-06-01 | E-GEOD-36693 | biostudies-arrayexpress
Project description:Efforts to improve the clinical outcome of highly aggressive triple-negative breast cancer (TNBC) have been hindered by the lack of effective targeted therapies. Thus, it is important to identify the specific gene targets/pathways driving the invasive phenotype to develop more effective therapeutics. Here we show that ubiquitin-associated and SH3 domain-containing B (UBASH3B), a protein tyrosine phosphatase, is overexpressed in TNBC, where it supports malignant growth, invasion, and metastasis largely through modulating epidermal growth factor receptor (EGFR). We also show that UBASH3B is a functional target of anti-invasive microRNA200a (miR200a) that is down-regulated in TNBC. Importantly, the oncogenic potential of UBASH3B is dependent on its tyrosine phosphatase activity, which targets CBL ubiquitin ligase for dephosphorylation and inactivation, leading to EGFR up-regulation. Thus, UBASH3B may function as a crucial node in bridging multiple invasion-promoting pathways, thereby providing a potential therapeutic target for TNBC.
2013-06-01 | GSE36693 | GEO
Project description:The invasion of Plasmodium merozoites into host erythrocytes is initiated through specific ligand–receptor interactions. This interaction results in subsequent invasion events, facilitated by forming a moving junction through AMA–1 and associated molecular complexes mediating parasite entry into the erythrocytic membrane. Previous studies have implicated erythrocyte surface glycosaminoglycans, particularly heparan sulfate proteoglycans, as critical receptor components in this invasion process. In this study, we sought to elucidate the molecular function of PbMAP2 (encoded by PbANKA_1137800), a previously uncharacterized Plasmodium berghei ANKA protein, in mediating merozoite attachment and invasion via heparan sulfate–dependent pathways. The PbMAP2 protein, predominantly situated at the extreme apical region of the P. berghei merozoite, binds to heparin and the erythrocyte surface during merozoite invasion. Additionally, mice either immunized with the PbMAP2 protein or passively immunized with sera derived from vaccinated mice demonstrated enhanced immunity against lethal challenges. Global mass spectrometric analysis indicates that PbMAP2 engages with several trafficking and secretion proteins associated with parasite invasion. Our findings pinpointed PbMAP2 is predominantly expressed at the extreme apical region of the P. berghei merozoite and engages in binding to the heparin–like receptors on the erythrocyte surface during merozoite invasion.
2025-03-06 | PXD061524 |
Project description:We previously reported that the Plasmodium falciparum putative serine/threonine protein phosphatase 7 (PP7) is a high confidence substrate of the cAMP-dependent protein kinase (PKA). Here we explore the function of PP7 in asexual P. falciparum blood stage parasites. We show that conditional disruption of PP7 leads to a severe growth arrest. We show that PP7 is a calcium-dependent phosphatase which interacts with calmodulin and calcium-dependent protein kinase 1 (CDPK1), consistent with a role in calcium signalling. Notably, PP7 was found to be dispensable for erythrocyte invasion, but was crucial for ring-stage development, with PP7-null parasites arresting shortly following invasion and showing no transition to ameboid forms. Phosphoproteomic analysis revealed that PP7 may regulate dephosphorylation of PKAc substrates, particularly in the presence of Ca2+. Its interaction with calmodulin and CDPK1 further emphasise a role in calcium signalling, while its impact on early ring development and PKAc substrate phosphorylation underscores its importance in parasite development.
2024-10-07 | PXD051277 | Pride
Project description:The Plasmodium falciparum DNA/RNA-binding protein PfAlba1 post-transcriptionally modulates the translational timing of erythrocyte invasion proteins
| PRJEB9611 | ENA
Project description:We demonstrate that Protein Phosphatase PfPPM2 regulates both asexual and sexual development of human malaria parasite P. falciparum. It is involved in the division of the parasite during asexual development and promotes its sexual differentiation. Phosphoproteomics studies revealed that PfPPM2 targets in the parasite include key regulators of protein translation and chromatin remodelling. We demonstrate that it regulates dephosphorylation of S33 of Heterochromatin Protein 1 (HP1), a regulator of heritable gene silencing and contributes to both mitotic proliferation as well as sexual differentiation of the parasite into sexual forms. Detailed investigations revealed that PfPPM2 mediated dephosphorylation of HP1 at S33 is a signal for parasite sexual conversion. HP1- S33 dephosphorylation impairs its interaction with trimethylated form of histone 3 (H3) at lysine 9 (H3K9me3), which is known to stabilize the heterochromatin. As a result, the expression of transcription of ap2g-which is repressed by HP1-H3K9me3-was stimulated resulting in sexual conversion of the parasite. Interestingly, the state of HP1-S33 phosphorylation seems to largely reflect the fate of the parasite-its optimal phosphorylation is important for asexual division whereas it is dephosphorylated form favours sexual differentiation. PfPPM2 also regulates protein synthesis in the parasite by repressing a signaling pathway involved in the phosphorylation of initiation factor eIF2α, which are likely to contribute to parasite division and possibly differentiation.
2025-04-08 | GSE275086 | GEO
Project description:Bacillus subtilis strain:SR1 | isolate:SR1 Genome sequencing and assembly
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Project description:Nicotiana tabacum strain:SR1 | cultivar:SR1 Transcriptome or Gene expression
| PRJNA271947 | ENA
Project description:Protein dephosphorylation mediated by phosphatases regulates spermatogenesis. However, which proteins are dephosphorylated and how they regulate spermatogenesis are largely unknown. Here, we show that germline-specific deletion of protein phosphatase 6 regulatory subunit 3 (PPP6R3), which determines substrate specificity of protein phosphatase 6 catalytic subunit, causes abnormal spermatogonial differentiation and male infertility, accompanied by translation inhibition. PPP6R3 directly interacts with EIF3C and EIF4G1 in KIT+ spermatogonia. Decreased levels of non-phosphorylated EIF3C and EIF4G1 after PPP6R3 deletion attenuate their enrichment for mRNAs associated with spermatogonial differentiation, and increased phosphorylation levels promote their degradation. Specifically, the phosphorylation status both of EIF3CS39 and EIF4G1S1217 are significantly upregulated in mutant mice. Overexpression of EIF3CS39A and EIF4G1S1217A mutants in Ppp6r3-cKO spermatogonial progenitor cells compensates for their differentiation efficiency by upregulating the translation rates of differentiation-associated mRNAs. Our findings demonstrate that dephosphorylation of EIF3C and EIF4G1 mediated by PPP6R3 is critical for translation activation during spermatogonial differentiation.
2025-06-20 | GSE278121 | GEO