Biology subjects

Nagaoka, H.

Publications and source records attributed to Nagaoka, H..

2 recordsLinked to original sources

bioRxiv2024

Pfs230 Domain 12 is a potent malaria transmission-blocking vaccine candidate

Malaria transmission-blocking vaccines (TBV) target sexual stage parasites that are transmitted to mosquitoes and critical for spread of the pathogen. The clinically most advanced TBV candidate contains part of the Pro-domain (Pro) and Domain 1 (D1) of Plasmodium falciparum surface protein Pfs230. Subunit vaccines that contain other domains of Pfs230 have so far failed to induce functional antibodies. Here, we produced eight single domain fragments of Pfs230 in Drosophila melanogaster S2 cells and assessed their immunogenicity in mouse immunizations. In addition to D1-specific antibodies, antibodies raised against Domain 12 (D12) showed strong recognition of Pfs230 on the surface of female parasites. Importantly, D12-specific antibodies showed strong functional transmission-reducing activity in membrane feeding assays with cultured parasites, an activity that was complement-dependent. Murine D12-specific antibodies further reduced mosquito transmission of parasites acquired from naturally infected parasite carriers. The D12 antigen was recognized by sera from an all-age cohort of individuals who had been naturally exposed to Plasmodium falciparum with antibody levels increasing with age. In conclusion, we identified Pfs230D12 as a promising new TBV candidate. Impact statementPfs230 Domain 12 induces antibodies in mice that strongly reduce transmission of lab-cultured and naturally circulating malaria parasites to mosquitoes.

immunology↗

bioRxiv2024

Zbtb38 inhibits apoptosis by transcriptionally regulating XIAP expression

The X-linked inhibitor of apoptosis protein (XIAP) is a key suppressor of apoptosis, crucial for cellular differentiation, embryogenesis, and cancer progression. However, its upstream regulatory mechanisms remain poorly understood. Here, we demonstrate that the zinc finger transcription factor Zbtb38, a negative regulator of apoptosis, modulates XIAP expression in both loss- and gain-of-function experiments, irrespective of p53 expression. Notably, XIAP overexpression rescues the apoptosis induced by Zbtb38 knockdown, indicating that Zbtb38-associated apoptosis is at least partially XIAP-dependent. Mechanistically, Zbtb38 binds to E-box motifs within upstream regulatory regions of XIAP and activates its transcription. During embryonic stem (ES) cell differentiation and embryogenesis, Zbtb38 depletion increases apoptosis and reduces XIAP and Bcl-2 expression, underscoring their functional relevance in these processes. Analysis of human tumor datasets reveals a strong positive correlation between ZBTB38 and XIAP expression, with elevated ZBTB38 levels associated with high-grade malignancies. Furthermore, Zbtb38 knockdown induces apoptosis in cancer cells with reduced XIAP expression, regardless of p53 expression. Collectively, these findings uncover a novel Zbtb38-XIAP axis that regulates apoptosis during cellular differentiation, development, and oncogenesis, and highlight its therapeutic potential in XIAP-driven and p53-deficient tumors.

cell biology↗