Schistosoma japonicum Histone Acetyltransferase 1 (SjHAT1): A Novel Anti-schistosomal Drug Target
Schistosomiasis remains a critical global health issue, necessitating novel therapies due to emerging praziquantel resistance. We previously developed a patented praziquantel derivative, DW-3-15, which demonstrated potent broad-spectrum schistosomicidal activity through SjHAT1 inhibition. Here, the full-length SjHAT1 cDNA is cloned by rapid amplification of cDNA ends methods. The amino acids encoded by the cDNA retains conserved catalytic residues of acetyltransferases although sharing only 34% identity with mammalian orthologs. Phylogenetic analyses place it in a distinct clade, indicating its divergence specific to Schistosoma species. The expression profiling of SjHAT1 reveals stage- and sex-specific patterns. Fluorescence in situ hybridization localizes SjHAT1 predominantly in female vitellaria and male parenchyma near the gynecophoral canal. Knockdown of SjHAT1 impairs worm survival, reduces female oviposition and disrupts ovarian and vitelline morphology both in vitro and in vivo. RNA-sequencing analysis reveals that SjHAT1 knockdown disrupts {beta}-alanyl-tryptamine pheromone signaling via downregulation of aromatic L-amino acid decarboxylase in males and multidrug resistance-associated protein 4 in females. Through exploring this dual-sex regulatory mechanisms, SjHAT1 may emerge as a promising therapeutic target for interrupting schistosomiasis transmission.