Multiple PDE3A modulators act as molecular glues promoting PDE3A-SLFN12 interaction and induce SLFN12 dephosphorylation and cell death.

The canonical function of phosphodiesterase 3A (PDE3A) is to hydrolyze the phosphodiester bonds in second messenger molecules, such as cyclic AMP (cAMP) and cyclic guanosine monophosphate (cGMP). Recently, a phosphodiesterase-activity-independent role for PDE3A was reported. In this noncanonical function, PDE3A physically interacts with Schlafen 12 (SLFN12) upon treatment of cells with cytotoxic PDE3A modulators. Here, we confirmed that the cytotoxic PDE3A modulators act as molecular glues to initiate the association of PDE3A and SLFN12. The PDE3A-SLFN12 interaction increases the protein stability of SLFN12 located in the cytoplasm, while at the same time also inducing SLFN12 dephosphorylation (including serines 368 and 573). Mutational analysis demonstrates that dephosphorylation is required for cell death induced by cytotoxic PDE3A modulators. Finally, we found that dephosphorylation promoted the rRNA RNase activity of SLFN12 and show that this nucleolytic activity is essential for SLFN12's cell-death-inducing function. Thus, our study deepens the understanding of the biochemical mechanisms underlying SLFN12-mediated cell death.

An alkaloid initiates phosphodiesterase 3A-schlafen 12 dependent apoptosis without affecting the phosphodiesterase activity.

The promotion of apoptosis in tumor cells is a popular strategy for developing anti-cancer drugs. Here, we demonstrate that the plant indole alkaloid natural product nauclefine induces apoptosis of diverse cancer cells via a PDE3A-SLFN12 dependent death pathway. Nauclefine binds PDE3A but does not inhibit the PDE3A's phosphodiesterase activity, thus representing a previously unknown type of PDE3A modulator that can initiate apoptosis without affecting PDE3A's canonical function. We demonstrate that PDE3A's H840, Q975, Q1001, and F1004 residues-as well as I105 in SLFN12-are essential for nauclefine-induced PDE3A-SLFN12 interaction and cell death. Extending these molecular insights, we show in vivo that nauclefine inhibits tumor xenograft growth, doing so in a PDE3A- and SLFN12-dependent manner. Thus, beyond demonstrating potent cytotoxic effects of an alkaloid natural product, our study illustrates a potentially side-effect-reducing strategy for targeting PDE3A for anti-cancer therapeutics without affecting its phosphodiesterase activity.

Transcriptional responses and mechanisms of copper nanoparticle toxicology on zebrafish embryos.

Copper nanoparticles (CuNPs) are used widely due to their attractive antimicrobial properties. However, their biosafety and kinetics on vertebrate embryogenesis are still limited. In this study, CuNPs were revealed to induce eye hypoplasia and almost no digestive gut in zebrafish embryos in a dose-dependent manner. Then, transcriptional responses of zebrafish embryos to CuNPs were investigated, and it was revealed that the genes related to wound healing and stimulus responses were up-regulated, but the genes associated with phototransduction and metabolisms were down-regulated. Differentially expressed genes (DEGs) in CuNPs-exposed and Cu2+-exposed embryos were compared further. Increased VEGF signaling and expression of fli1 were observed in CuNPs rather than Cu2+ treated embryos, but increased reactive oxygen species (ROS) and the resulting enhanced hemoglobin were observed in both CuNPs and Cu2+ treated embryos. This study for the first time revealed that CuNPs and Cu2+ both down-regulated the genes related to phototransduction and metabolisms, but up-regulated the genes associated with hemoglobin. Additionally, compared with Cu2+, CuNPs might be more effective in elevating blood vessels in embryos. Our results suggest that the biological effects of CuNPs are organogenesis-specific during fish embryogenesis, and both particles and ions might mediate their biological effects on embryogenesis.