Antas, P.; Machado, M.; Pinheiro, F.; Barros, D.; Ramalhinho, C.; Mendes, A.; Ferreira, B.; Carvoeiro, D.; Reverendo, M.; Duarte, I. F.; Narita, M.; Su, B.; Argüello, R. J.; Nal Rogier, B.; Pierre, P.; Almeida, C.; Gatti, E.

Inhibition of the phosphatidylinositol kinase vacuolar protein sorting 34 (VPS34) with the VPS34-IN1 drug has a range of effects on endosome dynamics. While VPS34 inhibition has been suggested as potential therapeutic approach for treating cancers, our findings indicate that it has minimal cytotoxic effects on leukemic BPDCN. VPS34-IN1, however, interferes with pDCs function by blocking the recruitment of SGK3 to endosomes, which is shown to be necessary for TLR7 signaling. In contrast, VPS34-IN1 triggers the STING activation and significantly enhances pDCs' response to the STING agonist 2'3'-cGAM. This cooperative action with VPS34-IN1 leads to increased expression of IFN-I, associated with an alteration of STING degradation and importantly, inhibition of cap-mediated mRNA translation. Inhibition of protein synthesis by VPS34-IN1 appears to be central to this synergy with STING activation, notably by compromising the expression of IFIT1/ISG56, a negative regulator of innate signaling. Thus, despite their limited toxicity towards different cancer lines, inhibitors targeting VPS34 and SGK3 may present promising compounds for controlling the expression of type-I IFNs in response to microbial stimuli and pathological contexts.