Inhibition of the phosphatidylinositol kinase vacuolar protein sorting 34 (VPS34) with the pharmacological compound VPS34-IN1 has multiple effects on endosome dynamics. Although VPS34 inhibition has been proposed as a chemotherapeutic strategy for treating cancers, little is known about its cytotoxicity on leukemic blastic plasmacytoid dendritic cell neoplasms (BDPCN).
 
In this study, we aimed to investigate the effects of VPS34-IN1 on BDPCN and its role in regulating type-I IFN expression. We found that VPS34-IN1 did not exhibit significant cytotoxicity on BDPCN but mediated the activation of stimulator of interferon genes (STING) and strongly potentiated plasmacytoid dendritic cell (pDC) response to the STING agonist 2’-3’-cGAMP. Translation intensity measurement, Immunofluorescence confocal microscopy, gene and cytokines expression analysis, CRISPR Cas9 KO
 
This synergy with VPS34-IN1 resulted in a strong enhancement of type-I IFN expression, which was dependent on both the alteration of STING degradation and cap-mediated mRNA translation inhibition. Furthermore, reduction of protein synthesis by VPS34-IN1 was found to control the expression of several key innate signaling regulators, such as the phosphatase-1 co-factor GADD34/PPP1R15a or the adaptor TAX1BP1. This, in turn, prolonged TBK1- and IRF3-dependent signaling downstream of STING.
 
Overall, our study suggests that VPS34 inhibitors may represent interesting compounds for harnessing type-I Interferon expression in different pathologic contexts.