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Publié dans: BioRxiv, 2024, ⟨10.1101/2024.06.17.599308⟩

Auteurs: Paulo Antas, Mariana Machado, Fátima Leite-Pinheiro, Daniela Barros, Carlota Ramalhinho, Andreia Mendes, Beatriz Ferreira, Daniela Carvoeiro, Marisa Reverendo, Iola Duarte, Miwako Narita, Bing Su, Rafael Argüello, Beatrice Nal, Philippe Pierre, Catarina Almeida, Evelina Gatti

Résumé

Abstract Inhibition of the phosphatidylinositol kinase vacuolar protein sorting 34 (VPS34) with the pharmacological compound VPS34-IN1 has a range of effects on the dynamics of endosomes. While VPS34 inhibition has been suggested as a potential therapeutic approach for treating certain cancers, our findings indicate that it has minimal cytotoxic effects on leukemic blastic plasmacytoid dendritic cell neoplasms (BPDCN). VPS34-IN1, however, interferes with plasmacytoid dendritic cells (pDCs) function by blocking the recruitment of serum and glucocorticoid-regulated kinase 3 (SGK3) to endosomes, which is shown to be necessary for Toll-like receptor 7 (TLR7) signaling. In a contrasting parallel, VPS34-IN1 triggers the activation of the stimulator of interferon genes (STING) and significantly enhances pDCs’ response to the STING agonist 2’3’-cyclic guanosine monophosphate-adenosine monophosphate (2’3’-cGAMP). This cooperative action with VPS34-IN1 leads to strongly increased expression of type-I interferons (IFNs), 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 various microbial stimuli and pathological contexts. One-sentence summary Pharmacological inhibition of VPS34 affects multiple signaling pathways downstream of innate immunity receptors and consequently can inhibit or potentiate type-I Interferon induction according to the danger or microbial stimuli received by plasmacytoid DCs.

Lien vers HAL – hal-04793449

Lien vers le DOI – 10.1101/2024.06.17.599308