INPP5D inhibits anti-malarial immunity by promoting IRF3 degradation through selective autophagy

As a member of the inositol polyphosphate-5-phosphatase family, INPP5D (inositol polyphosphate-5-phosphatase D) is an important regulator of immune cell activation. To date, the mechanisms underlying anti-malarial immunity have not been elucidated. We recently identified INPP5D as a negative regulator of IFN-I (type I interferon) signaling by promoting autophagic degradation of IRF3 (interferon regulatory factor 3) during malaria infection. Mechanistically, INPP5D enhances the association between IRF3 and the autophagy receptor CALCOCO2/NDP52 (calcium binding and coiled-coil domain 2), which promotes the K63-linked ubiquitination of IRF3 at K313 and serves as a signal for CALCOCO2-dependent selective macroautophagy (hereafter autophagy). Moreover, INPP5D is downregulated by IFN-I-induced miR-155-5p after Plasmodium yoelii (P. yoelii) nigeriensis N67 infection and plays a role as a feedback loop between IFN-I signaling and autophagy. Thus, our study reveals the key role of INPP5D in mediating the crosstalk between IFN-I response and autophagy during anti-malarial immune responses, and suggests that INPP5D may be a potential therapeutic target to control malaria. Abbreviations: ATG5; autophagy-related 5; CALCOCO2/NDP52, calcium binding and coiled-coil domain 2; CQ, chloroquine; INPP5D/SHIP1, inositol polyphosphate-5-phosphatase D; IRF3, interferon regulatory factor 3; IFN-I, type I interferon; 3-MA, 3-methyladenine.