文章基本信息

标题：Discovery of a novel SHIP1 agonist that promotes degradation of lipid-laden phagocytic cargo by microglia
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作者：Chiara Pedicone ; Sandra Fernandes ; Alessandro Matera 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2022
卷号：25
期号：4
页码：1-25
DOI：10.1016/j.isci.2022.104170
语种：English
出版社：Elsevier
摘要：SummaryHere, we describe the use of artificial intelligence to identify novel agonists of the SH2-containing 5′ inositol phosphatase 1 (SHIP1). One of the compounds, K306, represents the most potent agonist identified to date. We find that K306 exhibits selectivity for SHIP1 vs. the paralog enzyme SHIP2, and this activation does not require the C2 domain of SHIP1 which other known SHIP1 agonists require. Thus, K306 represents a new class of SHIP1 agonists with a novel mode of agonism. Importantly, we find that K306 can suppress induction of inflammatory cytokines and iNOS in macrophages or microglia, but not by their SHIP1-deficient counterparts. K306 also reduces TNF-α productionin vivoin an LPS-induced endotoxemia assay. Finally, we show that K306 enhances phagolysosomal degradation of synaptosomes and dead neurons by microglia revealing a novel function for SHIP1 that might be exploited therapeutically in dementia.Graphical abstractDisplay OmittedHighlights•Discovery of a potent SHIP1 selective agonist (K306) via artificial intelligence•SHIP1 agonism via K306 is independent of the C2 domain and increases PI(3,4)P2levels•K306 reduces IL-6, TNF-α, and iNOS induction in microglia and macrophages•K306 promotes phagocytic degradation of lipid-laden but not protein cargo in microgliaHealth sciences; Biochemistry; Biochemical mechanism; Cellular neuroscience; Artificial intelligence