Inactivation of PI3K-C2α deregulates cell death pathways and sensitizes to endotoxic shock

• 成果类型: Article
• 署名作者: Posor, York; Conduit, Sarah E.; Pearce, Wayne; Morelli, Daniele; Constantinou, Georgia; Whitehead, Maria; Sebire, Neil J.; Scudamore, Cheryl L.; Peltzer, Nieves; Walczak, Henning; Vanhaesebroeck, Bart
• 署名单位: University of London; University College London; Leibniz Association; Leibniz Forschungsinstitut furr Molekulare Pharmakologie (FMP); University of London; University College London; University of Cologne; University of Cologne; University of Stuttgart; University of Cologne
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9178
• DOI: 10.1073/pnas.2423358122
• 发表日期: 2025-07-22
• 关键词: noncanonical inflammasome activation; class-ii pi3k-c2-alpha; receptor endocytosis; in-vivo; caspase-8; apoptosis; fas; mice; requirement; expression

摘要

The organismal roles of the class II PI3K isoform PI3K-C2 alpha remain poorly understood. Recent studies have found PI3K-C2 alpha to promote arterial thrombosis and breast cancer metastasis, generating interest in this kinase as a drug target, with small molecule PI3K-C2 alpha inhibitors now available. However, the consequences of systemic PI3K-C2 alpha inactivation in the nondiseased, postnatal state are largely unknown. Here, we show that induction of genetic PI3K-C2 alpha inactivation in adult mice is well tolerated, without adverse effects on normal physiology. Surprisingly, however, mice with inactive PI3K-C2 alpha display strong sensitization to challenge with bacterial lipopolysaccharide (LPS), a model of endotoxic shock. This sensitization is recapitulated by vascular endothelial-specific deletion of PI3K-C2 alpha. Furthermore, sensitization to LPS can be fully rescued by disabling extrinsic induction of cell death by combined caspase-8-and RIPK3 deficiency.These observations validate the tolerability of systemic PI3K-C2 alpha inhibition in principle but reveal an unexpected role for PI3K-C2 alpha in the regulation of extrinsic cell death pathways.