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
Department of Oncology, University College London (UCL) Cancer Institute, University College London, London WC1E 6DD, United Kingdom.
Molecular Pharmacology and Cell Biology, Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Berlin 13125, Germany.
Proc Natl Acad Sci U S A. 2025 Jul 22;122(29):e2423358122. doi: 10.1073/pnas.2423358122. Epub 2025 Jul 17.
The organismal roles of the class II PI3K isoform PI3K-C2α remain poorly understood. Recent studies have found PI3K-C2α to promote arterial thrombosis and breast cancer metastasis, generating interest in this kinase as a drug target, with small molecule PI3K-C2α inhibitors now available. However, the consequences of systemic PI3K-C2α inactivation in the nondiseased, postnatal state are largely unknown. Here, we show that induction of genetic PI3K-C2α inactivation in adult mice is well tolerated, without adverse effects on normal physiology. Surprisingly, however, mice with inactive PI3K-C2α 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-C2α. 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-C2α inhibition in principle but reveal an unexpected role for PI3K-C2α in the regulation of extrinsic cell death pathways.
II类磷脂酰肌醇-3激酶同工型PI3K-C2α在生物体中的作用仍知之甚少。最近的研究发现PI3K-C2α可促进动脉血栓形成和乳腺癌转移，这引发了人们对将这种激酶作为药物靶点的兴趣，目前已有小分子PI3K-C2α抑制剂。然而，在非疾病的出生后状态下，全身PI3K-C2α失活的后果在很大程度上尚不清楚。在这里，我们表明，在成年小鼠中诱导遗传性PI3K-C2α失活耐受性良好，对正常生理没有不利影响。然而，令人惊讶的是，PI3K-C2α失活的小鼠对内毒素休克模型细菌脂多糖（LPS）攻击表现出强烈的敏感性。血管内皮特异性缺失PI3K-C2α可重现这种敏感性。此外，联合缺失半胱天冬酶-8和RIPK3以消除外在细胞死亡诱导，可完全挽救对LPS的敏感性。这些观察结果原则上证实了全身PI3K-C2α抑制的耐受性，但揭示了PI3K-C2α在调节外在细胞死亡途径中的意外作用。
