Carpentieri Giovanna, Leoni Chiara, Pietraforte Donatella, Cecchetti Serena, Iorio Egidio, Belardo Antonio, Pietrucci Daniele, Di Nottia Michela, Pajalunga Deborah, Megiorni Francesca, Mercurio Laura, Tatti Massimo, Camero Simona, Marchese Cinzia, Rizza Teresa, Tirelli Valentina, Onesimo Roberta, Carrozzo Rosalba, Rinalducci Sara, Chillemi Giovanni, Zampino Giuseppe, Tartaglia Marco, Flex Elisabetta
Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome 00146, Italy.
Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome 00161, Italy.
Hum Mol Genet. 2022 Feb 21;31(4):561-575. doi: 10.1093/hmg/ddab270.
Germline-activating mutations in HRAS cause Costello syndrome (CS), a cancer prone multisystem disorder characterized by reduced postnatal growth. In CS, poor weight gain and growth are not caused by low caloric intake. Here, we show that constitutive plasma membrane translocation and activation of the GLUT4 glucose transporter, via reactive oxygen species-dependent AMP-activated protein kinase α and p38 hyperactivation, occurs in primary fibroblasts of CS patients, resulting in accelerated glycolysis and increased fatty acid synthesis and storage as lipid droplets. An accelerated autophagic flux was also identified as contributing to the increased energetic expenditure in CS. Concomitant inhibition of p38 and PI3K signaling by wortmannin was able to rescue both the dysregulated glucose intake and accelerated autophagic flux. Our findings provide a mechanistic link between upregulated HRAS function, defective growth and increased resting energetic expenditure in CS, and document that targeting p38 and PI3K signaling is able to revert this metabolic dysfunction.
HRAS基因的种系激活突变会导致科斯特洛综合征（CS），这是一种易患癌症的多系统疾病，其特征是出生后生长发育迟缓。在CS患者中，体重增加和生长发育不良并非由热量摄入不足引起。在此，我们发现，在CS患者的原代成纤维细胞中，通过活性氧依赖性的AMP激活蛋白激酶α和p38过度激活，葡萄糖转运蛋白4（GLUT4）会持续发生质膜易位并被激活，导致糖酵解加速，脂肪酸合成增加，并以脂滴形式储存。加速的自噬通量也被确定为导致CS患者能量消耗增加的原因之一。渥曼青霉素对p38和PI3K信号通路的同时抑制能够挽救葡萄糖摄取失调和自噬通量加速的问题。我们的研究结果揭示了CS中HRAS功能上调、生长缺陷和静息能量消耗增加之间的机制联系，并证明靶向p38和PI3K信号通路能够逆转这种代谢功能障碍。
