Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France.
Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ), University of Zurich (UZH), Zurich, Switzerland.
Endocr Relat Cancer. 2022 Sep 30;29(11):615-624. doi: 10.1530/ERC-22-0099. Print 2022 Nov 1.
is a tumor suppressor gene frequently mutated in primary bilateral macronodular adrenal hyperplasia (PBMAH), an adrenal cause of Cushing's syndrome. The function of ARMC5 is poorly understood, aside from the fact that it regulates cell viability and adrenal steroidogenesis by mechanisms still unknown. Tumor suppressor genes play an important role in modifying intracellular redox response, which in turn regulates diverse cell signaling pathways. In this study, we demonstrated that inactivation in adrenocortical cells increased the expression of actors scavenging reactive oxygen species, such as superoxide dismutases (SOD) and peroxiredoxins (PRDX) by increasing the transcriptional regulator NRF1. Moreover, ARMC5 is involved in the NRF1 ubiquitination and in its half-life. Finally, inactivation alters adrenocortical steroidogenesis through the activation of p38 pathway and decreases cell sensitivity to ferroptosis participation to increase cell viability. Altogether, this study uncovers a function of ARMC5 as a regulator of redox homeostasis in adrenocortical cells, controlling steroidogenesis and cell survival.
是一种肿瘤抑制基因，常发生突变于双侧巨结节性肾上腺增生症（PBMAH），即库欣综合征的肾上腺病因。ARMC5 的功能除了通过尚不清楚的机制调节细胞活力和肾上腺类固醇生成外，了解甚少。肿瘤抑制基因在调节细胞内氧化还原反应中发挥着重要作用，而细胞内氧化还原反应又反过来调节多种细胞信号通路。在这项研究中，我们证明了在肾上腺皮质细胞中失活会通过增加转录调节因子 NRF1 的表达，来增加清除活性氧的因子（如超氧化物歧化酶[SOD]和过氧化物酶[PRDX]）的表达。此外，ARMC5 参与 NRF1 的泛素化及其半衰期。最后，失活通过激活 p38 通路改变肾上腺皮质类固醇生成，并降低细胞对铁死亡的敏感性，从而增加细胞活力。总之，这项研究揭示了 ARMC5 作为肾上腺皮质细胞氧化还原平衡调节剂的功能，控制类固醇生成和细胞存活。
