Tumor suppressor gene ARMC5 controls adrenal redox state through NRF1 turnover

Abstract

ARMC5 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 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 ARMC5 inactivation in adrenocortical cell increased expression of actors scavenging ROS, 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, ARMC5 inactivation alters adrenocortical steroidogenesis through activation of p38 pathway and decreases cell sensitivity to ferroptosis participating to increase cell viability. Altogether, this study uncovers a function of ARMC5 as a regulator of the redox homeostasis in adrenocortical cells, controlling steroidogenesis and cell survival.