SESTRINs: Emerging Dynamic Stress-Sensors in Metabolic and Environmental Health

Abstract

Proper timely management of various external and internal stresses is critical for metabolic and redox homeostasis in mammals. In particular, dysregulation of mechanistic target of rapamycin complex (mTORC) triggered from metabolic stress and accumulation of reactive oxygen species (ROS) generated from environmental and genotoxic stress are well-known culprits leading to chronic metabolic disease conditions in humans. Sestrins are one of the metabolic and environmental stress-responsive groups of proteins, which solely have the ability to regulate both mTORC activity and ROS levels in cells, tissues and organs. While Sestrins are originally reported as one of several p53 target genes, recent studies have further delineated the roles of this group of stress-sensing proteins in the regulation of insulin sensitivity, glucose and fat metabolism, and redox-function in metabolic disease and aging. In this review, we discuss recent studies that investigated and manipulated Sestrins-mediated stress signaling pathways in metabolic and environmental health. Sestrins as an emerging dynamic group of stress-sensor proteins are drawing a spotlight as a preventive or therapeutic mechanism in both metabolic stress-associated pathologies and aging processes at the same time.

Keywords: ROS; Sestrins; aging; cancer; environmental stress; mTORC; metabolic disease; obesity/inflammation.

FIGURE 1

Diagrams depicting the Sestrins-mediated stress signaling pathways and functional domains of Sestrin2 in the regulation of metabolism and disease. (A) Schematic diagram of Sestrins/mTORC/ROS pathways in obesity and metabolic diseases induced by metabolic dysregulation stress. Sestrins improve insulin sensitivity by blocking mTORC1/ribosomal protein S6 kinase 1(S6K1) and activating AMPK and mTORC1/AKT pathway. Sestrins also inhibit lipid accumulation and ER stress via mTORC1 inhibition through activating AMPK and binding GATOR2. Sestrins activate autophagy and mitophagy through mTORC1 inhibition and ULK1 activation, which contributes to reducing ROS and removing dysfunctional mitochondria. ULK1 phosphorylates Sestrin2 to induce mitophagy, and phosphorylated Sestrin2 activates ULK1 to further induce autophagy as positive feedback mechanism. Sestrins protect cells, tissues and organs by alleviating stresses and pathologies associated with obesity and metabolic dysfunctions. (B) Sestrin2 functional domains (Sesn-A, Sesn-B, and Sesn-C domains) and residues for: (i) protein stability and turnover through ubiquitinations by RNF186 and RBX-1; (ii) redox homeostasis through ROS regulation (Cys125); and (iii) nutrient sensing and regulation through leucine binding, ULK1 activation, and autophagy induction.

FIGURE 2

Diagrams depicting the roles of Sestrins in managing stress levels and health conditions. (A) Diagram depicting the possible roles of Sestrins in the regulation of ROS and autophagy in mammalian cells. (Normal condition) Redox-active function of Sestrins may suppress highly reactive damaging ROS and maintain pleiotropic ROS level such as mitohormesis in mammalian cells under normal nutrient and environmental factors. (Stress condition) Sestrins are induced by metabolic or genotoxic stresses such as overnutrition and oxidative damage. Chronic activation of mTORC1 may induce chronic excessive ROS, which results in aging-associated phenotypes such as fat accumulation, mitochondrial dysfunction, inflammation, and oxidative damage in mammalian cells. However, Sestrins inhibit mTORC1 activity and subsequently induce or regulate autophagy activity in the cells and tissues. Activated autophagy removes oxidized proteins and also clear damaged mitochondria which are producing excessive harmful ROS. Overall, Sestrins-mediated autophagy regulates the ROS level to trigger redox adaptations under stress conditions. The underlying mechanism of how pleiotropic level of ROS is maintained by Sestrins-mediated autophagy signaling pathway needs further investigation. (B) Graphic diagram explaining the correlation between Sestrins and stress levels in health and disease conditions.