Sestrin2 as a Novel Biomarker and Therapeutic Target for Various Diseases

Abstract

Sestrin2 (SESN2), a highly conserved stress-inducible metabolic protein, is known to repress reactive oxygen species (ROS) and provide cytoprotection against various noxious stimuli including genotoxic and oxidative stress, endoplasmic reticulum (ER) stress, and hypoxia. Studies demonstrate that the upregulation of Sestrin2 under conditions of oxidative stress augments autophagy-directed degradation of Kelch-like ECH-associated protein 1 (Keap1), which targets and breaks down nuclear erythroid-related factor 2 (Nrf2), a key regulator of various antioxidant genes. Moreover, ER stress and hypoxia are shown to induce Sestrins, which ultimately reduce cellular ROS levels. Sestrin2 also plays a pivotal role in metabolic regulation through activation of the key energy sensor AMP-dependent protein kinase (AMPK) and inhibition of mammalian target of rapamycin complex 1 (mTORC1). Other downstream effects of Sestrins include autophagy activation, antiapoptotic effects in normal cells, and proapoptotic effects in cancer cells. As perturbations in the aforementioned pathways are well documented in multiple diseases, Sestrin2 might serve as a potential therapeutic target for various diseases. Thus, the aim of this review is to discuss the upstream regulators and the downstream effectors of Sestrins and to highlight the significance of Sestrin2 as a biomarker and a therapeutic target in diseases such as metabolic disorders, cardiovascular and neurodegenerative diseases, and cancer.

Figure 1

Role of Sestrin2 in redox balance. Cellular homeostasis is achieved by counteracting the production of reactive oxygen species (ROS) with antioxidant molecules. Hypoxia, starvation, cancer, and genotoxic stress induce oxidative stress in cells and tip the cellular redox balance towards a pro-oxidant state. Sestrins help cells to restore their normal redox state through various mechanisms including stabilization of Nrf2 via the inhibition of Keap1 and recycling of peroxiredoxin (Prx). Keap1: Kelch-like ECH-associated protein 1; Nrf2: nuclear factor (erythroid-derived 2-) like 2.

Figure 2

Upregulation of Sestrin2 under endoplasmic reticulum stress, genotoxic stress, and hypoxia. UPR mediators play a significant role in ER stress-mediated upregulation of Sestrin2. Two of the three UPR mediators, IRE1 (via XBP1) and PERK (through P-eIF2 and Nrf2), upregulate Sestrin2. Similarly, independent of ER stress, p53 (in response to genotoxic stress) and hypoxia also activate Sestrin2 expression. ATF4: activating transcription factor 4; ATF6: activating transcription factor 6; IRE1: inositol-requiring enzyme 1; NRF2: nuclear factor (erythroid-derived 2-) like 2; P-eIF2: phosphorylated eukaryotic initiation factor 2; PERK: protein kinase RNA-like endoplasmic reticulum kinase; UPR: unfolded protein response; XBP1: X-box-binding protein-1.

Figure 3

Modulation of AMPK and mTOR pathway by Sestrins. Activation of mTOR signaling induces reactive oxygen species (ROS) generation, inhibits autophagy, and promotes protein synthesis and cell proliferation. Sestrins downregulate mTOR signaling pathway and activate AMPK signaling, which in turn relieves autophagy inhibition and reduces protein synthesis and cell proliferation. In addition, Sestrins decrease ROS generation through the inhibition of NAPDH oxidase 4- (NOX4-) dependent ROS generation pathway. 4EBP1: eukaryotic translation initiation factor 4E-binding protein 1; ATG1: autophagy-related protein 1; S6K: ribosomal protein S6 kinase; TSC1/2: tuberous sclerosis complex 1 and 2; ULK1: unc-51-like autophagy-activating kinase 1.

Figure 4

Protective effects of Sestrins in cardiovascular diseases, metabolic disorders, neurodegenerative diseases, and cancer. The antioxidant effects of Sestrins are primarily responsible for their protective effects against neurodegenerative diseases and other disease states associated with significant accumulation of ROS. Additionally, by modulating mTOR/AMPK signaling pathway by Sestrin2 indirectly represses tumor growth and activates autophagy. Consequently, autophagy activation confers a protective role of metabolic and heart diseases and aging. ATG1/13: autophagy-related protein 1 and 13; mTOR: mammalian target of rapamycin.

Figure 5

Sestrins inhibit ROS generation and mTOR activation and augment AMPK signaling and antioxidant levels in cells. These modulatory effects of Sestrins make them an attractive therapeutic target and a biomarker in various diseases such as neurodegenerative diseases, metabolic disorders, cardiovascular diseases, and cancer. AMPK: AMP-dependent protein kinase; mTOR: mammalian target of rapamycin; ROS: reactive oxygen species.