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.
Highlights
Sestrins (SESN) are highly conserved proteins with pleiotropic biological functions and are upregulated in cells under stressful conditions such as DNA damage, hypoxia, starvation, growth factor depletion, radiation, and oxidative stress [1, 2]
Apart from its actions mediated through AMP-dependent protein kinase (AMPK), Sestrins act as inhibitors of GTPaseactivating protein for Rag (Rag GTPases), which are important for mammalian target of rapamycin complex 1 (mTORC1) activity
It is critical to understand the role of Sestrins in the modulation of pathophysiologic mechanisms such as oxidative stress, autophagy, endoplasmic reticulum (ER) stress, apoptosis, and hypoxia, which are closely linked to altered mammalian target of rapamycin (mTOR)/ AMPK signaling in cells
Summary
Sestrins (SESN) are highly conserved proteins with pleiotropic biological functions and are upregulated in cells under stressful conditions such as DNA damage, hypoxia, starvation, growth factor depletion, radiation, and oxidative stress [1, 2]. Following their induction, Sestrins protect cells against genotoxic and oxidative stress and are, named as stressinducible metabolic regulators [1]. Sestrin proteins comprise of three distinct family members, characterized by specific protein-coding genes such as SESN1, SESN2, and SESN3, which share nearly 50% identical amino acid sequences [1, 3] Despite their genetic homology, identification of the specific biochemical functions of each Sestrin was challenging, as their protein structure contains an atypical structural domain. SESN3 is as a novel PA26 structure-related gene inducible by the forkhead box O (FoxO) family of transcription factors [6]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
