Janus-faced Sestrin2 controls ROS and mTOR signalling through two separate functional domains

Abstract

Sestrins are stress-inducible metabolic regulators with two seemingly unrelated but physiologically important functions: reduction of reactive oxygen species (ROS) and inhibition of the mechanistic target of rapamycin complex 1 (mTORC1). How Sestrins fulfil this dual role has remained elusive so far. Here we report the crystal structure of human Sestrin2 (hSesn2), and show that hSesn2 is twofold pseudo-symmetric with two globular subdomains, which are structurally similar but functionally distinct from each other. While the N-terminal domain (Sesn-A) reduces alkylhydroperoxide radicals through its helix–turn–helix oxidoreductase motif, the C-terminal domain (Sesn-C) modified this motif to accommodate physical interaction with GATOR2 and subsequent inhibition of mTORC1. These findings clarify the molecular mechanism of how Sestrins can attenuate degenerative processes such as aging and diabetes by acting as a simultaneous inhibitor of ROS accumulation and mTORC1 activation.

Recent Insights into the Biological Functions of Sestrins in Health and Disease

“…In addition, Sesns have been found to suppress mTOR lysosomal localization in a Rag-dependent manner by interacting with GATOR2 and inhibiting mTORC1 via an AMPK-independent mechanism [8]. The C-terminal domain of Sesn2 accommodates physical interaction with GATOR2 and subsequent inhibition of mTORC1 [4]. Intriguingly, the interaction of Sesns and GATOR2 has been demonstrated to be amino acid-sensitive [9].…”

“…The crystal structure of human Sesn2 (hSesn2) is revealed to contain twofold pseudo-symmetric with two globular subdomains, which contributes to its physiological functions [4]. Due to the helix-turn-helix oxidoreductase motif of N-terminal domain, hSesn2 has the function of reducing alkylhydroperoxide radicals [4]. However, investigations into the structures of Sesn1 and Sesn3 are limited.…”

“…Most vertebrates express all isoforms, while only one is expressed in most invertebrate species [1-3]. The crystal structure of human Sesn2 (hSesn2) is revealed to contain twofold pseudo-symmetric with two globular subdomains, which contributes to its physiological functions [4]. Due to the helix-turn-helix oxidoreductase motif of N-terminal domain, hSesn2 has the function of reducing alkylhydroperoxide radicals [4].…”

Therapeutic Potential of Everolimus on Core Autism Symptoms and Increasing Serum Ceruloplasmin and Transferrin Levels in a Pubescent Boy with Tuberous Sclerosis

“…Because mTOR is closely associated with antioxidant capacity [23,24], serum levels of antioxidant proteins such as Cp, and Tf were measured using a Bering BN Nephelometer (Siemens Healthcare Diagnostics K.K., USA) and a standard turbid metric assay and an automated biochemical analyzer (JCA-BM8000 series, JEOL Ltd., Tokyo, Japan). Interestingly, serum levels of Cp gradually increased from baseline to 16 weeks and then remained higher than the baseline levels ( Figure 2).…”

Le double visage de la Sestrine2 dans les processus pathologiques liés au vieillissement

“…Résolution de la structure de la hSesn2 : un pas en avant vers la compréhension d'une double régulation métabolique La structure de la Sesn2 humaine (hSesn2) -révélée par l'équipe de U.S. Cho en 2015 -est monomérique, pseudo-symétrique et composée de trois domaines [5]. Deux d'entre eux, Sesn-A et C, sont très similaires et adoptent une forme globulaire composée d'hélices α (Figure 1) rait avoir été dupliqué dans hSesn2.…”