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Sestrin-2

Definition:

Functions as an intracellular leucine sensor that negatively regulates the TORC1 signaling pathway through the GATOR complex. In absence of leucine, binds the GATOR subcomplex GATOR2 and prevents TORC1 signaling. Binding of leucine to SESN2 disrupts its interaction with GATOR2 thereby activating the TORC1 signaling pathway. This stress-inducible metabolic regulator also plays a role in protection against oxidative and genotoxic stresses. May negatively regulate protein translation in response to endoplasmic reticulum stress, via TORC1. May positively regulate the transcription by NFE2L2 of genes involved in the response to oxidative stress by facilitating the SQSTM1-mediated autophagic degradation of KEAP1. May also mediate TP53 inhibition of TORC1 signaling upon genotoxic stress. Moreover, may prevent the accumulation of reactive oxygen species (ROS) through the alkylhydroperoxide reductase activity born by the N-terminal domain of the protein. Was originally reported to contribute to oxidative stress resistance by reducing PRDX1. However, this could not be confirmed.

References:

[1]. Rachel L Wolfson, et al. Sestrin2 is a leucine sensor for the mTORC1 pathway. Science. 2016 Jan 1;351(6268):43-8. [Content Brief]

[2]. Hwan-Woo Park, et al. Hepatoprotective role of Sestrin2 against chronic ER stress. Nat Commun. 2014 Jun 20;5:4233. [Content Brief]

[3]. Robert A Saxton, et al. Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway. Science. 2016 Jan 1;351(6268):53-8. [Content Brief]

[4]. Anita Parmigiani, et al. Sestrins inhibit mTORC1 kinase activation through the GATOR complex. Cell Rep. 2014 Nov 20;9(4):1281-91. [Content Brief]

[5]. Andrei V Budanov, et al. p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling. Cell. 2008 Aug 8;134(3):451-60. [Content Brief]

[6]. Dong Wang, et al. E3 ligase RNF167 and deubiquitinase STAMBPL1 modulate mTOR and cancer progression. Mol Cell. 2022 Feb 17;82(4):770-784.e9. [Content Brief]

[7]. Hyun Ae Woo, et al. Sestrin 2 is not a reductase for cysteine sulfinic acid of peroxiredoxins. Antioxid Redox Signal. 2009 Apr;11(4):739-45. [Content Brief]

[8]. Hanseong Kim, et al. Janus-faced Sestrin2 controls ROS and mTOR signalling through two separate functional domains. Nat Commun. 2015 Nov 27;6:10025. [Content Brief]

[9]. Andrei V Budanov, et al. Regeneration of peroxiredoxins by p53-regulated sestrins, homologs of bacterial AhpD. Science. 2004 Apr 23;304(5670):596-600. [Content Brief]

[10]. Travis B Lear, et al. The RING-type E3 ligase RNF186 ubiquitinates Sestrin-2 and thereby controls nutrient sensing. J Biol Chem. 2019 Nov 8;294(45):16527-16534. [Content Brief]

[11]. Lynne Chantranupong, et al. The Sestrins interact with GATOR2 to negatively regulate the amino-acid-sensing pathway upstream of mTORC1. Cell Rep. 2014 Oct 9;9(1):1-8. [Content Brief]

[12]. Soo Han Bae, et al. Sestrins activate Nrf2 by promoting p62-dependent autophagic degradation of Keap1 and prevent oxidative liver damage. Cell Metab. 2013 Jan 8;17(1):73-84. [Content Brief]

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