Oncotarget | https://doi.org/10.18632/oncotarget.27367 Boxiao Ding, Alexander Haidurov, Ayesha Chawla, Anita Parmigiani, Gerarda van de Kamp, Alexandra Dalina, Fang Yuan, Jun Hee Lee, Peter M. Chumakov, Steven R....

Sestrins are a conserved family of stress-responsive proteins that play a crucial role in cellular metabolism, stress response, and ageing. Vertebrates have three Sestrin genes (SESN1, SESN2, and SESN3), while invertebrates encode only one. Initially identified as antioxidant proteins that regulate cell viability, Sestrins are now recognised as crucial inhibitors of the mechanistic target of rapamycin complex 1 kinase (mTORC1), a central regulator of anabolism, cell growth, and autophagy. Sestrins suppress mTORC1 through an inhibitory interaction with the GATOR2 protein complex, which, in concert with GATOR1, signals to inhibit the lysosomal docking of mTORC1. A leucine-binding pocket (LBP) is found in most vertebrate Sestrins, and when bound with leucine, Sestrins do not bind GATOR2, prompting mTORC1 activation. This review examines the evolutionary conservation of Sestrins and their functional motifs, focusing on their origins and development. We highlight that the most conserved regions of Sestrins are those involved in GATOR2 binding, and while analogues of Sestrins exist in prokaryotes, the unique feature of eukaryotic Sestrins is their structural presentation of GATOR2-binding motifs.

Sestrins are an evolutionarily conserved family of stress-responsive proteins that regulate cellular metabolism, redox balance, and survival. Their expression is induced by diverse cellular stresses through activation of transcription factors such as p53, NRF2, and FOXO. Through antioxidant activity and modulation of mTORC1 and mTORC2 signalling, Sestrins limit the accumulation of reactive oxygen species, regulate metabolic pathways, and promote autophagy. In this review, we analyse published studies reporting SESN1, SESN2, and SESN3 expression in human tissues, circulation, and experimental disease models. The available evidence indicates that Sestrin levels are dynamically regulated across multiple pathologies, including metabolic, ageing, cardiovascular, inflammatory, neurodegenerative, and degenerative disorders. Notably, changes in tissue Sestrin expression are often mirrored in circulation. These observations suggest that Sestrins may serve as informative biomarkers of cellular stress and disease states, and that monitoring their expression in tissues or blood could provide insight into disease progression and therapeutic response.

Sestrins (SESN1-3) are a family of stress-responsive proteins that regulate cellular metabolism and redox balance, both of which are frequently disrupted in cancer. As direct targets of stress-responsive transcription factors, including tumour suppressor p53, Sestrins function as leucine-dependent inhibitors of mTORC1 and potent antioxidants. Their downregulation is widely observed across multiple cancers and is associated with increased tumour growth and poor prognosis. Despite their consistent tumour-suppressive effects through mTORC1 inhibition and promotion of p53-dependent apoptosis, Sestrins exhibit a limited role in tumour initiation, which appears to be context-dependent. Their antioxidant activity reduces oxidative damage, thereby protecting against genomic instability and other cancer-promoting events. However, in certain contexts, Sestrins may promote tumour survival and progression by stimulating pro-survival pathways, such as AKT signalling through mTORC2 activation. This review examines the molecular mechanisms underlying these dual functions, with a particular focus on mTOR signalling and oxidative stress. We also discuss Sestrin expression patterns and functional outcomes in various cancer types, including lung, liver, colon, skin, prostate, and follicular lymphomas, highlighting their potential as diagnostic markers and therapeutic targets.