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Table 2 Biological functions of sestrins in pathophysiological processes

From: The functions and roles of sestrins in regulating human diseases

Conditions Upstream pathways Sestrins Downstream pathways Functions References
Oxidative stress p53, Nrf2/ARE, FoxO1, FoxO3, JNK/AP-1, PERK-C/EBPβ, NMDA receptor Sesn1/2/3 AMPK/mTORC1, Nrf2,
peroxiredoxin AhpC, Nox4, PDGFRβ, p38 MAPK, dopamine D2 receptor, and FoxO1
Increased expression of antioxidant enzymes (trigger antioxidant response) [1, 14, 35, 36, 38,39,40,41,42,43,44]
Genotoxic stress p53, FoxO3 Sesn1/2/3 AMPK/mTOR, AMPK/TOR, p-Beclin1-Parkin, JNK, PGC-1α DNA repair [8, 48]
Carcinogenesis p53 Sesn2 mTORC2/Akt Oncogenesis [53]
Hypernutrition Glucose, insulin, fatty acid, and triglyceride Sesn1/2/3 AMPK, mTORC1-S6K, mTORC2/Akt Maintain lipid and glucose homeostasis [1, 13, 22, 57, 58]
Nutrient starvation ATF4, Nrf2, JNK/ c-Jun, FoxO1, FoxO3, PGC-1α Sesn1/2 mTORC1 Inhibition of necrosis and apoptosis in cells, represses majority of protein translation, growth regulation, autophagy induction, regulate cellular energy homeostasis [35, 37]
Hypoxia p53, HIF-1, PI3K/Akt Sesn2 VEGF, AMPK-PHD Reduce hypoxic damage [6, 8, 54, 68]
ER stress PERK, PERK-C/EBPβ, ATF4/Nrf2, IRE1/XBP1, ATF6 Sesn2 AMPK/mTORC1, c/EBP homologous protein, p38, JNK, UPR, PERK-ATF4-CHOP Maintains autophagy homeostasis and prevents apoptosis [71,72,73,74,75,76,77,78,79]
Autophagy dysregulation AMPK/mTORC1, p53 Sesn2 AMPK/mTOR, PI3K/Akt/mTOR, AMPKα, mTORC1-ULK1-S6, autophagy protein p62/SQSTM1, Autophagy induction [1, 15, 82, 83]
Mitochondrial dysfunction ATF4, RBX1, p53 Sesn2 AMPK/mTOR, AMPK/TOR, p-Beclin1-Parkin, JNK, PGC-1α Mitophagy induction [85,86,87]
Immune dysregulation AMPK/mTORC1 Sesn2 NLRP3 inflammasome; Erk-JNK-p38 MAPK; AP-1, ULK1, SQSTM1, AMPK/ERs Hyper-inflammation; T-cell senescence; anti-inflammation [62, 75, 79, 85, 89,90,91, 94,95,96,97]
  1. Sesn, sestrin; Nrf2, nuclear factor erythroid 2-related factor 2; ARE, antioxidant responsive element; FoxO, forkhead box protein O; JNK, c-Jun N-terminal kinase; AP-1, activator protein 1; PERK, protein kinase RNA-like endoplasmic reticulum kinase; C/EBPβ, CCAAT/enhancer-binding protein beta; NMDA, N-methyl-d-aspartate; AMPK, AMP-activated protein kinase; mTORC1, mechanistic target of rapamycin complex 1; Nox4, NADPH oxidase 4; PDGFRβ, platelet-derived growth factor receptor beta; MAPK, mitogen-activated protein kinase; Beclin1, mammalian homolog of yeast ATG6; PGC-1α, peroxisome proliferator-activated receptor-gamma coactivator alpha; mTORC2, mechanistic target of rapamycin complex 2; S6K, ribosomal protein S6 kinase; HIF1, hypoxia-inducible factor 1; PI3K, phosphoinositide 3-kinase; PHD, prolyl hydroxylase; ATF4, activating transcription factor 4; IRE1, inositol-requiring enzyme 1; XBP1, X-box binding protein 1; ATF6, activating transcription factor 6; UPR, unfolded protein response; PERK, PKR-like ER kinase; CHOP, C/EBP homologous protein; ULK1, unc-51 like autophagy activating kinase 1; SQSTM1, sequestosome 1; RBX1, ring-box 1; NLRP3, Nod-like receptor family pyrin domain containing 3; Erk, extracellular signal-regulated kinase; ERs, estrogen receptors