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] |