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) | |
Genotoxic stress | p53, FoxO3 | Sesn1/2/3 | AMPK/mTOR, AMPK/TOR, p-Beclin1-Parkin, JNK, PGC-1α | DNA repair | |
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 | |
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 | |
Hypoxia | p53, HIF-1, PI3K/Akt | Sesn2 | VEGF, AMPK-PHD | Reduce hypoxic damage | |
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 | |
Autophagy dysregulation | AMPK/mTORC1, p53 | Sesn2 | AMPK/mTOR, PI3K/Akt/mTOR, AMPKα, mTORC1-ULK1-S6, autophagy protein p62/SQSTM1, | Autophagy induction | |
Mitochondrial dysfunction | ATF4, RBX1, p53 | Sesn2 | AMPK/mTOR, AMPK/TOR, p-Beclin1-Parkin, JNK, PGC-1α | Mitophagy induction | |
Immune dysregulation | AMPK/mTORC1 | Sesn2 | NLRP3 inflammasome; Erk-JNK-p38 MAPK; AP-1, ULK1, SQSTM1, AMPK/ERs | Hyper-inflammation; T-cell senescence; anti-inflammation |