Fig. 2: SESN2-regulated molecular network upon oxidative stress.

SESN2 is up-regulated during oxidative stress induced by hydrogen peroxide, methylglyoxal, angiotensin II, etc., which is facilitated by transcription factors including C/EBPβ, HIF-1, p53, Nrf2, AP-1, FoxO3, NF-κB, and ATF4. (i) SESN2 restrains mTORC1 activity through directly binding to GATOR2. GATOR1 is released from GATOR1/2 complex and inactivates Rag A/B via promoting GTP hydrolysis, which prevents mTORC1 binding and recruitment to lysosome. ULK1 is dissociated, then auto-phosphorylates, phosphorylates the complex components including Atg13, FIP200, and Atg101, and promotes autophagy. SESN2 also indirectly inactivates mTORC1 in an AMPK-dependent way. SESN2 promotes AMPK activation and Raptor phosphorylation to inhibit mTORC1 activation. Alternatively, AMPK activation leads to TSC2 phosphorylation and inhibits GTP binding to Rheb, which halts mTORC1 activation. (ii) SESN2-ULK1 interaction promotes the autophagic degradation of Keap1 in a p62/SQSTM1-dependent manner, and accelerates Nrf2 nuclear translocation, which contributes to the formation of Nrf2/Mafs/ARE complex and the expression of downstream antioxidant genes including SESN2. (iii) SESN2 interacts with ULK1 and phosphorylates Beclin1, which anchors Parkin before its location to mitochondria, reinforces PINK1-Parkin interaction, and initiates mitophagy. SESN2 also interacts with Parkin, facilitating its mitochondrial translocation and mitophagy. Alternatively, SESN2 colocalizes with ATP5A on the outer mitochondrial membrane where ATP5A attaches LC3 directly to trigger mitophagy.