Activating transcription factor 4‐dependent B cell translocation gene‐1 induction promotes ferroptosis

Abstract

Ferroptosis is a special type of programmed cell death that is characterized by iron‐dependent lipid peroxidation. The present study investigated the role of B cell translocation gene‐1 (BTG‐1) on sulfur amino acid deficiency (SAAD)‐mediated cell death. SAAD in HepG2 cells depleted the reduced glutathione, accelerated lipid peroxidation, increased cyclooxygenase 2 expression, and promoted cell death. SAAD‐mediated cell death was specifically inhibited by pretreatment with ferrostain or defroxamine, chemical inhibitors of ferroptosis. In parallel with cell death, SAAD increased expression of microtubule‐associated protein light chain 3‐II and facilitated acridine orange positive autophagic flux. Inhibition of autophagy accelerated the SAAD‐mediated cell death. Moreover, SAAD induced BTG‐1 expression in HepG2 cells. By using BTG‐1 promoter haboring reporter gene and siRNA, activating transcription factor 4 (ATF4) was identified as an essential transcription factor for SAAD‐mediated BTG‐1 induction. Knock out of BTG‐1 gene by CRISPR/Cas9 system decreased the cytotoxicity by SAAD. Furthermore, BTG‐1 deficiency increased microtubule‐associated protein light chain 3‐II and autophagic flux. Thus, present study demonstrates that SAAD induces ferroptosis, and the ATF4‐dependent BTG‐1 induction contributes to accelerate ferroptosis by inhibiting autophagy.Support or Funding InformationThis study was supported by the National Research Foundation of Korea (NRF) funded by Korea government (MSIP)(Grant No. 2018R1A5A2025272 and 2018R1A2B6007514).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.