Hydrogen peroxide induces Beclin 1-independent autophagic cell death by suppressing the mTOR pathway via promoting the ubiquitination and degradation of Rheb in GSH-depleted RAW 264.7 cells

다국어 초록 (Multilingual Abstract)

<P>A novel mechanism for H<SUB>2</SUB>O<SUB>2</SUB>-induced autophagic cell death in GSH-depleted RAW 264.7 cells, a murine macrophage cell line, is proposed. Under GSH-depleted conditions, H<SUB>2</SUB>O<SUB>2</SUB>-induced autophagic cell, characterized by an increased LC3-II/I ratio, a decreased level of p62 and the formation of autophagic vacuoles, was inhibited by bafilomycin A1 and by <I>Atg5</I> siRNA transfection, whereas the cell death was not inhibited by zVAD-fmk, by PI3K inhibitors or by <I>Beclin 1</I> siRNA transfection. In addition, H<SUB>2</SUB>O<SUB>2</SUB> treatment reduced the activity of mTOR and promoted the ubiquitination and degradation of Rheb, a key upstream activator of mTOR. Furthermore, proteasome inhibition with MG132 restored the expression of Rheb and increased mTOR activity, resulting in an increased viability of H<SUB>2</SUB>O<SUB>2</SUB>-treated cells. Collectively, these findings demonstrate that H<SUB>2</SUB>O<SUB>2</SUB> induces Beclin 1-independent autophagic cell death by suppressing the mTOR pathway via promoting the ubiquitination and degradation of Rheb in GSH-depleted RAW 264.7 cells.</P>