Endoplasmic Reticulum Stress, Autophagy, The Akt-tsc-mtor Signaling Pathway

The endoplasmic reticulum (ER) is an essential intracellular organelle providing apparatus for synthesizing nascent proteins as well as their further modification and correct folding. A variety of factors could disturb the homeostasis of ER, called ER stress. Several downstream signaling pathways could be induced to respond ER stress, and finally result in the restoration of the homeostasis. However, ER stress that can not be rescued results in autophagy and cell death, while the precise mechanism was largely unknown. Here we demonstrated that ER stress-induced cell death was mediated by autophagy which was partly attributed to the inactivation of the mammalian target of rapamycin (mTOR).Three widely used ER stress inducers including tunicamycin, DTT and MG132 led to the conversion of LC3-Ⅰto LC3-Ⅱ, a commonly used marker of autophagy, as well as the downregulation of mTOR concurrently. The presence of autophagy inhibitor greatly improved cell survival under ER stress. TSC-deficient cells with constitutive activation of mTOR exhibited more resistance to ER stress-induced autophagy, compared with their wild-type counterparts. Furthermore, our studies showed that ER stress-induced deactivation of mTOR was attributed to the downregulation of AKT/TSC/mTOR pathway. Phosphatase and tensin homolog (PTEN) and AMP-activated protein kinase (AMPK) as two regulators in this pathway seemed to be absent in this regulation. As a chemical chaperone helping the correct folding of proteins,4-phenylbutyric acid (4-PBA) partly rescued AKT/TSC/mTOR pathway in drug-induced acute ER stress.Moreover, constitutively-activated mTOR-induced long-term ER stress attenuated RTK/PI3K/AKT signaling pathway in response to the stimulation by various growth factors, which could also be partly restored by 4-PBA. Considering the recent report that constitutive activation of mTOR triggers ER stress, our study may help propose a signaling pathway responsible for ER stress-induced autophagy and a novel mechanism accounting for the negative feedback from mTOR to AKT.