Email this page

Print this page

Basic Research Paper

ER stress negatively regulates AKT/TSC/mTOR pathway to enhance autophagy

Liang Qin, Zheng Wang, Lianyuan Tao and Yun Wang

Disturbance to endoplasmic reticulum (ER) homeostasis that can not be rescued by the unfolded protein response (UPR) results in autophagy and cell death, but 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-I to LC3-II, a commonly used marker of autophagy, as well as the downregulation of mTOR concurrently. 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.

Authors

Liang Qin Corresponding author: liangqin2@gmail.com

Departments of Physiology & Pathology; Institute of Basic Medical Sciences & School of Basic Medicine; Chinese Academy of Medical Sciences and Peking Union Medical College; Beijing, China

Zheng Wang

Department of Medical Genetics; Institute of Basic Medical Sciences & School of Basic Medicine; Chinese Academy of Medical Sciences and Peking Union Medical College; Beijing, China

Lianyuan Tao

Department of General Surgery; Peking Union Medical College Hospital; Chinese Academy of Medical Sciences and Peking Union Medical College; Beijing, China

Yun Wang

Department of Medical Genetics; Institute of Basic Medical Sciences & School of Basic Medicine; Chinese Academy of Medical Sciences and Peking Union Medical College; Beijing, China