Che-1-induced inhibition of mTOR pathway enables stress-induced autophagy

Mammalian target of rapamycin (mTOR) is a key protein kinase that regulates cell growth, metabolism, and autophagy to maintain cellular homeostasis. Its activity is inhibited by adverse conditions, including nutrient limitation, hypoxia, and DNA damage. In this study, we demonstrate that Che-1, a RNA polymerase II-binding protein activated by the DNA damage response, inhibits mTOR activity in response to stress conditions. We found that, under stress, Che-1 induces the expression of two important mTOR inhibitors, Redd1 and Deptor, and that this activity is required for sustaining stress-induced autophagy. Strikingly, Che-1 expression correlates with the progression of multiple myeloma and is required for cell growth and survival, a malignancy characterized by high autophagy response. Synopsis The RNA polymerase-binding protein Che-1 inhibits the mTOR pathway in response to stress, thereby sustaining autophagy and multiple myeloma cell growth. Che-1 inhibits mTOR activity in response to cellular stress. Che-1 sustains Redd1 and Deptor expressions. Che-1 regulates autophagy by inhibiting mTORC1 activity. Che-1 expression increases during multiple myeloma progression and is required for cell survival. The RNA polymerase-binding protein Che-1 inhibits the mTOR pathway in response to stress, thereby sustaining autophagy and multiple myeloma cell growth.