PAQR3 augments amino acid deprivation-induced autophagy by inhibiting mTORC1 signaling

Abstract

Amino acids are the key activators of the mTOR complex 1 (mTORC1, mainly composed of mTOR, Raptor and mLST8) required for cell growth and proliferation. On the other hand, deprivation of amino acids induces autophagy via inhibition of mTORC1 signaling. We report here that amino acid-induced mTORC1 activity and amino acid deprivation-induced autophagy are regulated by PAQR3, a newly found tumor suppressor. At the cellular level, PAQR3 negatively regulates amino acid-induced activation of mTORC1. The N-terminal end of PAQR3 interacts with the WD domains of Raptor and mLST8 directly. PAQR3 reduces the interaction of mTOR with Raptor and mLST8, thus disrupts formation of intact mTORC1 complex. PAQR3 modulates leucine-induced alteration in cell size. In addition, PAQR3 knockdown reduces amino acid deprivation-induced autophagy. The inhibitory effect of PAQR3 knockdown on autophagy is abrogated by rapamycin treatment, indicating that PAQR3 modulates autophagy via its regulation on mTORC1 signaling. In conclusion, our finding reveals a new mode of regulation of mTORC1 signaling and autophagy by PAQR3 in response to alterations of amino acids.