mTORC1 Phosphorylates UVRAG to Negatively Regulate Autophagosome and Endosome Maturation

mTORC1 plays a key role in autophagy as a negative regulator. The currently known targets of mTORC1 in the autophagy pathway mainly function at early stages of autophagosome formation. Here, we identify that mTORC1 inhibits later stages of autophagy by phosphorylating UVRAG. Under nutrient-enriched conditions, mTORC1 binds and phosphorylates UVRAG. The phosphorylation positively regulates the association of UVRAG with RUBICON, thereby enhancing the antagonizing effect of RUBICON on UVRAG-mediated autophagosome maturation. Upon dephosphorylation, UVRAG is released from RUBICON to interact with the HOPS complex, a component for the late endosome and lysosome fusion machinery, and enhances autophagosome and endosome maturation. Consequently, the dephosphorylation of UVRAG facilitates the lysosomal degradation of epidermal growth factor receptor (EGFR), reduces EGFR signaling, and suppresses cancer cell proliferation and tumor growth. These results demonstrate that mTORC1 engages in late stages of autophagy and endosome maturation, defining a broader range of mTORC1 functions in the membrane-associated processes. [Display omitted] •mTORC1 binds and phosphorylates UVRAG•UVRAG Ser498 phosphorylation by mTORC1 enhances the UVRAG-RUBICON interaction•UVRAG Ser498 phosphorylation suppresses autophagosome and endosome maturation•Prevention of Ser498 phosphorylation enhances the lysosomal degradation of EGFR mTORC1 is known to regulate early stages of autophagy. In this study, Kim et al. report that mTORC1 also regulates late stages of autophagy as well as endosomal maturation by phosphorylating UVRAG. This finding defines a broad range of mTORC1 functions in the membrane-associated processes.