RNF152 is a transmembrane E3 ubiquitin ligase localized to lysosomal membranes that functions as a negative regulator of mTORC1 signaling and cell survival 1. Its primary mechanism involves mediating K63-linked polyubiquitination of RagA GTPase in response to amino acid starvation, recruiting the GATOR1 inhibitor complex to suppress mTORC1 activation 2. RNF152 also monoubiquitinates RHEB, promoting its association with the TSC-TBC complex for subsequent inhibition 3. Additionally, RNF152 catalyzes K48-linked polyubiquitination targeting proteins for proteasomal degradation 1. RNF152 itself is short-lived, undergoing ESCRT-dependent internalization into the lysosomal lumen for degradation in a conserved mechanism 4. Beyond mTOR regulation, RNF152 promotes ubiquitination and degradation of IRAK1 and Bcl-xL, with emerging roles in cancer biology. In lung adenocarcinoma, RNF152 acts as a tumor suppressor by reducing fatty acid oxidation through IRAK1 degradation 5. In colorectal cancer, RNF152-mediated Bcl-xL degradation sensitizes cells to EGFR-targeted therapies 6. RNF152 overexpression induces apoptosis 1, and emerging therapeutic approaches employ RNF152 as a target for lysosomal protein degradation platforms 7. Tissue-specific expression patterns suggest roles in kidney, nervous system, and colon diseases 8.