TRIM27 is a RING-mediated E3 ubiquitin ligase that functions as both a positive and negative regulator of autophagy through distinct mechanisms 1. Under normal conditions, TRIM27 negatively regulates autophagy by directly polyubiquitinating ULK1 at K568 and K571 with K48-linked ubiquitin chains, targeting it for proteasomal degradation 2. During starvation, TRIM27 cooperates with STK38L kinase to hyperubiquitinate ULK1, restraining autophagy amplitude and duration 2. Conversely, during Mycobacterium tuberculosis infection, TRIM27 acts as a host protective factor by functioning as a transcription activator of TFEB in an E3 ligase-independent manner 3. TRIM27 enhances CREB1-TFEB promoter binding, promoting autophagy flux activation to clear pathogens 3. TRIM27 also regulates endosomal trafficking through interaction with the WASH complex, controlling actin polymerization and receptor degradation 4. In cancer, TRIM27 ubiquitinates tumor suppressors including PTEN, IκBα and p53, and contributes to cisplatin resistance in esophageal cancer through KLF12 regulation 15. TRIM27 differential regulation of autophagy influences tumorigenesis and metastasis, with knockout mice showing increased basal autophagy levels 2.