Autophagy-related protein 5 and Autophagy-related protein 7 (ATG5 and ATG7)

Autophagy-related protein 5 (ATG5) and Autophagy-related protein 7 (ATG7) are core components of the macroautophagy machinery, essential for the formation of autophagosomes [1, 2]. ATG7 functions as an E1-like activating enzyme that initiates two ubiquitin-like conjugation pathways: the conjugation of ATG12 to ATG5 and the lipidation of ATG8 family proteins (such as LC3) [2, 12]. ATG5, once conjugated to ATG12, forms a multimeric complex with ATG16L1 that acts as an E3-like ligase to facilitate the final step of LC3 lipidation, which is a hallmark of autophagic membrane expansion [1, 7, 20]. Beyond their roles in canonical autophagy, these proteins are involved in LC3-associated phagocytosis (LAP), apoptosis regulation, and immune signaling [1, 2, 13]. In clinical contexts, ATG5 and ATG7 are implicated in various diseases; their deficiency is linked to neurodegenerative disorders like Parkinson's and Alzheimer's due to the accumulation of toxic protein aggregates, while in cancer, they can play dual roles by either suppressing early tumorigenesis or promoting the survival of established tumors under metabolic stress [2, 8, 11]. Therapeutic strategies targeting these proteins include the development of small-molecule inhibitors for ATG7 to sensitize cancer cells to chemotherapy and the exploration of activators to restore autophagic flux in degenerative conditions [8, 14]. However, systemic modulation of ATG5 and ATG7 presents significant safety challenges, as complete loss of function can lead to neonatal lethality, severe neurotoxicity, and metabolic collapse [2, 14].

Other names

APG5APG7hAPG5hAPG7ASP (Apoptosis-specific protein)GSA7Autophagy-related 5Autophagy-related 7SCAR25SCAR31

Inhibition of the E1-like enzymatic activity of ATG7 to block the conjugation of ATG12 to ATG5 and the lipidation of LC3, thereby preventing autophagosome formation and sensitizing cells to stress-induced death [2, 8].