Autophagy-related protein complexes (ATG complexes)

Autophagy-related protein complexes constitute the core molecular machinery responsible for macroautophagy, an evolutionarily conserved catabolic process that degrades and recycles cytoplasmic components [3, 15]. This machinery is organized into several functional modules, including the ULK1 initiation complex, the Class III PI3K (VPS34) nucleation complex, and the ATG12-ATG5-ATG16L1 conjugation system [3, 8, 11]. These complexes work in a coordinated sequence to form the autophagosome, a double-membrane vesicle that sequesters cargo for delivery to the lysosome [7, 15]. Autophagy plays a vital role in maintaining cellular health by removing damaged organelles, misfolded proteins, and intracellular pathogens, especially during metabolic stress [1, 10]. In clinical contexts, these complexes are targeted for their roles in cancer, where autophagy can promote tumor survival and drug resistance, and in neurodegenerative diseases, where impaired autophagy leads to the accumulation of toxic protein aggregates [2, 4, 16, 17]. Therapeutic strategies involve either inhibiting these complexes to sensitize cancer cells or activating them to enhance the clearance of pathogenic proteins [5, 15, 17]. Drugs such as ULK1 and VPS34 inhibitors are being developed to block the early stages of autophagosome formation [7, 20, 23]. Conversely, mTOR inhibitors and AMPK activators are used to induce autophagy in conditions where its activity is beneficial [4, 10, 18]. Monitoring autophagic flux through biomarkers like LC3-II and p62 is essential for evaluating the efficacy of these therapeutic interventions [2, 19, 24].

Other names

Autophagy machineryCore autophagy proteinsATG proteinsAutophagy initiation complexULK1 complexVPS34 complexATG12-ATG5-ATG16L1 complex

Modulation of autophagic flux through inhibition of initiation kinases (ULK1, VPS34), blockade of autophagosome-lysosome fusion, or indirect activation via nutrient-sensing pathways (mTOR, AMPK).