{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n ATG3 is a critical E2‐like enzyme in the autophagy machinery that mediates the conjugation of Atg8/LC3 family proteins to phosphatidylethanolamine, a modification required for autophagosome membrane expansion and maturation. In mammalian cells, ATG3 performs this lipidation reaction in collaboration with the E1‐like enzyme ATG7 and is essential for the generation of LC3 lipidation intermediates; disruption of ATG3 results in a complete block in LC3 conjugation and impairs proper autophagosome formation, as demonstrated by neonatal lethality and autophagosome defects in ATG3‐deficient mice."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition, ATG3 interacts with the ATG12–ATG5 conjugate, and a subset of ATG3 molecules becomes covalently modified by ATG12. This ATG12–ATG3 conjugate appears not to be strictly required for starvation‐induced autophagy but rather plays important roles in regulating mitochondrial homeostasis, endolysosomal trafficking, and even noncanonical cell death pathways associated with mitochondrial apoptosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, ATG3 function is influenced by membrane properties; it preferentially catalyzes the lipidation of LC3 on membranes presenting lipid‐packing defects or high curvature. This biophysical requirement ensures efficient modification of LC3 at specific sites on the growing phagophore and underscores a regulatory mechanism by which local membrane stress may promote autophagosome formation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its biochemical role in LC3 conjugation, ATG3 is also involved in noncanonical autophagy‐dependent signaling events. For instance, depletion of ATG3 suppresses caspase‐8 activation during stress‐induced cell death, thereby linking its function to the cross‐talk between autophagy and apoptosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " In addition, evidence in immune cells indicates that ATG3‐dependent autophagic processes contribute to mitochondrial quality control, which is critical for the generation and maintenance of memory natural killer cells."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, early studies that cloned the human homologue of yeast Apg3 (hApg3p) confirmed its essential activity as an E2‐like enzyme dedicated to the lipidation of multiple Atg8 family members, further emphasizing its central role in autophagy initiation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Overall, ATG3 emerges as a multifaceted enzyme that not only drives the canonical lipidation of LC3—thereby facilitating autophagosome biogenesis—but also participates in additional regulatory pathways that influence mitochondrial homeostasis, endosomal trafficking, and apoptotic signaling.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Yu-shin Sou, Satoshi Waguri, Jun-ichi Iwata, et al. 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