The C. elegans LC3 acts downstream of GABARAP to degrade autophagosomes by interacting with the HOPS subunit VPS39

Abstract

The formation of the autophagic vesicles requires the recruitment of ubiquitin-like Atg8 proteins to the membrane of nascent autophagosomes. Seven Atg8 homologs are present in mammals, split into the LC3 and the GABARAP/GATE-16 families, whose respective functions are unknown. Using Caenorhabditis elegans, we investigated the functions of the GABARAP and the LC3 homologs, LGG-1 and LGG-2, in autophagosome biogenesis. Both LGG-1 and LGG-2 localize to the autophagosomes but display partially overlapping patterns. During allophagy, a developmentally stereotyped autophagic flux, LGG-1 acts upstream of LGG-2 to allow its localization to autophagosomes. LGG-2 controls the maturation of LGG-1-positive autophagosomes and facilitates the tethering with the lysosomes through a direct interaction with the VPS-39 HOPS complex subunit. Genetic analyses sustain a sequential implication of LGG-1, LGG-2, RAB-7, and HOPS complex to generate autolysosomes. The duplications of Atg8 in metazoans thus allowed the acquisition of specialized functions for autophagosome maturation.