LC3-associated endocytosis and the functions of Rubicon and ATG16L1

Abstract

LC3-associated endocytosis (LANDO) is a noncanonical function of the autophagy machinery, in which LC3 (microtubule-associated protein light chain) is conjugated to rab5-positive endosomes, using a portion of the canonical autophagy pathway. LANDO was initially discovered in a murine model of Alzheimer's disease as a critical regulator of amyloid-β receptor recycling in microglial cells, playing a protective role against neuronal loss and memory impairment. Recent evidence suggests an emerging role of LANDO in cytokine receptor signaling and innate immunity. Here, we discuss the regulation of two crucial effectors of LANDO, Rubicon and ATG16L1, and their impact on endocytosis, autophagy, and phagocytosis.

Fig. 1.. Molecular machinery of canonical autophagy and noncanonical autophagy processes LC3-associated phagocytosis (LAP) and LC3-associated endocytosis (LANDO).

Schematic illustration of the differences in membrane trafficking and cascades of autophagy-related (ATG) proteins. LC3-II (orange circle) represents the lipidated form of LC3 (including both the LC3 and Gabarap family proteins).

Fig. 2.. Schematic Rubicon protein structure, binding partners, and functions in canonical and noncanonical autophagy.

Rubicon contains multiple functional domains that interact with several proteins and regulate its downstream signaling. RUN, RUN domain; PIKBD, PI3K-binding domain; CCD, coil-coiled domain; S-R, serine-rich region; H-C, helix-coil–rich domain; RH, Rubicon homology domain.

Fig. 3.. Schematic ATG16L1 protein structure, binding partners, and functions in canonical and noncanonical autophagy.

ATG16L1 contains multiple functional domains that interact with several proteins or phospholipids and regulate its downstream signaling. WD-40, β-transducin repeat containing approximately 40 amino acids and often terminated with tryptophan (W) and acid aspartic (D).

Fig. 4.. Emerging models for selecting single or double membranes.

Known mechanisms for selecting double-membrane phagophore and single-membrane endosome or phagosome. (A) Lipid-protein interactions between VPS34 complexes and membranes. Motifs of ATG14L BATS domain present in VPS34 complex I sense highly unsaturated lipids, curved double-membrane phagophores that contain Rab1a. Motifs of Beclin 1 BARA domain in VPS34 complex II sense negatively charged single-membrane endosomes that contain Rab5. (B) LC3 lipidation and lipid interaction between ATG16L1 domains and membranes. Interactions between the middle region of ATG16L1 complex with FIP200 and WIPI2 and PI3P allow its recruitment on double-membrane phagophores. Interaction between ATG16L1 WD domains and single membrane allows its recruitment on endosome or phagosome. While LC3 is conjugated only to PE on double-membrane phagophore during canonical autophagy, LC3 conjugation with PE or PS is observed on single-membrane endosomes or phagosomes. ATG4D catalyzes delipidation of LC3-PS.