Prefused Lysosomes Cluster on Autophagosome Regulated by VAMP8

Abstract

Lysosome-autophagosome fusion is critical to autophagosome maturation [1]. Although several proteins that regulate their fusion have been identified, the prefusion state and its regulatory mechanism remain unclear. Herein, we show that, upon stimulation, a prefusion architecture involving multiple lysosomes could form clusters around individual autophagosomes and thus facilitated fusion. The soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein on lysosomes—vesicle-associated membrane protein 8 (VAMP8)—played an important role in forming the prefusion state of lysosomal clusters. To hinder spontaneous fusion, several C-terminal residues of VAMP8 were phosphorylated for the partial zippering of the SNARE complex, which caused the accumulation of unfused lysosomes upon autophagosomes. The phosphorylation not only reduces spontaneous fusion for minimizing autophgic flux under normal conditions, but also preassembles multiple lysosomes to increase fusion possibility for fast resuming autophagy upon stimulation. 1. Tian, Z. et al. 2019 Prog. Lipid. Res. 73,:92-100.