The hookup model of the HOPS complex in autophagosome-lysosome fusion

Autophagy. 2024 Mar;20(3):714-715. doi: 10.1080/15548627.2023.2291938. Epub 2023 Dec 11.

Abstract

Macroautophagy/autophagy is a highly conserved process that involves the degradation of proteins, damaged organelles, and other cytoplasmic macromolecules. Autophagosome-lysosome fusion is critical for successful substrate degradation and is mediated by SNARE proteins. The fusion process requires additional vesicle docking and tethering-regulating factors. Our recent work has uncovered a functional model of autophagosome-lysosome fusion. We demonstrated that the six-subunit homotypic fusion and vacuole protein sorting (HOPS) complex can be assembled by two subcomplexes, the VPS39-VPS11 subcomplex (HOPS-2) and the VPS41-VPS16-VPS18-VPS33A subcomplex (HOPS-4). VPS39 binds with RAB2 on the autophagosome and VPS41 binds with RAB39A on the lysosome, which then promotes membrane tethering and autophagic SNARE-mediated membrane fusion. Moreover, we have revealed that ALS- and FTD-related C9orf72 is a guanine exchange factor (GEF) for RAB39A. In this punctum, we discuss how the C9orf72-RAB39A-HOPS axis function regulates autophagosome-lysosome fusion.

Keywords: Autophagosome-lysosome fusion; C9orf72; HOPS complex; RAB39A; membrane tethering.

MeSH terms

  • Autophagosomes / metabolism
  • Autophagy*
  • C9orf72 Protein / metabolism
  • Lysosomes / metabolism
  • Macroautophagy*
  • Membrane Fusion / physiology
  • SNARE Proteins / metabolism

Substances

  • C9orf72 Protein
  • SNARE Proteins

Grants and funding

This work was supported by grants 2019YFA0508602 (MOST (Ministry of Science and Technology of the People’s Republic of China)), M-0140 (NSFCSino-German Mobility Programme), and 92254307, 91754205 (NSFC (National Natural Science Foundation of China)) to Q.Z.