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

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
• membrane tethering
• RAB39A

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

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.