C9orf72-catalyzed GTP Loading of Rab39A Enables HOPS-mediated Membrane Tethering and Fusion in Mammalian Autophagy

Overview

Journal Nat Commun

Specialty Biology

Date 2023 Oct 11

PMID 37821429

Authors

Shen Zhang

Mindan Tong

Denghao Zheng

Huiying Huang

Linsen Li

Christian Ungermann

Yi Pan

Hanyan Luo

Ming Lei

Zaiming Tang

Wan Fu

She Chen

XiaoXia Liu

Qing Zhong

Affiliations

Soon will be listed here.

Abstract

The multi-subunit homotypic fusion and vacuole protein sorting (HOPS) membrane-tethering complex is required for autophagosome-lysosome fusion in mammals, yet reconstituting the mammalian HOPS complex remains a challenge. Here we propose a "hook-up" model for mammalian HOPS complex assembly, which requires two HOPS sub-complexes docking on membranes via membrane-associated Rabs. We identify Rab39A as a key small GTPase that recruits HOPS onto autophagic vesicles. Proper pairing with Rab2 and Rab39A enables HOPS complex assembly between proteoliposomes for its tethering function, facilitating efficient membrane fusion. GTP loading of Rab39A is important for the recruitment of HOPS to autophagic membranes. Activation of Rab39A is catalyzed by C9orf72, a guanine exchange factor associated with amyotrophic lateral sclerosis and familial frontotemporal dementia. Constitutive activation of Rab39A can rescue autophagy defects caused by C9orf72 depletion. These results therefore reveal a crucial role for the C9orf72-Rab39A-HOPS axis in autophagosome-lysosome fusion.

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