C9orf72-catalyzed GTP loading of Rab39A enables HOPS-mediated membrane tethering and fusion in mammalian autophagy

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 () and Qing Zhong ()
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Shen Zhang: Shanghai Jiao Tong University School of Medicine
Mindan Tong: Shanghai Jiao Tong University School of Medicine
Denghao Zheng: Shanghai Jiao Tong University School of Medicine
Huiying Huang: Shanghai Jiao Tong University School of Medicine
Linsen Li: Shanghai Jiao Tong University School of Medicine
Christian Ungermann: Osnabrück University, Department of Biology/Chemistry, Biochemistry section
Yi Pan: Shanghai Jiao Tong University School of Medicine
Hanyan Luo: Shanghai Jiao Tong University School of Medicine
Ming Lei: Shanghai Jiao Tong University School of Medicine
Zaiming Tang: Shanghai Jiao Tong University School of Medicine
Wan Fu: Shanghai Jiao Tong University School of Medicine
She Chen: National Institute of Biological Sciences
Xiaoxia Liu: Shanghai Jiao Tong University School of Medicine
Qing Zhong: Shanghai Jiao Tong University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-42003-0

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