C9orf72-catalyzed GTP loading of Rab39A enables HOPS-mediated membrane tethering and fusion in mammalian autophagy
Autor(en): | Zhang, Shen Tong, Mindan Zheng, Denghao Huang, Huiying Li, Linsen Ungermann, Christian Pan, Yi Luo, Hanyan Lei, Ming Tang, Zaiming Fu, Wan Chen, She Liu, Xiaoxia Zhong, Qing |
Stichwörter: | Animals; Autophagy; C9orf72 Protein; Catalysis; Guanosine Triphosphate; Mammals; Membrane Fusion; Saccharomyces cerevisiae Proteins; Vacuoles; guanine nucleotide exchange C9orf72; guanine nucleotide exchange factor; guanosine triphosphate; proteoliposome; Rab protein; recombinant protein; guanine nucleotide exchange C9orf72; guanosine triphosphate; Saccharomyces cerevisiae protein; catalysis; catalyst; cell organelle; enzyme activity; membrane; protein; amyotrophic lateral sclerosis; animal cell; Article; autophagosome; autophagy (cellular); catalysis; cell vacuole; frontotemporal dementia; immunofluorescence; immunoprecipitation; in vitro study; lysosome; mammal; membrane fusion; nonhuman; prenylation; protein function; protein purification; protein targeting; transmission electron microscopy; animal; catalysis; cell vacuole; genetics; mammal; membrane fusion; metabolism; physiology | Erscheinungsdatum: | 2023 | Herausgeber: | Nature Research | Journal: | Nature Communications | Volumen: | 14 | Ausgabe: | 1 | Zusammenfassung: | 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. © 2023, Springer Nature Limited. |
Beschreibung: | Cited by: 0; All Open Access, Gold Open Access |
ISSN: | 2041-1723 | DOI: | 10.1038/s41467-023-42003-0 | Externe URL: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-85173640137&doi=10.1038%2fs41467-023-42003-0&partnerID=40&md5=b9bc6e65b2526528320c45a755dfc0d7 |
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geprüft am 19.05.2024