The HOPS complex mediates autophagosome–lysosome fusion through interaction with syntaxin 17
Open accessAbstract
Membrane fusion is generally controlled by Rabs, soluble N-ethylmaleimide–sensitive factor attachment protein receptors (SNAREs), and tethering complexes. Syntaxin 17 (STX17) was recently identified as the autophagosomal SNARE required for autophagosome–lysosome fusion in mammals and Drosophila. In this study, to better understand the mechanism of autophagosome–lysosome fusion, we searched for STX17-interacting proteins. Immunoprecipitation and mass spectrometry analysis identified vacuolar protein sorting 33A (VPS33A) and VPS16, which are components of the homotypic fusion and protein sorting (HOPS)–tethering complex. We further confirmed that all HOPS components were coprecipitated with STX17. Knockdown of VPS33A, VPS16, or VPS39 blocked autophagic flux and caused accumulation of STX17- and microtubule-associated protein light chain (LC3)–positive autophagosomes. The endocytic pathway was also affected by knockdown of VPS33A, as previously reported, but not by knockdown of STX17. By contrast, ultraviolet irradiation resistance–associated gene (UVRAG), a known HOPS-interacting protein, did not interact with the STX17–HOPS complex and may not be directly involved in autophagosome–lysosome fusion. Collectively these results suggest that, in addition to its well-established function in the endocytic pathway, HOPS promotes autophagosome–lysosome fusion through interaction with STX17.
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RAB7A is located in the HOPS, Rab proteins involved in autophagosome formation, and mitophagy core sub-groups.
“Indeed, some genes belong to more than one category due to their multiple role (indicated in red in the Supplementary Table 1): for example, the regulator of vesicular transport “RAB7A” is located in i) the “HOPS” [32], ii) the “Rab proteins involved in autophagosome formation” [33], and iii) the “mitophagy core” [34] sub-groups.”
From A gene toolbox for monitoring autophagy transcription (2021) · cites this paper as [32]
Citation [32] is attached to the claim that RAB7A belongs in the HOPS subgroup, not to the other two subgroup assignments. The Introduction (page unavailable) lists the six proteins that constitute HOPS—Vps11, Vps16, Vps18, Vps33, Vps39, and Vps41—and discusses Rab7 separately; it does not identify Rab7 as a HOPS component. (LLM, conf=0.85)
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- Authors
- Jiang, P., Nishimura, T., Sakamaki, Y., Itakura, E., Hatta, T., Natsume, T., & Mizushima, N.
- Affiliations
- Tokyo Medical and Dental University (JP)
- National Institute of Advanced Industrial Science and Technology (JP)
- Corresponding author
- Mizushima, Noboru
- Venue
- Molecular Biology of the Cell
- Published
- 2014-04-15
- Volume
- 25
- Issue
- 8
- Pages
- 1327-1337
- ISSN
- 1059-1524 (ISSN-L)
- 1939-4586
- PMC
- PMC3982997
- OpenAlex
- W2133284292
- Cited by
- 501
- References
- 8
- Citations by year
- 2026: 25 · 2025: 34 · 2024: 46 · 2023: 41 · 2022: 37 · 2021: 55 · 2020: 47 · 2019: 45 · 2018: 51 · 2017: 38 · 2016: 38 · 2015: 31 · 2014: 12
- FWCI
- 30.05
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- cc-by-nc-sa
- Locations
- Molecular Biology of the Cell (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- China Scholarship Council
- Japan Society for the Promotion of Science (25111005)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Keywords
- HOPS complex, autophagosome-lysosome fusion, STX17, VPS33A, VPS16, VPS39, autophagic flux, SNARE proteins, membrane fusion, endocytic pathway, UVRAG
- MeSH terms
- Autophagy-Related Proteins, Animals, Cell Fusion, HeLa Cells, Humans, Lysosomes, Membrane Fusion, Microtubule-Associated Proteins, Oligopeptides, Phagosomes, Protein Binding, Tumor Suppressor Proteins, Vesicular Transport Proteins, RNA Interference, RNA, Small Interfering, Intracellular Signaling Peptides and Proteins, Green Fluorescent Proteins, Qa-SNARE Proteins, Mice, HEK293 Cells
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