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The STX17-SNAP47-VAMP7/VAMP8 complex is the default SNARE complex mediating autophagosome–lysosome fusion

Cell Research volume 34, pages 151–168 (2024)Cite this article

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Abstract

Autophagosome–lysosome fusion mediated by SNARE complexes is an essential step in autophagy. Two SNAP29-containing SNARE complexes have been extensively studied in starvation-induced bulk autophagy, while the relevant SNARE complexes in other types of autophagy occurring under non-starvation conditions have been overlooked. Here, we found that autophagosome–lysosome fusion in selective autophagy under non-starvation conditions does not require SNAP29-containing SNARE complexes, but requires the STX17-SNAP47-VAMP7/VAMP8 SNARE complex. Further, the STX17-SNAP47-VAMP7/VAMP8 SNARE complex also functions in starvation-induced autophagy. SNAP47 is recruited to autophagosomes following concurrent detection of ATG8s and PI(4,5)P2 via its Pleckstrin homology domain. By contrast, SNAP29-containing SNAREs are excluded from selective autophagy due to inactivation by O-GlcNAcylation under non-starvation conditions. These findings depict a previously unknown, default SNARE complex responsible for autophagosome–lysosome fusion in both selective and bulk autophagy, which could guide research and therapeutic development in autophagy-related diseases.

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Fig. 1: SNAP47 primarily localizes to mitophagosomes.
Fig. 2: SNAP47 is required for mitophagosome–lysosomesome fusion.
Fig. 3: SNAP47 functions in starvation-induced autophagy.
Fig. 4: SNAP47 forms a ternary SNARE complex with STX17 and VAMP7/VAMP8.
Fig. 5: The binding between PH domain of SNAP47 and PI(4,5)P2 is required for SNAP47 recruitment to autophagic vacuoles.
Fig. 6: ATG8 family proteins are required for SNAP47 recruitment to autophagic vacuoles.
Fig. 7: SNAP29 O-GlcNAcylation inhibits its recruitment to mitophagosomes.

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All data are available in the main text or the supplementary materials.

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Acknowledgements

We are deeply grateful to Dr. Li Yu (Tsinghua University) and Yuhai Jia (Nanjing Normal University) for helpful suggestions on this study. We thank Dr. Michael Lazarou (Monash University) for sharing ATG8 KO cell lines. We thank Dr. Liang Ge (Tsinghua University) for sharing the HTT(Q103) plasmid. The work was supported by grants from NSFC (92254302, 91854116, 32170685 and 31771529 to Y.R.). The work was partially supported by the Fundamental Research Funds for the Central Universities (5003510089 and 2023BR028 to Y.R.).

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  1. These authors contributed equally: Fenglei Jian, Shen Wang.

Authors and Affiliations

  1. School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonostic Infectious Disease, Huazhong University of Science and Technology, Wuhan, Hubei, China

    Fenglei Jian, Rui Tian, Yufen Wang, Chuangpeng Li, Chao Fang & Yueguang Rong

  2. Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, China

    Shen Wang & Cong Ma

  3. Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

    Yan Li & Shixuan Wang

  4. Cell Architecture Research Center, Huazhong University of Science and Technology, Wuhan, Hubei, China

    Yueguang Rong

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Contributions

F.J. and Y.R. conceived and designed the biological and biochemical experiments. F.J., R.T., Y.W., and C.L. carried out the biological and biochemical experiments. S.W. C.M. and Y.R. designed and S.W. carried out the in vitro liposome fusion and single vesicle binding experiments. F.J., S.W., C.M., C.F., Y.L., S.X.W. and Y.R. analyzed the data and wrote the manuscript with the help of all authors.

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Correspondence to Cong Ma or Yueguang Rong.

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Jian, F., Wang, S., Tian, R. et al. The STX17-SNAP47-VAMP7/VAMP8 complex is the default SNARE complex mediating autophagosome–lysosome fusion. Cell Res 34, 151–168 (2024). https://doi.org/10.1038/s41422-023-00916-x

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