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Temporal dissection of the roles of Atg4 and ESCRT in autophagosome formation in yeast

Cell Death & Differentiation volume 32, pages 866–879 (2025)Cite this article

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Abstract

Autophagosomes are formed by the enlargement and sealing of phagophores. This is accompanied by the recruitment and release of autophagy-related (Atg) proteins that function therein. Presently, the relationship among factors that act after the initial emergence of the phagophore is unclear. The endosomal sorting complexes required for transport (ESCRT) machinery and Atg4 are known to function in phagophore sealing and Atg8 release, respectively. Here we show that biochemically, both Atg4 and ESCRT promoted phagophore sealing. Intriguingly, Atg4-mediated release of Atg8 from the phagophore promoted phagophore sealing even in the absence of ESCRT. This sealing activity could be reconstituted in vitro using cell lysate and purified Atg4. To elucidate the temporal relationship between Atg4 and ESCRT, we charted a timeline of the autophagosome formation cycle based on the trafficking of Atg proteins and mapped the actions of Atg4 and ESCRT to specific stages. The temporal impact of Atg4-mediated release of Atg8 from phagophore was mapped to the stage after the assembly of phagophore assembly site (PAS) scaffold and phosphatidylinositol-3-kinase (PtdIns-3-K) complex; its retardation only extended the duration of Atg8 release stage, leading to delayed phagophore sealing and accumulation of multiple phagophores. The impacts of ESCRT were mapped to two stages. In addition to promoting phagophore sealing, it also dictates whether PtdIns-3-K recruitment can occur by controlling Atg9 trafficking, thereby determining the incidence of autophagosome formation. Accordingly, ESCRT deficiency led to a combination of reduced autophagosome frequency and extended autophagosome formation duration, manifesting as reduced autophagic flux but normal apparent Atg8 puncta number. Our study thus identifies Atg4-mediated Atg8 shedding as a novel membrane scission mechanism and reveals a new early-stage role for ESCRT in autophagy.

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Fig. 1: Vacuolar tethering of Atg4 led to accumulation and coalescence of autophagic intermediates.
Fig. 2: Deficiencies of Atg4 and ESCRT produce additive effects on autophagy.
Fig. 3: Atg4 and ESCRT act in parallel to promote phagophore sealing.
Fig. 4: Mapping the temporal impact of Atg4 and ESCRT in autophagosome formation.
Fig. 5: Inferring the temporal impact of Atg4 and ESCRT from colocalization analysis.
Fig. 6: ESCRT regulates the incidence of PtdIns-3-K assembly.
Fig. 7: ESCRT regulates PtdIns-3-K via controlling Atg9 trafficking.
Fig. 8: Roles of Atg4 and ESCRT in different stages of autophagosome formation.

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Data availability

All data supporting the findings of this study are available within the paper and its supplementary files.

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Acknowledgements

The authors would like to thank Drs. Caiji Gao (South China Normal University, CN), Lv Hong (Fudan University, CN), Jia-Hong Lu (University of Macau, CN), Yoshinori Ohsumi (Tokyo Institute of Technology, JP), Christian Ungermann (University of Osnabrück, DE), Lois Weisman (University of Michigan, Ann Arbor, US), Cong Yi (Zhejiang University, CN), and Xin-Qing Zhao (Shanghai Jiao Tong University) for gifts of strains and reagents, thank Ms Ge Wang, Dr Jing Liu, and Dr Meng-Yu Yan (Instrumental Analysis Center, SJTU) for technical assistance in TEM.

Funding

This work was supported by National Natural Science Foundation of China (91754110, 32270796) and Shanghai Municipal Science and Technology Commission (22ZR1433800).

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  1. These authors contributed equally: Hui Li, Jing-Zhen Song, Cheng-Wen He.

Authors and Affiliations

  1. Shanghai Sixth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, PR China

    Hui Li

  2. State Key Laboratory of Microbial Metabolism & Joint International Research Laboratory of Metabolic & Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, PR China

    Hui Li, Jing-Zhen Song, Cheng-Wen He, Meng-Xi Xie, Zheng-Tan Zhang, You Zhou, Xin-Jing Li, Li Cui, Jing Zhu, Qingqiu Gong & Zhiping Xie

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Conceptualization: HL and ZX; Investigation: HL, JZS, CWH, MXX, ZTZ, YZ, XJL, and LC; Writing—Original Draft: HL and ZX; Project administration: JZ; Supervision: QG and ZX; Funding acquisition: ZX.

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Li, H., Song, JZ., He, CW. et al. Temporal dissection of the roles of Atg4 and ESCRT in autophagosome formation in yeast. Cell Death Differ 32, 866–879 (2025). https://doi.org/10.1038/s41418-024-01438-8

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