Abstract
Under stress, the endomembrane system undergoes reorganization to support autophagosome biogenesis, which is a central step in autophagy. How the endomembrane system remodels has been poorly understood. Here we identify a new type of membrane contact formed between the ER–Golgi intermediate compartment (ERGIC) and the ER-exit site (ERES) in the ER–Golgi system, which is essential for promoting autophagosome biogenesis induced by different stress stimuli. The ERGIC–ERES contact is established by the interaction between TMED9 and SEC12 which generates a short distance opposition (as close as 2–5 nm) between the two compartments. The tight membrane contact allows the ERES-located SEC12 to transactivate COPII assembly on the ERGIC. In addition, a portion of SEC12 also relocates to the ERGIC. Through both mechanisms, the ERGIC–ERES contact promotes formation of the ERGIC-derived COPII vesicle, a membrane precursor of the autophagosome. The ERGIC–ERES contact is physically and functionally different from the TFG-mediated ERGIC–ERES adjunction involved in secretory protein transport, and therefore defines a unique endomembrane structure generated upon stress conditions for autophagic membrane formation.
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Acknowledgements
L. G. is deeply grateful to Dr Randy Schekman for the post-doctoral training at UC Berkeley. We thank Dr Hongguang Xia (Zhejiang University, China), Dr Houchaima Ben-Tekaya (University of Basel, Switzerland), and Dr Yueguang Rong (Huazhong University of Science and Technology, China) for reagents, Peng Zhao and Huijiao Bai at Tsinghua University for technical assistance. We thank Dr Li Yu, Dr Ye-Guang Chen (Tsinghua University, China), Dr Wei Liu (Zhejiang University, China), Dr Quan Chen (Nankai University, China), Dr Hong Zhang (Institute of Biophysics, Chinese Academy of Sciences, China) and Dr Qing Zhong (Shanghai Jiao Tong University, China) for helpful suggestions on the study. The authors would like to acknowledge the assistance of Imaging Core Facility, Technology Center for Protein Sciences, Tsinghua University. The work is funded by National Key R&D Program of China (2019YFA0508602), the National Natural Science Foundation of China (91854114, 32061143009, 31872832, 31872826), Beijing Natural Science Foundation (JQ20028), Tsinghua Independent Research Program (2019Z06QCX02), Tsinghua University COVID-19 Emergency Aid Fund (2020Z99CFZ024), and Tsinghua-Peking Center for Life Sciences.
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Shulin L., and L.G. performed experiments, analyzed data, and wrote the manuscript. R.Y., J.X., S.Z., X.M., Y.L., and J.-J.G.L. performed experiments. M.Z., Q.S., L.C., Sai L., and K.X. analyzed data.
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Li, S., Yan, R., Xu, J. et al. A new type of ERGIC–ERES membrane contact mediated by TMED9 and SEC12 is required for autophagosome biogenesis. Cell Res 32, 119–138 (2022). https://doi.org/10.1038/s41422-021-00563-0
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DOI: https://doi.org/10.1038/s41422-021-00563-0
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