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Oligomeric CHMP7 mediates three-way ER junctions and ER-mitochondria interactions

Cell Death & Differentiation volume 30, pages 94–110 (2023)Cite this article

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Abstract

In metazoans the endoplasmic reticulum (ER) undergoes extensive remodeling during the cell cycle. The endosomal sorting complexes required for transport (ESCRT) protein CHMP7 coordinates ESCRT-III dependent nuclear envelope reformation during mitotic exit. However, potential roles of ER-associated CHMP7 at non-mitotic stages remain unclear. Here we discovered a new role of CHMP7 in mediating three-way ER and ER-mitochondrial membrane contact sites (MCSs). We showed that CHMP7 localizes to multiple cellular membranes including the ER, mitochondrial-associated membranes (MAMs) and the outer mitochondrial membrane (OMM) via its N-terminal membrane-binding domain. CHMP7 undergoes dynamic assembly at three-way ER junctions and ER-mitochondrial MCSs through hydrophobic interactions among α helix-1 and α helix-2 of the C-terminal CHMP-like domain, which was required for tethering different organelles in vivo. Furthermore, CHMP7 mediates the formation of three-way ER junctions in parallel with Atlastins (ATLs). Importantly, CHMP7 also regulates ER-mitochondrial interactions and its depletion affects mitochondrial division independently of ESCRT complex. Taken together, our results suggest a direct role of CHMP7 in the formation of the ER contacts in interphase.

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Fig. 1: The localization of CHMP7 relative to the ER, and ER-mitochondrial MCSs.
Fig. 2: Dynamic assembly of CHMP7 at the three-way ER and ER-mitochondrial MCSs.
Fig. 3: The assembly of CHMP7 at ER contacts requires helices 1&2 of CT domain.
Fig. 4: The hydrophobic residues of the two α helices are responsible for CHMP7 assembly at contacts.
Fig. 5: CHMP7 regulates the formation of 3-way ER junctions.
Fig. 6: CHMP7 regulates ER-mitochondrial interactions.
Fig. 7: CHMP7 affects mitochondrial division.
Fig. 8: The working model of CHMP7 at ER contacts.

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank Ping Liu (the Optical Bioimaging Core Facility of WNLO-HUST), Linfang Yang (Huazhong University of Science and Technology) for imaging assistance, and Wenjun Pu (Shenzhen Bay Laboratory) for technical help with CHMP7 Halo KI.

Funding

JX was supported by National Natural Science Foundation of China (81901166). LD was supported by the Guangdong Basic and Applied Basic Research Foundation (2020A1515110542) and Shenzhen Bay Laboratory Open Fund (SZBL2020090501004). WJ was supported by National Natural Science Foundation of China (32122025; 91854109), and the Program for HUST Academic Frontier Youth Team (2018QYTD11).

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Author notes

  1. These authors contributed equally: Qingzhu Chu, Jingru Wang.

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Qingzhu Chu, Jingru Wang, Yuanjiao Du, Tiantian Zhou, Anbing Shi & Wei-Ke Ji

  2. Cell Architecture Research Center, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China

    Anbing Shi & Wei-Ke Ji

  3. Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China

    Juan Xiong

  4. Shenzhen Bay Laboratory, Shenzhen, 518132, China

    Lin Deng

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Contributions

QC, JW, YD, TZ, JX, WJ, LD and conceived the project and designed the experiments. QC, JW, YD, TZ performed the experiments. QC, JW, YD, TZ, AS, JX, WJ, LD analyzed and interpreted the data. WJ prepared the manuscript with inputs and approval from all authors.

Corresponding authors

Correspondence to Juan Xiong, Wei-Ke Ji or Lin Deng.

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All experimental procedures involving animals were approved by Animal Use and Care Committee of Huazhong University of Science and Technology, Wuhan, China. All animal care and use followed the guidelines of the Animal Care and Use Committee of Huazhong University of Science and Technology. During all procedures of experiments, the number of animals and their suffering by treatments were minimized.

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Chu, Q., Wang, J., Du, Y. et al. Oligomeric CHMP7 mediates three-way ER junctions and ER-mitochondria interactions. Cell Death Differ 30, 94–110 (2023). https://doi.org/10.1038/s41418-022-01048-2

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