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RNF185 regulates proteostasis in Ebolavirus infection by crosstalk between the calnexin cycle, ERAD, and reticulophagy

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Listed:
  • Jing Zhang

    (Chinese Academy of Agricultural Sciences)

  • Bin Wang

    (Chinese Academy of Agricultural Sciences
    MSD (Ningbo) Animal Health Technology Co., Ltd.)

  • Xiaoxiao Gao

    (Chinese Academy of Sciences)

  • Cheng Peng

    (Chinese Academy of Sciences)

  • Chao Shan

    (Chinese Academy of Sciences
    Chinese Academy of Sciences)

  • Silas F. Johnson

    (Michigan State University)

  • Richard C. Schwartz

    (Michigan State University)

  • Yong-Hui Zheng

    (Chinese Academy of Agricultural Sciences
    Michigan State University)

Abstract

Virus infection affects cellular proteostasis and provides an opportunity to study this cellular process under perturbation. The proteostasis network in the endoplasmic reticulum (ER) is composed of the calnexin cycle, and the two protein degradation pathways ER-associated protein degradation (ERAD) and ER-to-lysosome-associated degradation (ERLAD/ER-phagy/reticulophagy). Here we show that calnexin and calreticulin trigger Zaire Ebolavirus (EBOV) glycoprotein GP1,2 misfolding. Misfolded EBOV-GP1,2 is targeted by ERAD machinery, but this results in lysosomal instead of proteasomal degradation. Moreover, the ER Ub ligase RNF185, usually associated with ERAD, polyubiquitinates EBOV-GP1,2 on lysine 673 via ubiquitin K27-linkage. Polyubiquinated GP1,2 is subsequently recruited into autophagosomes by the soluble autophagy receptor sequestosome 1 (SQSTM1/p62), in an ATG3- and ATG5-dependent manner. We conclude that EBOV hijacks all three proteostasis mechanisms in the ER to downregulate GP1,2 via polyubiquitination and show that this increases viral fitness. This study identifies linkages among proteostasis network components previously thought to function independently.

Suggested Citation

  • Jing Zhang & Bin Wang & Xiaoxiao Gao & Cheng Peng & Chao Shan & Silas F. Johnson & Richard C. Schwartz & Yong-Hui Zheng, 2022. "RNF185 regulates proteostasis in Ebolavirus infection by crosstalk between the calnexin cycle, ERAD, and reticulophagy," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33805-9
    DOI: 10.1038/s41467-022-33805-9
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    1. Moritz Hacke & Patrik Björkholm & Andrea Hellwig & Patricia Himmels & Carmen Ruiz de Almodóvar & Britta Brügger & Felix Wieland & Andreas M. Ernst, 2015. "Inhibition of Ebola virus glycoprotein-mediated cytotoxicity by targeting its transmembrane domain and cholesterol," Nature Communications, Nature, vol. 6(1), pages 1-9, November.
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    1. Ilyas Khan & Sunan Li & Lihong Tao & Chong Wang & Bowei Ye & Huiyu Li & Xiaoyang Liu & Iqbal Ahmad & Wenqiang Su & Gongxun Zhong & Zhiyuan Wen & Jinliang Wang & Rong-Hong Hua & Ao Ma & Jie Liang & Xia, 2024. "Tubeimosides are pan-coronavirus and filovirus inhibitors that can block their fusion protein binding to Niemann-Pick C1," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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