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AMFR-mediated Flavivirus NS2A ubiquitination subverts ER-phagy to augment viral pathogenicity

Author

Listed:
  • Linliang Zhang

    (Hubei University)

  • Hongyun Wang

    (Wuhan University)

  • Chao Han

    (Wuhan University)

  • Qi Dong

    (Wuhan University)

  • Jie Yan

    (Wuhan University)

  • Weiwei Guo

    (Chinese Academy of Sciences
    University of the Chinese Academy of Sciences)

  • Chao Shan

    (Chinese Academy of Sciences
    University of the Chinese Academy of Sciences)

  • Wen Zhao

    (Wuhan University Taikang Medical School (School of Basic Medical Sciences))

  • Pu Chen

    (Wuhan University Taikang Medical School (School of Basic Medical Sciences))

  • Rui Huang

    (Wuhan University)

  • Ying Wu

    (Wuhan University)

  • Yu Chen

    (Wuhan University)

  • Yali Qin

    (Hubei University)

  • Mingzhou Chen

    (Hubei University
    Wuhan University
    Wuhan University)

Abstract

Flaviviruses strategically utilize the endoplasmic reticulum (ER) in their replication cycles. However, the role of ER autophagy (ER-phagy) in viral replication process remains poorly understood. Here, we reveal that prolonged Zika virus (ZIKV) infection results from the degradation of ER-phagy receptor FAM134B, facilitated by viral NS2A protein. Mechanistically, ER-localized NS2A undergoes K48-linked polyubiquitination at lysine (K) 56 by E3 ligase AMFR. Ubiquitinated NS2A binds to FAM134B and AMFR orchestrates the degradation of NS2A-FAM134B complexes. AMFR-catalyzed NS2A ubiquitination not only targets FAM134B degradation but also hinders the FAM134B-AMFR axis. Notably, a recombinant ZIKV mutant (ZIKV-NS2AK56R), lacking ubiquitination and ER-phagy inhibition, exhibits attenuation in ZIKV-induced microcephalic phenotypes in human brain organoids and replicates less efficiently, resulting in weakened pathogenesis in mouse models. In this work, our mechanistic insights propose that flaviviruses manipulate ER-phagy to modulate ER turnover, driving viral infection. Furthermore, AMFR-mediated flavivirus NS2A ubiquitination emerges as a potential determinant of viral pathogenecity.

Suggested Citation

  • Linliang Zhang & Hongyun Wang & Chao Han & Qi Dong & Jie Yan & Weiwei Guo & Chao Shan & Wen Zhao & Pu Chen & Rui Huang & Ying Wu & Yu Chen & Yali Qin & Mingzhou Chen, 2024. "AMFR-mediated Flavivirus NS2A ubiquitination subverts ER-phagy to augment viral pathogenicity," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54010-w
    DOI: 10.1038/s41467-024-54010-w
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