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

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 () and Mingzhou Chen ()
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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
Chao Shan: 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

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-54010-w

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