2. Academic Validation
  3. AMFR-mediated Flavivirus NS2A ubiquitination subverts ER-phagy to augment viral pathogenicity

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

  • Nat Commun. 2024 Nov 6;15(1):9578. doi: 10.1038/s41467-024-54010-w.
Linliang Zhang # 1,  Hongyun Wang # 2,  Chao Han 2,  Qi Dong 2,  Jie Yan 2,  Weiwei Guo 3 4,  Chao Shan 3 4,  Wen Zhao 5,  Pu Chen 5,  Rui Huang 6,  Ying Wu 6,  Yu Chen 7,  Yali Qin 8,  Mingzhou Chen 9 10 11
Affiliations

Affiliations

  • 1 School of Life Sciences, Hubei University, Wuhan, 430062, China.
  • 2 State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, 430072, China.
  • 3 State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430072, China.
  • 4 University of the Chinese Academy of Sciences, Beijing, 100039, China.
  • 5 Tissue Engineering and Organ Manufacturing (TEOM) Lab, Department of Biomedical Engineering, Wuhan University Taikang Medical School (School of Basic Medical Sciences), Wuhan, 430072, China.
  • 6 State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, Institute of Medical Virology, TaiKang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan, 430072, China.
  • 7 State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, 430072, China. chenyu@whu.edu.cn.
  • 8 School of Life Sciences, Hubei University, Wuhan, 430062, China. yqin@hubu.edu.cn.
  • 9 School of Life Sciences, Hubei University, Wuhan, 430062, China. chenmz@hubu.edu.cn.
  • 10 State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, 430072, China. chenmz@hubu.edu.cn.
  • 11 Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430072, China. chenmz@hubu.edu.cn.
  • # Contributed equally.
PMID: 39505910 DOI: 10.1038/s41467-024-54010-w
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.

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