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

Linliang Zhang1, Hongyun Wang2, Chao Han2

  • 1School of Life Sciences, Hubei University, Wuhan, 430062, China.

Nature Communications
|November 6, 2024
PubMed

Insights

Zika virus (ZIKV) infection degrades the ER-phagy receptor FAM134B via the viral NS2A protein, hindering ER turnover and promoting prolonged infection. A mutant ZIKV lacking this mechanism shows reduced pathogenesis.

Area of Science:

  • Virology
  • Cellular Biology
  • Autophagy

Background:

  • Flaviviruses, including Zika virus (ZIKV), depend on the endoplasmic reticulum (ER) for replication.
  • The role of ER autophagy (ER-phagy) in viral replication is not well understood.

Purpose of the Study:

  • To investigate the mechanism by which ZIKV manipulates ER-phagy during infection.
  • To elucidate the role of viral protein NS2A and ER-phagy receptor FAM134B in ZIKV pathogenesis.

Main Methods:

  • Investigated the interaction between ZIKV NS2A and FAM134B in infected cells.
  • Utilized ubiquitination assays to determine NS2A modification by AMFR.
  • Generated and analyzed a recombinant ZIKV mutant (ZIKV-NS2AK56R) lacking NS2A ubiquitination.
  • Assessed viral replication and pathogenesis in human brain organoids and mouse models.

Main Results:

  • ZIKV infection leads to FAM134B degradation, mediated by viral NS2A protein.
  • NS2A is polyubiquitinated by AMFR at K56, which targets FAM134B for degradation.
  • AMFR-mediated NS2A ubiquitination inhibits the FAM134B-AMFR axis, impairing ER-phagy.
  • ZIKV-NS2AK56R mutant showed attenuated replication, reduced microcephaly in organoids, and weakened pathogenesis in mice.

Conclusions:

  • Flaviviruses, exemplified by ZIKV, exploit ER-phagy pathways for replication by degrading key receptors like FAM134B.
  • AMFR-mediated ubiquitination of viral NS2A is a critical mechanism for inhibiting ER turnover and driving viral pathogenesis.
  • Targeting the NS2A ubiquitination pathway presents a potential strategy for antiviral therapies.

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