How AMFR-driven tagging of a viral protein blocks cellular cleanup to increase flavivirus harm

Prolonged Zika virus (ZIKV) infection is linked to the degradation of the ER-phagy receptor FAM134B by the viral NS2A protein.

• ZIKV infection leads to the degradation of FAM134B, which is crucial for the autophagy process in the endoplasmic reticulum.
• The NS2A protein of ZIKV undergoes a specific type of protein tagging (K48-linked polyubiquitination) that facilitates this degradation.
• Ubiquitinated NS2A interacts with FAM134B, leading to the breakdown of complexes that include both proteins.
• A mutant form of ZIKV, which does not undergo this ubiquitination process, shows reduced viral replication and severity of associated brain abnormalities in human brain organoids and mouse models.
• Findings suggest that flaviviruses may exploit the autophagy process to enhance their replication and influence disease severity.

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