Flavivirus NS2A orchestrates reticulophagy to enhance viral pathogenicity

Selective endoplasmic reticulum (ER) autophagy (reticulophagy) is essential for maintaining ER homeostasis. The E3 ligase AMFR facilitates the ubiquitination of the reticulophagy receptor RETREG1/FAM134B, thereby promoting the dynamic flux of the reticulophagy process. Flaviviruses exploit the ER during their replication cycles, highlighting the importance of ER quantity and accessibility in flavivirus infections. However, the role of reticulophagy in viral replication and the complex mechanisms by which viruses modulate reticulophagy to enhance pathogenicity remain poorly understood. In a recent study, we demonstrate that the Zika virus (ZIKV) hijacks the ER-located E3 ligase AMFR to ubiquitinate NS2A, leading to the degradation of the key reticulophagy receptor RETREG1. This inhibition of the reticulophagy process promotes virus-induced microcephaly in human brain organoids and enhances viral pathogenicity in mouse models. Notably, the AMFR-mediated ubiquitination of ZIKV-NS2A and its functional interaction with RETREG1 are conserved across the NS2A of other flaviviruses, including those from Dengue virus, West Nile virus, and Japanese encephalitis virus.