Editors' ChoiceVirology

Zika and ubiquitin

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Science Signaling  22 Sep 2020:
Vol. 13, Issue 650, eabe8636
DOI: 10.1126/scisignal.abe8636

Ubiquitylation of the Zika virus envelope protein drives viral entry and pathogenesis.

Unlike other flaviviruses, Zika virus (ZIKV) causes neurological problems and replicates in reproductive tissues. To investigate the underlying mechanism for these properties, Giraldo et al. performed mass spectrometry–based analysis of cells infected with ZIKV or other flaviviruses to identify viral proteins that underwent posttranslational modifications. The envelope (E) protein of ZIKV, which is essential for viral entry, underwent Lys63 (K63)-linked polyubiquitylation at residue K38, which is conserved among flaviviruses, as well as at the nonconserved residue K281. Recombinant ZIKV mutated at the E protein ubiquitylation sites [E(K38R) and E(K281R)] exhibited attenuated replication in various human cell lines. Infection of mice with E(K281R) ZIKV resulted in reduced viral loads specifically in the brain and reproductive tissues compared to those in mice infected with wild-type ZIKV; viral loads in other tissues were more similar. Loss of the E3 ubiquitin ligase TRIM7 in brain and placental cell lines resulted in reduced replication of wild-type ZIKV but not of E(K38R) ZIKV. In ZIKV-infected cells, TRIM7 was recruited to the Golgi, where it colocalized with E protein. ZIKV particles released from cells had detectable K63-polyubiquitylated E protein, which was less abundant in particles released from TRIM7-deficient cells. ZIKV-infected TRIM7-deficient mice had reduced viral loads in the brain and reproductive tissues compared to those in infected wild-type mice. Finally, a monoclonal antibody against K63-linked ubiquitin, but not one against K48-linked ubiquitin, inhibited ZIKV replication in vitro and in vivo. Together, these data suggest that K63-linked polyubiquitylation of ZIKV E protein promotes viral entry in a tissue-specific manner that is dependent on the E3 ligase TRIM7.

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