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The hepatovirus pX protein contains ancient signals for ESCRT-dependent capsid quasi-envelopment

ABSTRACT: Hepatoviruses, a common cause of acute hepatitis in humans, are atypical picornaviruses released from cells in small vesicles resembling exosomes. We show the nonlytic release of these quasi-enveloped virions is mediated by a C-terminal extension of the VP1 capsid protein (pX) that binds the Bro1 domains of ALIX and HD-PTP, and recruits the ubiquitin ligase ITCH to drive an association with endosomal sorting complexes required for transport (ESCRT). Fusing pX to a self-assembling, de novo designed nanocage protein resulted in ESCRT-dependent release mediated by a 20-amino acid core sequence containing a Y[KR]xxR[LM] motif conserved in viruses from bats to humans. Mutations in this motif ablate release and lead virus to accumulate intracellularly. Our study identifies an exceptionally potent viral export signal mediating extracellular release of virus-sized protein assemblies, identifies its key cellular binding partners, and shows non-lytic release of quasi-enveloped virus is a tightly orchestrated and ancient evolutionary trait of hepatoviruses.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell

SUBMITTER: Ling Xie

LAB HEAD: Stanley M. Lemon

PROVIDER: PXD022107 | Pride | 2022-08-02

REPOSITORIES: Pride

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