The Multipass Translocon Modulates Ribosomal Frameshifting and Spike Protein Maturation in the Alphavirus Structural Polyprotein

Description

Like other enveloped RNA viruses, alphaviruses synthesize and assemble their envelope glycoproteins at the endoplasmic reticulum (ER) membrane. There, protein-conducting channels called translocons thread the nascent proteins across the lipid bilayer and help fold them into their correct shapes. We previously showed that a hydrophobic segment in the Sindbis virus structural polyprotein forms cotranslational interactions with the translocon that enhance −1 programmed ribosomal frameshifting (−1PRF), a recoding event that regulates polyprotein biogenesis. Recent discoveries suggest this segment, which corresponds to the second transmembrane domain of the E2 protein, could serve as a signal that recruits the multipass translocon (MPT). Here, we show that knocking out certain components of the MPT increases −1PRF efficiency. These shifts in recoding track with changes in the membrane topology of the nascent polyprotein and in its downstream proteolytic processing in a manner that ultimately reduces viral fitness. Together, our results indicate that −1PRF and spike protein maturation in alphaviruses is tuned by the dynamic remodeling of the ER translocon. Such coupling could allow polyprotein biogenesis to adapt to different stages of viral replication and to distinct host or vector environments.

Institutions

• Purdue University West Lafayette

  Indiana, West Lafayette
• Indiana University

  Indiana, Bloomington

Categories

Funders

• National Institute of General Medical Sciences

  National Institutes of Health

  Maryland, Bethesda

  Grant ID: R35152086

Licence