MassIVE MSV000086660

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Ribosome quality control activity potentiates vaccinia virus protein synthesis during infection

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Description

Ribosomes are highly abundant cellular machines that perform the essential task of translating the genetic code into proteins. Cellular translation activity is finely tuned and proteostasis insults, such as those incurred upon viral infection, activate stress signaling pathways that result in translation reprogramming. Viral infection selectively shuts down host mRNA while redistributing ribosomes for selective translation of viral mRNAs. The intricacies of this selective ribosome shuffle from host to viral mRNAs are poorly understood. Here, we uncover a role for the ribosome associated quality control (RQC) factor ZNF598, a sensor for collided ribosomes, as a critical factor for vaccinia virus mRNA translation. Collided ribosomes are sensed by ZNF598, which ubiquitylates 40S subunit proteins uS10 and eS10 and thereby initiates RQC-dependent nascent chain degradation and ribosome recycling. We show that vaccinia infection in human cells enhances uS10 ubiquitylation indicating an increased burden on RQC pathways during viral propagation. Consistent with an increased RQC demand, we demonstrate that vaccinia virus replication is impaired in cells which either lack ZNF598 or contain a ubiquitylation deficient version of uS10. Using SILAC-based proteomics and concurrent RNAseq analysis, we determine that host translation of vaccinia virus mRNAs is compromised in cells that lack RQC activity as compared to control cells whereas there was little evidence of differences in host or viral transcription. Additionally, vaccinia virus infection resulted in a loss of cellular RQC activity, suggesting that ribosomes engaged in viral protein production recruit ZNF598 away from its function in host translation. Thus, co-option of ZNF598 by vaccinia virus plays a critical role in translational reprogramming that is needed for optimal viral propagation. [doi:10.25345/C51J4V] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: Ribosome quality control, Vaccinia virus, ZNF598, uS10, eS10

Contact

Principal Investigators:
(in alphabetical order) 		Eric J. Bennett, UCSD, United States
Submitting User: Amit_Fulzele1803

Publications

Sundaramoorthy E, Ryan AP, Fulzele A, Leonard M, Daugherty MD, Bennett EJ.
Ribosome quality control activity potentiates vaccinia virus protein synthesis during infection.
J Cell Sci. Epub 2021 Apr 28.

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