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Determination of host cell proteins constituting the molecular microenvironment of coronavirus replicase complexes by proximity-labeling

By V’kovski Philip, Gerber Markus, Kelly Jenna, Pfaender Stephanie, Ebert Nadine, Braga Lagache Sophie, Simillion Cedric, Portmann Jasmine, Stalder Hanspeter, Gaschen Véronique, Bruggmann Remy, Stoffel Michael, Heller Manfred, Ronald Dijkman, Thiel Volker

Posted 14 Sep 2018
bioRxiv DOI: 10.1101/417907 (published DOI: 10.7554/eLife.42037)

Positive-sense RNA viruses hijack intracellular membranes that provide niches for viral RNA synthesis and a platform for interactions with host proteins. However, little is known about host factors at the interface between replicase complexes and the host cytoplasm. We engineered a biotin ligase into a coronaviral replication/transcription complex (RTC) and identified >500 host proteins constituting the RTC microenvironment. siRNA-silencing of each RTC-proximal host factor demonstrated importance of vesicular trafficking pathways, ubiquitin-dependent and autophagy-related processes, and translation initiation factors. Notably, detection of translation initiation factors at the RTC was instrumental to visualize and demonstrate active translation proximal to replication complexes of several coronaviruses. Collectively, we establish a spatial link between viral RNA synthesis and diverse host factors of unprecedented breadth. Our data may serve as a paradigm for other positive-strand RNA viruses and provide a starting point for a comprehensive analysis of critical virus-host interactions that represent targets for therapeutic intervention.

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