Human Coronavirus-229E Hijacks Key Host-Cell RNA-Processing Complexes for Replication

The recent rise in zoonotic coronavirus outbreaks underscores
the
urgency to understand virus–host interactions to develop potent
antiviral therapeutics. Systems biology approaches, particularly proteomics,
have been invaluable in providing a global overview of such interactions.
However, these conventional approaches rely on measuring protein abundance
changes that do not capture all molecular changes associated with
altered regulatory pathways. In this study, we employed a high-throughput
structural proteomics approach called limited proteolysis-based mass
spectrometry (LiP-MS) to capture protein conformational changes, which
we demonstrate are better proxies for functional alterations. We applied
this tool to profile the molecular landscape of different human lung
cells following human coronavirus-229E (HCoV-229E) infection. We found
that HCoV-229E uses a multipronged approach to hijack key RNA-processing
pathways and assemblies as part of a host-shutoff strategy to achieve
effective replication. We confirm our results with structural data
derived from changes in the assemblies after infection. We go on to
show that modulation of two of these assemblies, the Nop56-associated
pre-rRNA complex and the spliceosome C-complex, can attenuate HCoV-229E
replication, indicating that we have identified viable host-cell therapeutic
targets with potential to provide broad efficacy against coronavirus
infection.