Viral Evolution Shaped by Host Proteostasis Networks

Abstract

Understanding the factors that shape viral evolution is critical for developing effective antiviral strategies, accurately predicting viral evolution, and preventing pandemics. One fundamental determinant of viral evolution is the interplay between viral protein biophysics and the host machineries that regulate protein folding and quality control. Most adaptive mutations in viruses are biophysically deleterious, resulting in a viral protein product with folding defects. In cells, protein folding is assisted by a dynamic system of chaperones and quality control processes known as the proteostasis network. Host proteostasis networks determine the fates of viral proteins with biophysical defects, either by assisting with folding or by targeting them for degradation. In this review, we discuss and analyze new discoveries revealing that host proteostasis factors can profoundly shape the sequence space accessible to evolving viral proteins. We also discuss the many opportunities for research progress proffered by the proteostasis perspective on viral evolution and adaptation. Expected final online publication date for the Annual Review of Virology, Volume 10 is September 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

The immune-evasive proline-283 substitution in influenza nucleoprotein increases aggregation propensity without altering the native structure

“…In addition, the biophysical defects of Pro 283 NP outlined in this work were observed in the presence of Asp 16 in the background amino acid sequence. Asp 16 is an adaptive substitution that can partially compensate the viral fitness loss caused by the three MxA escape mutations in the 1918 pandemic strain of influenza (Val 100 , Pro 283 , and Tyr 313 ) (15,35).…”

“…In addition, the biophysical defects of Pro 283 NP outlined in this work were observed in the presence of Asp 16 in the background amino acid sequence. Asp 16 is an adaptive substitution that can partially compensate the viral fitness loss caused by the three MxA escape mutations in the 1918 pandemic strain of influenza (Val 100 , Pro 283 , and Tyr 313 ) (15,35). We analyzed the folding consequences of Pro 283 substitution in the presence of Asp 16 because the reduced fitness of Pro 283 NP-encoding influenza in a host chaperonedepleted environment was found in this amino acid background (13).…”

“…The observations that the viability of Pro 283 NP-encoding influenza depends on both temperature and the availability of HSF1regulated chaperones suggest that the fitness defect could be attributable to protein-folding challenges caused by the Pro 283 substitution, yet no study has identified a molecular-level explanation for this fitness defect. Elucidating the underlying molecular basis of fitness loss caused by the Pro 283 substitution would yield key insights into the constraints on viral protein evolution, and how host cell chaperones may be hijacked to address these constraints and expand viral mutational landscapes (16).…”

The Immune-Evasive Proline 283 Substitution in Influenza Nucleoprotein Increases Aggregation Propensity Without Altering the Native Structure

“…Emerging studies since 2010s began to show that host proteostasis networks can shape the evolution of viral proteins (13,(36)(37)(38)(39)(40)(41). Nevertheless, while it is evident that host proteostasis factors, particularly chaperones, can define the fitness of viral protein variants, the molecular mechanism has been largely left unclear (16). Our biophysical characterization of Pro283 NP suggests that host-cell chaperones can potentially rescue Pro283 NP by stabilizing an aggregation-prone conformation, or promoting the rapid conversion of the aggregation-prone conformation to a folded conformation In addition, it is important to note that the unfolding/refolding studies performed in this work are in vitro, and aggregation-prone intermediates formed during in vitro refolding sometimes are not observed when protein are allowed to co-translationally fold (42).…”

“…The observations that the viability of Pro283-encoding influenza depends on both temperature and the availability of HSF1-regulated chaperones suggest that the fitness defect can potentially be attributed to protein-folding challenges caused by the Pro283 substitution, yet no study has identified a molecular-level explanation for this fitness defect. Elucidating the underlying molecular basis of fitness loss caused by the Pro283 substitution would yield key insights into the molecular-level constraints on viral protein evolution, and how host cell chaperones may be hijacked to address these constraints and expand viral mutational landscapes (16).…”