The high mutation rates of enteroviruses are essential for their adaptability and pathogenesis. These virus populations do not have a single identical sequence, but rather exist as quasispecies, i.e. clouds of virus with related sequences. Mutations accumulated during virus replication may lead to the destabilization of proteins and Increase their tendency to misfold and aggregate. Molecular chaperones, which promote protein folding and protect the proteome from stress and misfolding, are proposed to buffer detrimental mutations, by restoring the proper conformation of destabilized proteins. Chaperones also communicate with the Ubiquifin Proteasome System (UPS) protein to ensure correct Quality Control (QC) of damaged proteins. Enteroviruses are completely dependent on the cellular chaperone and QC machinery for their protein production and function. Given the very high mutation rates of these viruses, we hypothesize that chaperones and QC components are key to modulating virus diversity, evolution and pathogenesis. Central to our hypothesis Is the idea that viral protein stability is a major constrain on virus evolution and sequence diversity. We propose that chaperones keep viral mutant proteins functional while QC pathways clear nonfunctional dominant negative mutants. This project will examine how these processes modulate the poliovirus, EV71 and coxsakievirus B6 sequence space and viral adaptability. To accomplish this, we will perturb specific components of the protein homeostasis machinery and determine the consequences on population diversity, evolution and pathogenesis.

Public Health Relevance

Enteroviruses have been associated with many clinically recognized, life-threatening syndromes. Virus evolution is at the core of virus drug resistant, immunological survey escape and pathogenesis. Understanding protein homeostasis will illuminate the rules that govern virus diversity, evolution and pathogenesis, and it may allow the development of safe and effective vaccines and anti-enterovirus drugs.

National Institute of Health (NIH)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Francisco
San Francisco
United States
Zip Code
Xiao, Yinghong; Rouzine, Igor M; Bianco, Simone et al. (2016) RNA Recombination Enhances Adaptability and Is Required for Virus Spread and Virulence. Cell Host Microbe 19:493-503
Webb, Benjamin; Sali, Andrej (2016) Comparative Protein Structure Modeling Using MODELLER. Curr Protoc Bioinformatics 54:5.6.1-5.6.37
Cimermancic, Peter; Weinkam, Patrick; Rettenmaier, T Justin et al. (2016) CryptoSite: Expanding the Druggable Proteome by Characterization and Prediction of Cryptic Binding Sites. J Mol Biol 428:709-19
Whitfield, Zachary J; Andino, Raul (2016) Characterization of Viral Populations by Using Circular Sequencing. J Virol 90:8950-3
Verschueren, Erik; Von Dollen, John; Cimermancic, Peter et al. (2015) Scoring Large-Scale Affinity Purification Mass Spectrometry Datasets with MiST. Curr Protoc Bioinformatics 49:8.19.1-16
Ramage, Holly R; Kumar, G Renuka; Verschueren, Erik et al. (2015) A combined proteomics/genomics approach links hepatitis C virus infection with nonsense-mediated mRNA decay. Mol Cell 57:329-40
Davis, Zoe H; Verschueren, Erik; Jang, Gwendolyn M et al. (2015) Global mapping of herpesvirus-host protein complexes reveals a transcription strategy for late genes. Mol Cell 57:349-60
Schulte, Michael B; Draghi, Jeremy A; Plotkin, Joshua B et al. (2015) Experimentally guided models reveal replication principles that shape the mutation distribution of RNA viruses. Elife 4:
Costa, Helio A; Leitner, Michael G; Sos, Martin L et al. (2015) Discovery and functional characterization of a neomorphic PTEN mutation. Proc Natl Acad Sci U S A 112:13976-81
Shah, Priya S; Wojcechowskyj, Jason A; Eckhardt, Manon et al. (2015) Comparative mapping of host-pathogen protein-protein interactions. Curr Opin Microbiol 27:62-8

Showing the most recent 10 out of 41 publications