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.

Agency
National Institute of Health (NIH)
Type
Research Program Projects (P01)
Project #
5P01AI091575-04
Application #
8690750
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
DUNS #
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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
Stern, Adi; Bianco, Simone; Yeh, Ming Te et al. (2014) Costs and benefits of mutational robustness in RNA viruses. Cell Rep 8:1026-36
Acevedo, Ashley; Andino, Raul (2014) Library preparation for highly accurate population sequencing of RNA viruses. Nat Protoc 9:1760-9
Morris, John H; Knudsen, Giselle M; Verschueren, Erik et al. (2014) Affinity purification-mass spectrometry and network analysis to understand protein-protein interactions. Nat Protoc 9:2539-54
Acevedo, Ashley; Brodsky, Leonid; Andino, Raul (2014) Mutational and fitness landscapes of an RNA virus revealed through population sequencing. Nature 505:686-90
Hagai, Tzachi; Azia, Ariel; Babu, M Madan et al. (2014) Use of host-like peptide motifs in viral proteins is a prevalent strategy in host-virus interactions. Cell Rep 7:1729-39
Pechmann, Sebastian; Frydman, Judith (2014) Interplay between chaperones and protein disorder promotes the evolution of protein networks. PLoS Comput Biol 10:e1003674
Fraser, James S; Gross, John D; Krogan, Nevan J (2013) From systems to structure: bridging networks and mechanism. Mol Cell 49:222-31
Geller, Ron; Andino, Raul; Frydman, Judith (2013) Hsp90 inhibitors exhibit resistance-free antiviral activity against respiratory syncytial virus. PLoS One 8:e56762
Roguev, Assen; Talbot, Dale; Negri, Gian Luca et al. (2013) Quantitative genetic-interaction mapping in mammalian cells. Nat Methods 10:432-7

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