Enteroviruses are characterized by their high replication rates and extreme sequence plasficity, which allow them to rapidly adapt to different environments and hosts. These viruses depend entirely on the host protein homeostasis machinery, composed of molecular chaperones and quality control (QC) components such as the ubiquitin-proteasome system, for viral protein production and function. Enterovirus replication poses several challenges to the cellular protein homeostasis machinery as the need to produce high amounts of protein in a very short time places a big burden for the host protein production and folding machineries. Furthermore, enteroviral proteins tend to be large, complex and multifunctional, and thus likely to require the assistance of molecular chaperones to fold. Indeed, we have shown that the Hsp90 chaperone system is essential for capsid folding and assembly for many, perhaps most, picornaviruses, including the enterovirus polio- and coxsakie-viruses. Since other aspects of enterovirus replication Involve additional large multlprotein complexes, chaperones are likely to be broadly required for other aspects of the viral cycle. An important challenge to protein homeostasis in RNA viruses arises from their very high mutation rates, which pose a big burden to viral protein stability and are likely to produce high levels of non-functional or destabilized proteins. These mutant proteins must be either maintained in a funcfional state or eliminated from the cell to prevent dominant negative effects on viral function. We hypothesize that these functions are carried out by chaperones, which can buffer metastable proteins, as well as by the ubiquitin-proteasome system, which targets misfolded proteins for degradation. To understand the molecular and cellular mechanisms by which cellular chaperone and quality control machineries control viral protein homeostasis, and allow the virus to replicate we propose the following Aims:
Aim 1 : Define the chaperone components required for enterovirus replication.
Aim 2 : Define the role of the Quality control (QC) machinery in picornavirus replication Aim 3: Examine the plasticity and interplay of chaperone and QC pathways during viral infection

Public Health Relevance

The rapid evolution of RNA viruses is a major challenge to the management of chronic Infections and the control of emerging infecfious agents. Understand the link between how molecular mechanisms of virus replication are molded by the host protein homeostasis machinery and their ability to evolve and adapt Is a fundamental and novel quesfion in virology that may lead to more effective antiviral therapies.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-BB-M)
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; Dolan, Patrick Timothy; Goldstein, Elizabeth Faul et al. (2017) Poliovirus intrahost evolution is required to overcome tissue-specific innate immune responses. Nat Commun 8:375
Stern, Adi; Yeh, Ming Te; Zinger, Tal et al. (2017) The Evolutionary Pathway to Virulence of an RNA Virus. Cell 169:35-46.e19
Menéndez-Arias, Luis; Andino, Raul (2017) Viral polymerases. Virus Res 234:1-3
Tassetto, Michel; Kunitomi, Mark; Andino, Raul (2017) Circulating Immune Cells Mediate a Systemic RNAi-Based Adaptive Antiviral Response in Drosophila. Cell 169:314-325.e13
Whitfield, Zachary J; Dolan, Patrick T; Kunitomi, Mark et al. (2017) The Diversity, Structure, and Function of Heritable Adaptive Immunity Sequences in the Aedes aegypti Genome. Curr Biol 27:3511-3519.e7
Lidsky, Peter V; Andino, Raul; Rouzine, Igor M (2017) Variability in viral pathogenesis: modeling the dynamic of acute and persistent infections. Curr Opin Virol 23:120-124
Whitfield, Zachary J; Andino, Raul (2016) Characterization of Viral Populations by Using Circular Sequencing. J Virol 90:8950-3
Webb, Benjamin; Sali, Andrej (2016) Comparative Protein Structure Modeling Using MODELLER. Curr Protoc Bioinformatics 54:5.6.1-5.6.37
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
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 428:709-719

Showing the most recent 10 out of 48 publications