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Viroporins: structure and biological functions

Nature Reviews Microbiology volume 10, pages 563–574 (2012)Cite this article

Subjects

Key Points

  • Viroporins are small virally encoded hydrophobic proteins that oligomerize in the membrane of host cells, leading to the formation of hydrophilic pores. This activity modifies several cellular functions, including membrane permeability, Ca2+ homeostasis, membrane remodelling and glycoprotein trafficking.

  • A classification scheme for viroporins is proposed on the basis of their structure and membrane topology. Thus, class I and class II viroporins are defined according to the number of transmembrane domains in the protein (one and two, respectively), and subclasses are defined according to their orientation in the membrane.

  • The main function of viroporins during viral replication is to participate in virion morphogenesis and release from host cells. In addition, some viroporins are involved in viral entry and genome replication.

  • The structure and activity of several viroporins, such as picornavirus protein 2B (P2B), influenza A virus matrix protein 2 (M2), hepatitis C virus p7 and HIV-1 viral protein U (Vpu), have been analysed in detail.

  • New members of this expanding family of viral proteins have been described, from both RNA and DNA viruses. In addition to having a common general structure, all of these new viroporins have the ability to increase membrane permeability.

  • Viroporins represent ideal targets to block viral replication and the spread of infection. Although a number of selective inhibitors of viroporin ion channels have been analysed in detail, optimized screening systems promise to provide new and more potent antiviral compounds in the near future.

Abstract

Viroporins are small, hydrophobic proteins that are encoded by a wide range of clinically relevant animal viruses. When these proteins oligomerize in host cell membranes, they form hydrophilic pores that disrupt a number of physiological properties of the cell. Viroporins are crucial for viral pathogenicity owing to their involvement in several diverse steps of the viral life cycle. Thus, these viral proteins, which include influenza A virus matrix protein 2 (M2), HIV-1 viral protein U (Vpu) and hepatitis C virus p7, represent ideal targets for therapeutic intervention, and several compounds that block their pore-forming activity have been identified. Here, we review recent studies in the field that have advanced our knowledge of the structure and function of this expanding family of viral proteins.

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Figure 1: Classification of viroporins according to the number of transmembrane domains and the membrane topology of the constituent monomers.
Figure 2: Cytopathic effects of viroporins and their functions during the viral life cycle.
Figure 3: Model of a viroporin promoting viral budding at the plasma membrane.
Figure 4: Three-dimensional structures of selected viroporins.

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Acknowledgements

L.C. is supported by the Spanish Ministerio de Ciencia e Innovacion (MICIIN) (grant BFU2009-07352), and J.L.N. is supported by the MICIIN (grant BIO2011-29792) and the Basque Government (grant GIU-06/42). The authors also acknowledge the institutional grant from the Fundacion Ramón Areces to the Centro de Biología Molecular Severo Ochoa at the Universidad Autónoma de Madrid, Spain, and the Spanish Science Research Council (CSIC). The authors thank M. E. González for critical reading of this manuscript.

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Authors and Affiliations

  1. Biophysics Unit, University of the Basque Country and Spanish Science Research Council (CSIC),

    José Luis Nieva

  2. Biochemistry Department, University of the Basque Country, PO Box 644, Bilbao, 48080, Spain

    José Luis Nieva

  3. Department of Infectious Diseases - Molecular Virology, University of Heidelberg, Im Neuenheimer Feld 345, Heidelberg, 69120, Germany

    Vanesa Madan

  4. Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid and CSIC, C/Nicolás Cabrera 1, Cantoblanco, 28049, Madrid, Spain

    Luis Carrasco

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  1. José Luis Nieva
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Glossary

Patch clamping

A high-resolution electrophysiological technique that allows currents to be recorded through single ion channels. The technique uses glass pipettes to electrically isolate channel-containing membrane patches. Current flow can be recorded in cell-attached and excised membrane patches.

Hygromycin B test

An experiment to test membrane permeability. Hygromycin, an inhibitor of translation, does not easily pass through the plasma membrane of control cells, but after cell permeabilization by viroporins, the inhibitor is able to reach its target (the ribosome) and block protein synthesis.

Ionophore

A lipophilic compound that inserts into membranes and transports ions in favour of the electrochemical gradient.

Adamantane

A rigid molecule with a backbone based on three interconnected cyclohexane rings. Derivatives of adamantane (amantadine and rimantadine) have been shown to be effective inhibitors of viroporin activity in some cases.

Molecular dynamics simulations

Computational simulations that calculate the time-dependent motions of atoms in a molecular system. This method is used to obtain microscopic-level information about the fluctuations and conformational changes of proteins.

Inflammasomes

Protein complexes that are involved in the processing and release of pro-inflammatory cytokines during the innate immune response to viral infection.

Autophagosome

A double-membraned vesicle that captures cellular components (including proteins, membrane fragments and whole organelles) and delivers them to lysosomes for degradation through a process called autophagy.

Asymmetrical conductance

The capacity of an ion channel to conduct preferentially outward or preferentially inward ion fluxes.

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Nieva, J., Madan, V. & Carrasco, L. Viroporins: structure and biological functions. Nat Rev Microbiol 10, 563–574 (2012). https://doi.org/10.1038/nrmicro2820

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