Viroporin
Viroporins are small and usually hydrophobic multifunctional viral proteins that modify cellular membranes, thereby facilitating virus release from infected cells.[2][3] Viroporins are capable of assembling into oligomeric ion channels or pores in the host cell's membrane, rendering it more permeable and thus facilitating the exit of virions from the cell. Many viroporins also have additional effects on cellular metabolism and homeostasis mediated by protein-protein interactions with host cell proteins.[3] Viroporins are not necessarily essential for viral replication, but do enhance growth rates. They are found in a variety of viral genomes but are particularly common in RNA viruses. Many viruses that cause human disease express viroporins. These viruses include hepatitis C virus, HIV-1, influenza A virus, poliovirus, respiratory syncytial virus, and SARS-CoV.[3][4][5]
Structure
Viroporins are usually small - under 100 or 120 amino acid residues - and contain at least one region capable of folding into an amphipathic transmembrane helix. Some examples also contain stretches of basic amino acids, or stretches of aromatic amino acids thought to reside in the interfacial region of the membrane.[3] Oligomers of these proteins, most often tetramers,[6] form ion channels or pores of usually weak ion selectivity that permit diffusion of ions across the cell membrane. The molecular architecture of the pore, its degree of selectivity, the extent to which it incorporates lipids from the surrounding membrane, and the presence of portions of the protein that extend beyond the membrane all vary among viroporins and indicate that these proteins have a diverse array of functional roles.[4][5]
Classification
A proposed classification scheme sorts viroporins into four classes based on their topology and orientation in the membrane. Class I viroporins possess a single transmembrane helix; in class IA the C-terminus is oriented into the cytosol and in class IB the N-terminus is so oriented. Class II viroporins possess a helix-turn-helix motif with both helices crossing the membrane; in class IIA both termini are oriented externally (extracellularly or toward the lumen of the endoplasmic reticulum) and in class IIB the termini are oriented toward the cytosol.[5] Likely exceptions to this scheme exist, such as the rotavirus protein non-structural protein 4.[7][8]
Function
Essentiality
Most viroporins are not essential, but their absence significantly reduces the efficiency of viral propagation. There is significant variation in the consequences of viroporin depletion: while hepatitis C virus is incapable of propagation without its p7 protein viroporin, influenza A virus and HIV-1 see decreases in in vitro viral titer of 10- to 100-fold in the absence of their respective viroporins, but remain capable of propagation.[4][9] In most cases absence of viroporin in the viral genome can be rescued by the presence of viroporin in trans, and sometimes viral replication can be partially rescued in the presence of another virus' viroporin.[5]
Membrane permeabilization
The most well-studied and well-established function of viroporins is the permeabilization of the cell membrane to ions and small solutes.[10] Before viroporins themselves were understood as a class, it was well known that many viruses induce membrane permeabilization in infected cells; viroporins are at least partially responsible for this effect, particularly when it occurs late in the viral replication cycle.[2][3][11] Viroporins expressed transgenically, in the absence of their virus of origin, induce the same effect, a feature that has facilitated viroporin discovery.[5][12]
In most cases, pores formed by viroporins are nonselective or only weakly selective for particular ions or small molecules.[9] However, some examples do show strong selectivity; examples include the influenza A virus M2 proton channel protein, which is highly selective for protons and is active at low pH, and the Chlorella virus Kcv protein, which is selective for potassium ions. An alternative mechanism is illustrated by the SARS-CoV E protein, which forms a pore that integrates membrane lipids whose polar head groups influence ion selectivity.[4]
Loss of membrane polarization can promote viral yields through a variety of mechanisms that operate throughout the viral life cycle. In enveloped viruses, viroporins are not highly concentrated in the viral envelope, but nevertheless their presence may promote viral entry into the cell; the influenza A virus provides a well-studied example. Viroporins in the membranes of organelles such as the Golgi apparatus can influence those organelles' internal environments, which can modulate protein trafficking of viral proteins or protect the proteins from the low pH they would otherwise encounter in these cellular compartments. In non-enveloped viruses, the membrane permeability changes may be sufficient to induce cell lysis, thereby permitting the new virions to exit the cell. In enveloped viruses, viroporins' depolarization effect is thought to promote viral budding.[4][5] Abrogating the ion channel or pore function of viroporins, either through mutations that block conductance without disrupting other functions or through channel-blocking drugs, usually reduces or eliminates viral propagation.[4]
Genome replication
Most viruses encoding virporins can replicate their genomes in the absence of the viroporin, even if they are impaired in propagation. Rotaviruses and picornaviruses, however, rely on their viroporins to facilitate the formation of viroplasm, or specialized intracellular compartments remodeled from the membrane of the endoplasmic reticulum in which genome replication occurs.[5]
Protein-protein interactions
Some viroporins have established functional effects exerted through protein-protein interactions. For example, the HIV-1 viroporin Vpu promotes viral budding through interactions with the CD4 receptor and tetherin, though the precise molecular mechanism of this interaction is not known.[6][7][9] The JC polyomavirus agnoprotein functions as a viroporin in addition to other roles mediated through interactions with viral proteins such as major capsid protein VP1.[13]
Role in disease
Virulence factors
Viroporins can also be considered virulence factors; in viruses in which viroporins are not essential, their pathogenicity is attenuated in the absence of viroporin beyond the level expected by the effects on viral propagation. In some cases the membrane permeabilization effects of viroporins activate the inflammasome, a protein complex associated with activation of innate immunity which, when overactive, can cause disease symptoms.[4]
Oncoproteins
The human papillomavirus 16 E5 protein, the least well-studied of the three known oncogenic HPV proteins, was reported in 2012 to be a viroporin.[14] This was the first known example of an oncogenic viroporin.[7]
Drug targets
Because some viroporins are essential for viral propagation, they are often considered to be appealing drug targets for development of antiviral drugs.[3][9] Although many chemical compounds have been reported to interfere with the ion channel functions of various viroporins, clinical usage is relatively rare. Amantadine, which was discovered in the 1960s and has been in clinical use against influenza A for some time, is an example of a viroporin-targeting drug;[4][15][16] however, a 2014 Cochrane review did not find benefit for its use.[17]
Examples
Viroporins can be found in a large number of viruses with distinct genomic organizations and replication mechanisms.
This table represents a composite of Table 1 from Gonzalez et al. 2003,[3] Table 1 from Wang et al. 2011,[6] and Table 1, Box 1, and Box 2 from Nieva et al. 2012.[5]
See also
- Holins, small pore-forming transmembrane proteins produced by dsDNA bacteriophages
References
- ^ Thomaston JL, Alfonso-Prieto M, Woldeyes RA, Fraser JS, Klein ML, Fiorin G, DeGrado WF (November 2015). "High-resolution structures of the M2 channel from influenza A virus reveal dynamic pathways for proton stabilization and transduction". Proceedings of the National Academy of Sciences of the United States of America. 112 (46): 14260–5. Bibcode:2015PNAS..11214260T. doi:10.1073/pnas.1518493112. PMC 4655559. PMID 26578770.
- ^ a b Carrasco L (August 1995). "Modification of membrane permeability by animal viruses". Advances in Virus Research. 45: 61–112. doi:10.1016/S0065-3527(08)60058-5. ISBN 9780120398454. PMC 7131156. PMID 7793329.
- ^ a b c d e f g h Gonzalez ME, Carrasco L (September 2003). "Viroporins". FEBS Letters. 552 (1): 28–34. doi:10.1016/S0014-5793(03)00780-4. PMID 12972148. S2CID 209557930.
- ^ a b c d e f g h Nieto-Torres JL, Verdiá-Báguena C, Castaño-Rodriguez C, Aguilella VM, Enjuanes L (July 2015). "Relevance of Viroporin Ion Channel Activity on Viral Replication and Pathogenesis". Viruses. 7 (7): 3552–73. doi:10.3390/v7072786. PMC 4517115. PMID 26151305.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ a b c d e f g h i Nieva JL, Madan V, Carrasco L (July 2012). "Viroporins: structure and biological functions". Nature Reviews. Microbiology. 10 (8): 563–74. doi:10.1038/nrmicro2820. PMC 7097105. PMID 22751485.
- ^ a b c d Wang K, Xie S, Sun B (February 2011). "Viral proteins function as ion channels". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1808 (2): 510–5. doi:10.1016/j.bbamem.2010.05.006. PMC 7094589. PMID 20478263.
- ^ a b c Luis Nieva J, Carrasco L (October 2015). "Viroporins: Structures and Functions beyond Cell Membrane Permeabilization". Viruses. 7 (10): 5169–71. doi:10.3390/v7102866. PMC 4632374. PMID 26702461.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Hu L, Crawford SE, Hyser JM, Estes MK, Prasad BV (August 2012). "Rotavirus non-structural proteins: structure and function". Current Opinion in Virology. 2 (4): 380–8. doi:10.1016/j.coviro.2012.06.003. PMC 3422752. PMID 22789743.
- ^ a b c d González ME (August 2015). "Vpu Protein: The Viroporin Encoded by HIV-1". Viruses. 7 (8): 4352–68. doi:10.3390/v7082824. PMC 4576185. PMID 26247957.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Gonzalez ME, Carrasco L (2005). "Viral proteins that enhance membrane permeability". In Fischer WB (ed.). Viral membrane proteins : structure, function, and drug design. New York: Kluwer Academic/Plenum Publishers. pp. 79–90. doi:10.1007/0-387-28146-0_6. ISBN 978-0-387-28146-9. S2CID 81259776.
- ^ Carrasco L, Otero MJ, Castrillo JL (1989). "Modification of membrane permeability by animal viruses". Pharmacology & Therapeutics. 40 (2): 171–212. doi:10.1016/0163-7258(89)90096-x. PMID 2499894.
- ^ Pinto LH, Holsinger LJ, Lamb RA (May 1992). "Influenza virus M2 protein has ion channel activity". Cell. 69 (3): 517–28. doi:10.1016/0092-8674(92)90452-I. PMID 1374685. S2CID 3135930.
- ^ Suzuki T, Orba Y, Okada Y, Sunden Y, Kimura T, Tanaka S, Nagashima K, Hall WW, Sawa H (March 2010). "The human polyoma JC virus agnoprotein acts as a viroporin". PLOS Pathogens. 6 (3): e1000801. doi:10.1371/journal.ppat.1000801. PMC 2837404. PMID 20300659.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Wetherill LF, Holmes KK, Verow M, Müller M, Howell G, Harris M, Fishwick C, Stonehouse N, Foster R, Blair GE, Griffin S, Macdonald A (May 2012). "High-risk human papillomavirus E5 oncoprotein displays channel-forming activity sensitive to small-molecule inhibitors". Journal of Virology. 86 (9): 5341–51. doi:10.1128/JVI.06243-11. PMC 3347351. PMID 22357280.
- ^ Oxford JS (January 2007). "Antivirals for the treatment and prevention of epidemic and pandemic influenza". Influenza and Other Respiratory Viruses. 1 (1): 27–34. doi:10.1111/j.1750-2659.2006.00006.x. PMC 4634659. PMID 19453477.
- ^ Oxford JS, Galbraith A (1980). "Antiviral activity of amantadine: a review of laboratory and clinical data". Pharmacology & Therapeutics. 11 (1): 181–262. doi:10.1016/0163-7258(80)90072-8. PMID 6159656.
- ^ Alves Galvão MG, Rocha Crispino Santos MA, Alves da Cunha AJ (November 2014). "Amantadine and rimantadine for influenza A in children and the elderly". The Cochrane Database of Systematic Reviews. 11 (11): CD002745. doi:10.1002/14651858.CD002745.pub4. PMC 7093890. PMID 25415374.