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Viroporins are small and usually
hydrophobic In chemistry, hydrophobicity is the chemical property of a molecule (called a hydrophobe) that is seemingly repelled from a mass of water. In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, thu ...
multifunctional viral
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
s that modify cellular membranes, thereby facilitating
virus A virus is a submicroscopic infectious agent that replicates only inside the living Cell (biology), cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea. Viruses are ...
release from infected cells. Viroporins are capable of assembling into oligomeric
ion channel Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by Gating (electrophysiol ...
s or pores in the host cell's membrane, rendering it more permeable and thus facilitating the exit of
virion A virion (plural, ''viria'' or ''virions'') is an inert virus particle capable of invading a Cell (biology), cell. Upon entering the cell, the virion disassembles and the genetic material from the virus takes control of the cell infrastructure, t ...
s from the cell. Many viroporins also have additional effects on cellular metabolism and
homeostasis In biology, homeostasis (British English, British also homoeostasis; ) is the state of steady internal physics, physical and chemistry, chemical conditions maintained by organism, living systems. This is the condition of optimal functioning fo ...
mediated by protein-protein interactions with host cell proteins. Viroporins are not necessarily essential for
viral replication Viral replication is the formation of biological viruses during the infection process in the target host cells. Viruses must first get into the cell before viral replication can occur. Through the generation of abundant copies of its genome ...
, but do enhance growth rates. They are found in a variety of viral
genome A genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding genes, other functional regions of the genome such as ...
s but are particularly common in
RNA virus An RNA virus is a virus characterized by a ribonucleic acid (RNA) based genome. The genome can be single-stranded RNA (ssRNA) or double-stranded (Double-stranded RNA, dsRNA). Notable human diseases caused by RNA viruses include influenza, SARS, ...
es. 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.


Structure

Viroporins are usually small - under 100 or 120
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
residues - and contain at least one region capable of folding into an amphipathic
transmembrane A transmembrane protein is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequently u ...
helix. Some examples also contain stretches of
basic Basic or BASIC may refer to: Science and technology * BASIC, a computer programming language * Basic (chemistry), having the properties of a base * Basic access authentication, in HTTP Entertainment * Basic (film), ''Basic'' (film), a 2003 film ...
amino acids, or stretches of aromatic amino acids thought to reside in the interfacial region of the membrane. Oligomers of these proteins, most often tetramers, form
ion channel Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by Gating (electrophysiol ...
s or pores of usually weak ion selectivity that permit diffusion of ions across the
cell membrane The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of a cell from the outside environment (the extr ...
. The molecular architecture of the pore, its degree of selectivity, the extent to which it incorporates
lipid Lipids are a broad group of organic compounds which include fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include storing ...
s 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.


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 The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein Proteins are large biomolecules and macromolecules that comp ...
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 The endoplasmic reticulum (ER) is a part of a transportation system of the eukaryote, eukaryotic cell, and has many other important functions such as protein folding. The word endoplasmic means "within the cytoplasm", and reticulum is Latin for ...
) and in class IIB the termini are oriented toward the cytosol. Likely exceptions to this scheme exist, such as the
rotavirus Rotaviruses are the most common cause of diarrhea, diarrhoeal disease among infants and young children. Nearly every child in the world is infected with a rotavirus at least once by the age of five. Immunity (medical), Immunity develops with ...
protein non-structural protein 4.


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. 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.


Membrane permeabilization

The most well-studied and well-established function of viroporins is the permeabilization of the
cell membrane The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of a cell from the outside environment (the extr ...
to ions and small solutes. 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. Viroporins expressed transgenically, in the absence of their virus of origin, induce the same effect, a feature that has facilitated viroporin discovery. In most cases, pores formed by viroporins are nonselective or only weakly selective for particular ions or small molecules. 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 Potassium is a chemical element; it has Symbol (chemistry), symbol K (from Neo-Latin ) and atomic number19. It is a silvery white metal that is soft enough to easily cut with a knife. Potassium metal reacts rapidly with atmospheric oxygen to ...
ions. An alternative mechanism is illustrated by the SARS-CoV E protein, which forms a pore that integrates membrane
lipid Lipids are a broad group of organic compounds which include fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include storing ...
s whose polar head groups influence ion selectivity. The homologous E protein of
SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is a strain of coronavirus that causes COVID-19, the respiratory illness responsible for the COVID-19 pandemic. The virus previously had the Novel coronavirus, provisional nam ...
has been structurally characterized by solid-state NMR and found to form a pentamer permeable to
cation An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by convent ...
s. 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
organelle In cell biology, an organelle is a specialized subunit, usually within a cell (biology), cell, that has a specific function. The name ''organelle'' comes from the idea that these structures are parts of cells, as Organ (anatomy), organs are to th ...
s such as the
Golgi apparatus The Golgi apparatus (), also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle found in most eukaryotic Cell (biology), cells. Part of the endomembrane system in the cytoplasm, it protein targeting, packages proteins ...
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
virion A virion (plural, ''viria'' or ''virions'') is an inert virus particle capable of invading a Cell (biology), cell. Upon entering the cell, the virion disassembles and the genetic material from the virus takes control of the cell infrastructure, t ...
s to exit the cell. In enveloped viruses, viroporins' depolarization effect is thought to promote viral budding. Abrogating the ion channel or pore function of viroporins, either through
mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...
s that block conductance without disrupting other functions or through channel-blocking drugs, usually reduces or eliminates viral propagation.


Genome replication

Most viruses encoding viroporins can replicate their genomes in the absence of the viroporin, even if they are impaired in propagation.
Rotavirus Rotaviruses are the most common cause of diarrhea, diarrhoeal disease among infants and young children. Nearly every child in the world is infected with a rotavirus at least once by the age of five. Immunity (medical), Immunity develops with ...
es and picornaviruses, however, rely on their viroporins to facilitate the formation of
viroplasm A viroplasm, sometimes called "virus factory" or "virus inclusion", is an Inclusion bodies, inclusion body in a Cell (biology), cell where viral replication and assembly occurs. They may be thought of as viral factories in the cell. There are many ...
, or specialized intracellular compartments remodeled from the membrane of the
endoplasmic reticulum The endoplasmic reticulum (ER) is a part of a transportation system of the eukaryote, eukaryotic cell, and has many other important functions such as protein folding. The word endoplasmic means "within the cytoplasm", and reticulum is Latin for ...
in which genome replication occurs.


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
CD4 In molecular biology, CD4 (cluster of differentiation 4) is a glycoprotein that serves as a co-receptor for the T-cell receptor (TCR). CD4 is found on the surface of immune cells such as helper T cells, monocytes, macrophages, and dendritic c ...
and tetherin, though the precise molecular mechanism of this interaction is not known. 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.


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 A protein complex or multiprotein complex is a group of two or more associated polypeptide chains. Protein complexes are distinct from multidomain enzymes, in which multiple active site, catalytic domains are found in a single polypeptide chain. ...
associated with activation of innate immunity which, when overactive, can cause disease symptoms.


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. This was the first known example of an oncogenic viroporin.


Drug targets

Because some viroporins are essential for viral propagation, they are often considered to be appealing
drug target A biological target is anything within a living organism to which some other entity (like an endogenous ligand or a drug) is directed and/or binds, resulting in a change in its behavior or function. Examples of common classes of biological targets ...
s for development of antiviral drugs. Although many chemical compounds have been reported to interfere with the ion channel functions of various viroporins, clinical usage is relatively rare.
Amantadine Amantadine, sold under the brand name Gocovri among others, is a medication used to treat dyskinesia associated with parkinsonism and influenza caused by type A influenzavirus, though its use for the latter is no longer recommended because ...
, 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; however, a 2014 Cochrane review did not find benefit for its use in children or elderly people and the US CDC does not recommend drugs of this class due to widespread resistance
mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...
s.


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, Table 1 from Wang et al. 2011, and Table 1, Box 1, and Box 2 from Nieva et al. 2012.


See also

* Holins, small pore-forming transmembrane proteins produced by dsDNA
bacteriophage A bacteriophage (), also known informally as a phage (), is a virus that infects and replicates within bacteria. The term is derived . Bacteriophages are composed of proteins that Capsid, encapsulate a DNA or RNA genome, and may have structu ...
s


References


External links

*
Links to Viroporin families
in TCDB database {{Viral proteins Viral protein class Protein families