Viroporins are proteins encoded by viruses that function as modifiers of membrane permeability, to trigger downstream cellular signals. These proteins can form ion channels or pores in the cell membranes, with preferential localization at the endoplasmic reticulum, the Golgi apparatus, and the plasma membranes. . These proteins are coined viroporins due to the similarity to the ion channels called porins.
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Viroporins assembly
Viroporins What was first described in 1992 following the discovery of the ion channel activity of the M2 protein of the influenza virus A. Viroporins are comprised of between 50 and 120 amino acids and form homo-oligomers. Homo-oligomerisation is a process by which low molecular weight polymers are formed by the bonding of several identical monomers. This gives rise to a hydrophilic pore which allows ion transport to occur across the cell membrane.
Viroporins can form domains that span both a hydrophobic membrane and a hydrophilic site is all or lumen because they are comprised of amphipathic α-helices. Ampipathicity refers to the segregation of hydrophobic and hydrophilic amino acid residues between the opposite faces of a protein α-helix, allowing insertion across a membrane.
Once they homo-oligomerize, they create size limited pores in the plasma or internal membranes, often in the endoplasmic reticulum. Often, they contain a stretch of basic amino acids; because these are hydrophilic, when present in the membrane they subsequently caused membrane destabilization and disrupt cellular function.
The creation of these ion channels results in the modification of several cellular functions, including membrane permeability, calcium homeostasis, glycoprotein trafficking, and membrane remodeling.
Classification of viroporins
Several viroporins have evolved to produce distinct effects in host cells, playing a differential role in the viral life cycle. viroporins are divided into two classes according to the number of transmembrane domains (the number of times the protein appears above the bilayer), subclasses are described according to the orientation in the membrane.
Class I viroporins single membrane-spanning domain and are further split into class IA and IB according to whether their amino and carboxyl terminus appear in the lumen or cytosol.
Class II viroporins how to transmembrane domains that are all connected by a loop of basic amino acids paradise as with class I, class II viroporins all stop divided into class IIA ( the N- and C- termini both face the endoplasmic reticulum lumen) and IIB (the opposite orientation):
a | Class I viroporins have one membrane-spanning domain. The A subclass contains proteins that are inserted into the membrane with either a lumenal amino terminus and cytosolic carboxyl terminus (class IA). The B subclass contains a cytosolic amino terminus and a lumenal carboxyl terminus (class IB).
In addition, class IA members are usually phosphorylated at the C terminus. b | Class II viroporins form helix–turn–helix hairpin motifs that span the membrane. Subclass A has N and C termini in the lumen, whereas members of subclass B have cytosolic N and C termini.
These viral ion channel proteins are implicated at several stages of the virus infection lifecycle. The main function is to participate in virion production and release from host cells. Viroporins Also support the entry of viruses into the host cell and genome replication. Studies demonstrate that the deletion of genes encoding viroporins results in a significant reduction in the formation of viral particles. This results in reduced pathogenicity (the ability of the virus to cause disease).
The picornavirus protein 2B (P2B), influenza A virus matrix protein 2 (M2), hepatitis C virus p7 (HCV p7), and HIV-1 viral protein U (Vpu) structures have been analyzed in detail and have revealed unique functions. The latter viroporin has greatly expanded knowledge of the structure and function of these viroporins
The biological function of viroporins
The function of viroporins is primarily to assist in the process of viral entry, replication, and exit. Owing to the ion channel characteristics, they achieve this objective by disrupting ion gradients, thereby affecting chemoelectric-driven homeostatic mechanisms that maintain cellular structure and function.
- Membrane permeability and calcium homeostasis: viroporins alter membrane potential; viroporins that are located at the plasma membrane can disrupt the ionic gradient across the membrane, leading to membrane depolarization
- Calcium homeostasis: the poliovirus protein 2B can assemble pause in the membrane of the endoplasmic reticulum which induces the release of calcium from the endoplasmic reticulum lumen into the cytosol. Consequently, the inner mitochondrial membrane potential which governs the process of ATP synthesis is disrupted as mitochondria can take up the ER-calcium
- Golgi and trans Golgi dissipation of the proton gradient: the viroporins influenza A virus (IAV), M2, and HCV p7 equilibrate the proton concentration with the cytosol which reduces the acidification of the vesicle compartments. This alteration of the intracellular ionic gradient impairs glycoprotein transport. By disrupting the ionic balance in the Golgi, M2 activates host inflammasomes. These are protein complexes that are involved in the processing and release of pro-inflammatory cytokines during the innate immune response to viral infection. Consequently, immune system activation occurs
- Viral progeny assembly, budding, and release: the last step in the maturation of envelope viruses is the budding of virus particles from the plasma membrane or intracellular vesicles. By inserting viroporins into the membrane, the chemoelectrical barrier is broken as ions are conducted across the membrane. This dissipates the membrane potential of the plasma membrane or internal vehicles which therefore stimulates budding.
Viroporins as therapeutic targets
Viroporins represent attractive targets in antiviral therapy as they are gatekeepers of viral release. Inhibiting their membrane permeabilizing activity has been proven to be possible in both artificial membranes and cell culture systems. Therefore, the use of classic viroporin inhibitors could potentiate the efficacy of antiviral treatments.
An example of such targeted viroporin therapy is Amantadine. This was the first drug shown to block IAV uncoating as a result of inhibiting the ion channel activity of M2. However, Amantadine resistant variants have failed to maintain a sustained antiviral response in patients, specifically those harboring mutations in the HCV p7 viroporin. Elucidation of high-resolution crystallographic pore structures are predicted to inform the rational design of specific viroporin inhibitors.
References:
- Nieva JL, Madan V & Carrasco L. (2012) Viroporins: structure and biological functions. Nat Rev Microbiol. doi:10.1038/nrmicro2820.
- Nieva JL, Carrasco L. (2015) Viroporins: Structures and Functions beyond Cell Membrane Permeabilization. Viruses. doi:10.3390/v7102866.
- Gonzalez ME, Carrasco L. (2003) Viroporins FEBS Lett. doi: 10.1016/s0014-5793(03)00780-4.
- Nieto-Torres JL, Verdiá-Báguena C, Castaño-Rodriguez C, et al. (2015) Relevance of Viroporin Ion Channel Activity on Viral Replication and Pathogenesis. Viruses. doi:10.3390/v7072786.
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