Viral Membrane Channels: Role and Function in the Virus Life Cycle

Sze, Ching Wooen; Tan, Yee-Joo

From a biological standpoint, viruses are infectious genetic entities that can only replicate inside a living organism. Due to their relatively small genome sizes, viruses hijack and reprogram the host cellular pathways to facilitate their propagation. Viruses are classified into two general categories based Viruses 2015, 7 3262 on the type of genetic materials they carried, either RNA or DNA viruses. These viral genomes encode structural proteins for virion formation as well as enzymatic and accessory proteins to aid in infection and replication. One common type of accessory protein encoded by most viruses is the viral ion channel protein, viroporin. Viroporins are a class of small pore-forming proteins that have been shown to aid in multiple stages of the viral life cycle, from the initial genome replication to the final viral release stage (for a more recent review on viroporins, see [1] [2] [3] [4] [5] [6] ). Viroporins have at least one trans-membrane domain (TMD) and sometimes an extracellular membrane region that interacts with viral or host proteins. The hydrophobic regions of the proteins are capable of forming aqueous pores in the host lipid bilayer upon oligomerization. These pores could be ion-selective with a controlled gating mechanism, or non-selective ones that permeabilize the membrane. A cluster of basic residues within the viroporin aids in membrane insertion by interacting with the negatively charged phospholipids. The first and most extensively studied viroporin, M2 of influenza A virus (IAV), was identified in 1992 [7] ; since then, several viral ion channel proteins have been discovered in other pathogenic animal viruses, including Hepatitis C virus (HCV), Human immunodeficiency virus (HIV)-1, and Coronaviruses (CoV) ( Table 1) . Translocation of DNA genome from ER to cytosol Viral release [44] [45] [46] [47] [48] spectroscopy, has successfully resolved the structure of several viroporins [50] [51] [52] [53] . For example, the M2 of IAV forms a tetrameric pore on the plasma membrane that adopts different conformations as it conducts proton across the membrane [54] [55] [56] , whereas for p7 of HCV, a hexameric flower-shaped complex was revealed via single-particle electron microscopy [57, 58] . p7 has also been found to exist in heptameric form using transmission electron microscopy [59] and a model of how both forms could coexist was proposed [60] . Several key residues that line the inside of the ion channel have been shown to be essential for the activation of the protein via protonation. For instance, mutating the two key histidine residues, H22 and H51 of the human respiratory syncytial virus (hRSV), SH viroporin rendered the ion channel inactive [61] , which is reminiscent of the H37 residue in the M2 ion channel [62] .