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Viroporins in the Influenza Virus


Viroporins in the Influenza Virus

Janet To et al. Cells.


Influenza is a highly contagious virus that causes seasonal epidemics and unpredictable pandemics. Four influenza virus types have been identified to date: A, B, C, and D, where only A-C are known to infect humans. Influenza A (IAV) and B (IBV) viruses are responsible for seasonal influenza epidemics in humans and are responsible for up to a billion flu infections annually. The M2 protein is present in all influenza types and belongs to the class of viroporins (i.e., small proteins that form ion channels that increase membrane permeability in virus-infected cells). In influenza A and B, AM2 and BM2 are predominantly proton channels, although they also show some permeability to monovalent cations. In contrast, M2 proteins in influenza C (ICV) and D (IDV), CM2 and DM2, appear to be especially selective for chloride ions, with possibly some permeability to protons. These differences point to different biological roles for M2 in types A and B versus C and D, which is also reflected in their sequences. AM2 is by far the best characterized viroporin, and mechanistic details and rationale of its acid activation, proton selectivity, unidirectionality and relative low conductance are just beginning to be understood. The present review summarizes the biochemical and structural aspects of influenza viroporins and discusses the most relevant aspects of function, inhibition and interaction with the host.

Keywords: influenza virus; ion channel inhibition; matrix protein 2 (M2); protein-protein interactions; viroporins.

Conflict of interest statement

The authors declare no conflict of interest.


Figure 1
Figure 1
Sequence alignment of M2 viroporins in influenza. Influenza A M2 (AM2; strain A/Udorn/1972 H3N2), influenza B M2 (BM2; strain B/Taiwan/70061/2006), influenza C M2 (CM2; strain C/Ann Arbor/1/1950) and influenza D M2 (DM2; strain D/swine/Oklahoma/1334/2011). The predicted transmembrane regions are underlined. The functional motifs HxxxW (in AM2 and BM2) and YxxxK (in CM2 and DM2) are indicated in bold red font. Numbering corresponds to AM2. Sequences were retrieved from UniProt (
Figure 2
Figure 2
Acid activation mechanism of the AM2 channel. Left: At a high pH (e.g., 7 to 8), the AM2 channel adopts a Cclosed conformation. The closed Trp41 tetrad dehydrates the His37 tetrad and raises the His37 deprotonation barrier, thereby blocking proton conduction. The low charge state of the His37 tetrad at a high pH reduces the electrostatic repulsion with incoming protons, allowing proton permeation from the viral exterior. Right: At a low pH (below 6), the positive charge on the His37 tetrad increases and the Trp41 gate and C-terminal open and become more hydrated, lowering the His37 deprotonation barrier and increasing proton conductance, thereby leading to channel activation in the Copen conformation. Scheme adapted from [70].

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