Mechanistic Insights into the Divergent Membrane Activities of a Viroporin from Chikungunya Virus and Its Transframe Variant

Alphaviruses, a genus of vector-borne viruses in the Togaviridae family, encode a small ion-channel-forming protein, 6K, and its transframe variant (TF) during infections. Although 6K/TF have vital roles in glycoprotein transport, virus assembly, and budding, there is no mechanistic explanation for these functions. We investigated the distinct biochemical functionalities of 6K and TF from the mosquito-borne alphavirus, Chikungunya Virus. We show that like 6K, TF is also capable of forming ion channels in bilayer membranes. The assemblies formed by 6K in membranes are structurally more complex and potentially more ion-restrictive than those formed by TF. Both 6K and TF show strong affinity toward the ER membranes, indicating that the localization of these components at the plasma membrane, as previously reported, is either linked to post-translational modification or mediated through interaction with binding partners. These structural and functional insights may elucidate the distinct roles of 6K and TF in the alphavirus life cycle.