E-protein is involved in several aspects of the virus life cycle, such as assembly, budding, envelope formation and pathogenesis. E protein’s ion channel activity is found in the transmembrane region of the protein. The membrane potential has been regulated by E-protein controlling the ion flow between the intracellular and extracellular environtment. The ion conductivity triggered by E-protein via the manipulation of COVID-19 genome seems to be a novel route involved in virus pathogenesis. Although, the E-protein has been interacted with other coronavirus proteins as well as host cell proteins. E-protein’s ion channel activity and the alteration of coronavirus cell ion balance by E-protein is a necessary process for virus production but the effect of E-protein ion channel activity in virus pathogenesis remains elusive.