The Golgi-resident protein ACBD3 facilitates the interaction between enteroviral 3A proteins and Exportin-1

Enteroviruses are among the most common viral pathogens in humans, causing illnesses ranging from the common cold to severe and sometimes life-threatening diseases such as acute haemorrhagic conjunctivitis or poliomyelitis. To replicate efficiently within host cells, enteroviruses hijack several host factors, including the lipid kinase PI4KB and the adaptor protein ACBD3. During infection, ACBD3 is recruited to viral replication sites through a direct interaction between its C-terminal GOLD domain and viral non-structural 3A proteins. Here, we identify exportin 1 (XPO1) as a host factor involved in enteroviral replication. We demonstrate that 3A proteins of various enteroviruses recruit the host proteins ACBD3 and XPO1 to form a stable ternary complex. Chemical inhibition of XPO1 with selinexor, (originally developed as an anti-cancer medication), significantly attenuates coxsackievirus B3 replication in human cells. Consequently, our study identifies XPO1 as a host target for potential anti-enteroviral interventions, highlighting an immediate opportunity for drug repurposing.