The β4 subunit of Cav1.2 channels is required for an optimal interferon response in cardiac muscle cells

Channeling antiviral immunity?The intracellular β4 subunit of the voltage-gated calcium channel Cav1.2 plays a major role in the proper localization and function of the pore-forming α subunit, but it has also been implicated in regulating gene expression in neurons and lymphocytes. Tammineni et al. found that β4 abundance and nuclear localization were increased in a cardiac cell line in response to treatment with type I interferon (IFN) or infection with dengue virus. The β4 subunit physically interacted with the transcriptional regulator IRF7 and was associated with the increased expression of IFN-stimulated genes. In cells overexpressing the β4 subunit, dengue virus replication was inhibited. Together, these data suggest that the β4 subunit may play a channel-independent role in the antiviral response.The auxiliary β4 subunit of the cardiac Cav1.2 channel plays a poorly understood role in gene transcription. Here, we characterized the regulatory effects of the β4 subunit in H9c2 rat cardiac cells on the abundances of Ifnb mRNA [which encodes interferon-β (IFN-β)] and of the IFN-β–related genes Ddx58, Ifitm3, Irf7, Stat2, Ifih1, and Mx1, as well as on the abundances of the antiviral proteins DDX58, IRF7, STAT2, and IFITM3. Knocking down the β4 subunit in H9c2 cells reduced the expression of IFN-β–stimulated genes. In response to inhibition of the kinase JAK1, the abundances of β4 subunit mRNA and protein were decreased. β4 subunit abundance was increased, and it translocated to the nucleus, in cells treated with IFN-β, infected with dengue virus (DENV), or transfected with poly(I:C), a synthetic analog of double-stranded RNA. Cells that surrounded the virus-infected cells showed translocation of β4 subunit proteins to nuclei in response to spreading infection. We showed that the β4 subunit interacted with the transcriptional regulator IRF7 and that the activity of an Irf7 promoter–driven reporter was increased in cells overexpressing the β4 subunit. Last, overexpressing β4 in undifferentiated and differentiated H9c2 cells reduced DENV infection and decreased the abundance of the viral proteins NS1, NS3, and E-protein. DENV infection and poly(I:C) also increased the concentration of intracellular Ca2+ in these cells. These findings suggest that the β4 subunit plays a role in promoting the expression of IFN-related genes, thereby reducing viral infection.