Intracellular localization of human ZBP1: Differential regulation by the Z-DNA binding domain, Zα, in splice variants

Abstract

We investigated the subcellular distribution of human ZBP1, which harbors the N-terminal Z-DNA binding domains, Zα and Zβ. ZBP1 was distributed primarily in the cytoplasm and occasionally as nuclear foci in interferon (IFN)-treated primary hepatocellular carcinoma cells, and in several other transfected cell types. In leptomycin B (LMB)-treated cells, endogenous ZBP1 efficiently accumulated in nuclear foci, which overlapped PML oncogenic domains (PODs) or nuclear bodies (NBs). In transfection assays, the unique C-terminal region of ZBP1 was necessary for its typical cytoplasmic localization. Interestingly, the Zα-deleted form displayed an increased association with PODs compared to wild-type and, unlike wild-type, perfectly accumulated in PODs in LMB-treated cells, implying that the presence of Zα domain also facilitates the cytoplasmic localization. Our results demonstrate that ZBP1 is localized primarily in the cytoplasm but also associated with nuclear PODs in IFN or LMB-treated cells. Given that about half of ZBP1 mRNA lacks exon 2 encoding the Zα domain, our data also suggest that the localization of ZBP1 may be differentially regulated by the Z-DNA binding domain, Zα, in splice variants.