Specific inhibition of transcription factor NF-κB through intracellular protein delivery of IκBα by the Herpes virus protein VP22

Abstract

In many cancers, a high constitutive activation of transcription factor NF-κB has been implicated in tumor progression and apoptosis resistance, making NF-κB an attractive target for cancer therapy. Here, we describe the specific inhibition of NF-κB by the intracellular delivery of IκBα through VP22-mediated protein transduction. The Herpes virus protein VP22 has attracted great attention in gene therapy, because of its ability to migrate from an original expressing cell into surrounding recipient cells, resulting in high levels of protein transduction. To evaluate the use of VP22 as a vehicle for NF-κB inhibition, we expressed several versions of VP22-IκBα fusion proteins in baculovirus, bacteria, and mammalian cells. While we could not detect transcellular migration of different VP22-IκBα constructs, interestingly, baculovirally expressed VP22-IκBα was efficiently delivered into cells after exogenous administration. The purified and imported VP22-IκBα retained its function and efficiently inhibited both constitutive and inducible NF-κB activation. We further show that the 34 C-terminal amino acids of VP22 were sufficient for the import property, suggesting also that the ability of intercellular migration and cellular import are not linked to each other. Together, our results demonstrate that recombinant VP22 acts as an efficient vehicle for the exogenous delivery of IκBα and, moreover, might find applications to block NF-κB activation specifically.