Downregulation of diacylglycerol kinase ζ enhances activation of cytokine-induced NF-κB signaling pathway

The transcription factor NF-κB family serves as a key component of many pathophysiological events such as innate and adaptive immune response, inflammation, apoptosis, and oncogenesis. Various cell signals trigger activation of the regulatory mechanisms of NF-κB, resulting in its nuclear translocation and transcriptional initiation. The diacylglycerol kinase (DGK) family, a lipid second messenger-metabolizing enzyme in phosphoinositide signaling, is shown to regulate widely various cellular processes. Results of recent studies suggest that one family member, DGKζ, is closely involved in immune and inflammatory responses. Nevertheless, little is known about the regulatory mechanism of DGKζ on NF-κB pathway in cytokine-induced inflammatory signaling. This study shows that siRNA-mediated DGKζ knockdown in HeLa cells facilitates degradation of IκB, followed by nuclear translocation of NF-κB p65 subunit. In addition, DGKζ-deficient MEFs show upregulation of p65 subunit phosphorylation at Serine 468 and 536 and its interaction with CBP transcriptional coactivator upon TNF-α stimulation. These modifications of p65 subunit might engender enhanced NF-κB transcriptional reporter assay of DGKζ knockdown cells. These findings provide further insight into the regulatory mechanisms of cytokine-induced NF-κB activation.