Protein kinase Cdelta activates RelA/p65 and nuclear factor-kappaB signaling in response to tumor necrosis factor-alpha.

Abstract

Nuclear factor-kappaB (NF-kappaB) is tightly modulated by IkappaB kinases and IkappaBalpha in the cytoplasm. On stimulation, NF-kappaB translocates into the nucleus to initiate transcription; however, regulation of its transcriptional activity remains obscure. Here, we show that protein kinase C (PKC) delta controls the main subunit of NF-kappaB, RelA/p65. On exposure to tumor necrosis factor-alpha (TNF-alpha), the expression of RelA/p65 target genes such as IkappaBalpha, RelB, and p100/p52 is up-regulated in a PKCdelta-dependent manner. The results also show that PKCdelta is targeted to the nucleus and forms a complex with RelA/p65 following TNF-alpha exposure. Importantly, kinase activity of PKCdelta is required for RelA/p65 transactivation. In concert with these results, PKCdelta activates RelA/p65 for its occupancy to target-gene promoters, including IkappaBalpha and p100/p52. Moreover, functional analyses show that inhibition of PKCdelta is associated with substantial attenuation of NF-kappaB activity in response to TNF-alpha. These findings provide evidence that PKCdelta orchestrates RelA/p65 transactivation, a requisite for NF-kappaB signaling pathway in the nucleus.