NAP1L1 regulates NF-κB signaling pathway acting on anti-apoptotic Mcl-1 gene expression

Publication date: Available online 4 July 2017
Source:Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
Author(s): Toshiaki Tanaka, Yasukazu Hozumi, Mitsuyoshi Iino, Kaoru Goto
Nuclear factor-κB (NF-κB) participates in apoptosis signaling pathway under various pathophysiological conditions. It exerts transcriptional control on the anti-apoptotic Bcl-2 family, such as Bcl-2, Bcl-xl, and Mcl-1, which act on the mitochondrial outer membrane. Previously, we described that NF-κB is negatively regulated by diacylglycerol kinase ζ (DGKζ), an enzyme that phosphorylates a lipid second messenger diacylglycerol. DGKζ downregulation enhances inhibitors of NF-κB α (IκBα) degradation and p65 subunit phosphorylation, leading to enhanced NF-κB transcriptional activity. Transcriptional machinery is tightly regulated by assembly/disassembly and modification of nucleosomal components. Of those, the human NAP1-like protein (NAP1L) family functions in the transport, assembly/disassembly of nucleosome core particles. We previously identified NAP1L1 and NAP1L4 as novel DGKζ binding partners, but the mechanism by which NAP1Ls are involved in NF-κB signaling pathway remains unclear. Here we show that knockdown of NAP1L1 suppresses IκBα degradation and nuclear transport of p65 subunit after treatment with TNF-α stimulation, leading to attenuation of the NF-κB transcriptional activity, whereas NAP1L4 knockdown remains silent. Moreover, ChIP assay reveals that NAP1L1 knockdown attenuates p65 binding to the Mcl-1 promoter after TNF-α stimulation. This attenuation leads to reduced expression of anti-apoptotic Mcl-1, thereby decreasing the mitochondrial membrane potential and subsequent apoptosis after treatment with TNF-α and CHX. Collectively, results of this study suggest that NAP1L1 downregulation renders the cell vulnerable to apoptotic cell death through attenuation of NF-κB transcriptional activity on the anti-apoptotic Mcl-1 gene.



from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2tftfF7
via IFTTT