| First Author | Pradère JP | Year | 2016 |
| Journal | Sci Signal | Volume | 9 |
| Issue | 442 | Pages | ra85 |
| PubMed ID | 27555662 | Mgi Jnum | J:259719 |
| Mgi Id | MGI:6140391 | Doi | 10.1126/scisignal.aab2820 |
| Citation | Pradere JP, et al. (2016) Negative regulation of NF-kappaB p65 activity by serine 536 phosphorylation. Sci Signal 9(442):ra85 |
| abstractText | Nuclear factor kappaB (NF-kappaB) is a master regulator of inflammation and cell death. Whereas most of the activity of NF-kappaB is regulated through the inhibitor of kappaB (IkappaB) kinase (IKK)-dependent degradation of IkappaB, IKK also phosphorylates subunits of NF-kappaB. We investigated the contribution of the phosphorylation of the NF-kappaB subunit p65 at the IKK phosphorylation site serine 536 (Ser(536)) in humans, which is thought to be required for the activation and nuclear translocation of NF-kappaB. Through experiments with knock-in mice (S534A mice) expressing a mutant p65 with an alanine-to-serine substitution at position 534 (the murine homolog of human Ser(536)), we observed increased expression of NF-kappaB-dependent genes after injection of mice with the inflammatory stimulus lipopolysaccharide (LPS) or exposure to gamma irradiation, and the enhanced gene expression was most pronounced at late time points. Compared to wild-type mice, S534A mice displayed increased mortality after injection with LPS. Increased NF-kappaB signaling in the S534A mice was at least in part explained by the increased stability of the S534A p65 protein compared to that of the Ser(534)-phosphorylated wild-type protein. Together, our results suggest that Ser(534) phosphorylation of p65 in mice (and, by extension, Ser(536) phosphorylation of human p65) is not required for its nuclear translocation, but instead inhibits NF-kappaB signaling to prevent deleterious inflammation. |
