| First Author | Tomasi ML | Year | 2016 |
| Journal | Am J Pathol | Volume | 186 |
| Issue | 9 | Pages | 2326-36 |
| PubMed ID | 27561301 | Mgi Jnum | J:235581 |
| Mgi Id | MGI:5796861 | Doi | 10.1016/j.ajpath.2016.05.007 |
| Citation | Tomasi ML, et al. (2016) Ubiquitin-Conjugating Enzyme 9 Phosphorylation as a Novel Mechanism for Potentiation of the Inflammatory Response. Am J Pathol 186(9):2326-36 |
| abstractText | Lipopolysaccharide (LPS), a bacterial endotoxin, induces inflammation in macrophages via activation of NF-kappaB signaling. Sumoylation is a post-translational modification mediated by the small ubiquitin-like modifier, SUMO. Ubiquitin-conjugating enzyme 9 (UBC9) is the only known SUMO conjugating enzyme. LPS treatment lowers SUMO-1 and UBC9 mRNA levels in primary astrocytes. UBC9 can degrade NF-kappaB inhibitor alpha (Ikbalpha) via a SUMO2/3-ubiquitin pathway. However, UBC9 may also promote Ikbalpha stability by SUMO-1 conjugation that further regulates NF-kappaB signaling. The role of UBC9 in liver inflammation is unknown. We reported that CDK1-mediated phosphorylation of UBC9 enhanced its stability. Herein, we describe an anti-inflammatory role of UBC9 that is lost when it is phosphorylated during inflammation. LPS exposure caused induction in UBC9 phosphorylation and CDK1 activation specifically in Kupffer cells in vivo and in RAW264.7 macrophages in vitro. Silencing or overexpression experiments in vitro and in vivo showed that UBC9 was required to blunt the proinflammatory response elicited by LPS. LPS stimulation raised the binding of phospho-UBC9 but not the unphosphorylated counterpart, to Ikbalpha in RAW264.7 macrophages. Hence, phospho-UBC9 may promote NF-kappaB signaling by regulating Ikbalpha and this may be a novel mechanism that deregulates liver inflammatory signaling. |
