title: Ubiquitin-Conjugating Enzyme 9 Phosphorylation as a Novel Mechanism for Potentiation of the Inflammatory Response.
abstract: Lipopolysaccharide (LPS), a bacterial endotoxin, induces inflammation in macrophages via activation of NF-κB 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-κB inhibitor α (Ikbα) via a SUMO2/3-ubiquitin pathway. However, UBC9 may also promote Ikbα stability by SUMO-1 conjugation that further regulates NF-κB 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 Ikbα in RAW264.7 macrophages. Hence, phospho-UBC9 may promote NF-κB signaling by regulating Ikbα and this may be a novel mechanism that deregulates liver inflammatory signaling.
authors: Division of Gastroenterology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California. Electronic address: marialauda.tomasi@cshs.org.
authors: Maria Lauda
authors: ML
authors: Tomasi
authors: Division of Gastroenterology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California. Electronic address: komal.ramani@cshs.org.
authors: Komal
authors: K
authors: Ramani
authors: Division of Gastroenterology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.
authors: Minjung
authors: M
authors: Ryoo
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004731:Endotoxins / Q000633:toxicity; D004797:Enzyme-Linked Immunosorbent Assay; D006505:Hepatitis / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D000067996:RAW 264.7 Cells; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism*; D000098843:Ubiquitin-Conjugating Enzyme UBC9
chemical_list: D004731:Endotoxins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D044763:Ubiquitin-Conjugating Enzymes; D000098843:Ubiquitin-Conjugating Enzyme UBC9