SCFFBXL19 E3 ligase regulates CBP ubiquitination and degradation and reduces lung injury (406.1)

Abstract

Rationale: CREB‐binding protein (CBP), a versatile acetyltransferase, plays a critical role in the pathology of Acute Lung Injury (ALI) via regulation of proinflammatory gene expression. However, molecular regulation of CBP at the level of protein stability has not been well studied. Three enzyme complexes (E1, E2, and E3) are involved in linking ubiquitin chains onto target proteins. F‐box protein is a substrate‐recognition component within the SCF E3 ligase complex. Here, we investigate the role of F‐box protein, FBXL19, in the regulation of CBP ubiquitination and degradation. Methods and Results: We found that FBXL19‐V5 over‐expression reduced both endogenous and over‐expressed CBP in mouse lung epithelial cells (MLE12). Further, over‐expression of FBXL19 induced CBP ubiquitination, which was reduced in FBXL19 knock‐down cells. Co‐immunoprecipitation and co‐immunostaining studies showed that FBXL19 is associated with CBP. To investigate the role of FBXL19 in CBP‐mediated histone acetylation and proinflammatory gene expression, we transfected human lung epithelial cells with FBXL19‐V5 plasmid prior to bacterial endotoxin treatment. FBXL19‐V5 attenuated LPS‐induced histone H4 acetylation at lysine residue 8 (H4K8) and IL‐8 release. Further, we found that over‐expression of FBXL19 in mouse lungs by intratracheal lentiviral vector gene delivery system attenuated intratracheal LPS‐induced acetylation of H4K8 in mouse lung tissues and IL‐6 in bronchoalveolar lavage fluids.Conclusions: SCFFBXL19 targets CBP for its ubiquitination and degradation. Over‐expression of FBXL19 reduces CBP‐mediated histone acetylation and cytokine release. FBXL19 protects against lung inflammation in bacterial endotoxin‐induced murine model of acute lung injury. These data may provide a potential therapeutic strategy to target FBXL19 / CBP pathway to lessen the severe of lung inflammatory diseases.Grant Funding Source: The study is supported by NIH RO1 HL091916 and HL112791 (to YZ) and American Heart Association Scien