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Regulation of lysophosphatidic acid receptor 1 stability modulates cytokine release in lung injury
Author(s) -
Zhao Yutong,
Wei Jianxin,
Dong Su,
Bowser Rachel K,
Zhang Lina,
Jacko Anastasia M,
Zhao Jing
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.700.3
Subject(s) - lysophosphatidic acid , ubiquitin , ubiquitin ligase , cytokine , receptor , microbiology and biotechnology , biology , chemistry , biochemistry , immunology , gene
Lysophosphatidic acid receptor 1 (LPA1), a member of G‐protein‐coupled receptors (GPCRs), is a druggable target for treating pulmonary inflammatory diseases, such as acute lung injury and pulmonary fibrosis. However, the molecular regulation of LPA1 stability, a factor that critically impacts its biological activity, remains largely unknown. To investigate the molecular regulation of LPA1 stability, we focus on investigating ubiquitination of LPA1. We identified two enzymes that catalyze ubiquitination and deubiquitination of LPA1. The ubiquitin E3 ligase Nedd4L targets LPA1 for its site specific ubiquitination and degradation in the lysosome. Nedd4L negatively regulates LPA/LPA1‐mediated cytokine release, suggesting targeting LPA1 stability is potential strategy for regulating LPA signaling. The stability of LPA1 is up‐regulated by ubiquitin‐specific protease 11 (USP11), which deubiquitinates and stabilizes LPA1, thus enhancing LPA1‐mediated pro‐inflammatory effects. LPA1 is associated with USP11 in quiescent cells, while LPA treatment triggers LPA1 dis‐association with USP11 and in turn binding to Nedd4L. We have shown that LPA1 contributes to LPS‐induced cytokine release through interaction with CD14. Here, we show that knockdown of USP11 reduces LPA1 stability, levels of LPA1, and LPA1/CD14 interaction complex; thereby diminishing both LPA‐ and LPS‐induced inflammatory responses. C57/BL mice were infected with USP11 shRNA lentivirus for 7 days, and then mice were challenged with intratracheal LPS. USP11 shRNA reduced USP11 levels in lungs and attenuated LPS‐increased BAL protein, IL‐6, KC, and neutrophil infiltration. Our findings identify an ubiquitin E3 ligase and a deubiquitinating enzyme responsible for regulation of LPA1 stability and biological activities. This study provides new targets for the development of anti‐inflammatory molecules to lessen LPA1‐mediated lung injury. Support or Funding Information This work was supported by the US National Institutes of Health (R01HL091916 and R01HL112791 to Y.Z, R01GM115389 to J.Z.), American Heart Association 12SDG9050005 (J.Z.), and American Lung Association Biomedical Research Grant RG350146 (J.Z.).