IL-33, acting via its receptor, ST2L, is a highly potent cytokine implicated in septic injury. The IL-33/ST2L axis appears indispensable in inflammatory signaling as blockade of the ST2L receptor significantly attenuates systemic inflammation. Thus, maneuvers designed to selectively modulate availability of ST2L might lessen the severity of sepsis. However, to date, very little is known regarding the molecular regulation of ST2L expression. In the process of studying bacterial sepsis, we discovered that a new orphan protein, FBXL19 (F-box protein 19, SCFFBXL19), specifically targets phosphorylated ST2L for its ubiquitination and degradation. Our published and preliminary works also shows that ST2L is phosphorylated by glycogen synthase kinase (GSK3?), and that activation of the IL-33/ST2L axis induces cleavage of PARP and PKC? thereby promoting apoptosis. Further, FBXL19 mediated disposal of ST2L attenuates IL-33/ST2L-induced pro-inflammatory signaling, apoptosis, and lessens the severity of inflammatory organ injury in septic murine models. These data led to our novel hypothesis that GSK3?-driven phosphorylation of ST2L serves as a molecular signature for F-box protein mediated ubiquitination and degradation of ST2L in sepsis-associated injury. We will test this hypothesis by executing two specific Aims: (1) To investigate the mechanisms by which GSK3? promotes ST2L degradation and regulates IL-33/ST2L signaling, and (2) To investigate the mechanisms by which FBXL19 and its ligand promotes ST2L ubiquitination and degradation thereby attenuating septic lung injury. These studies will lay the groundwork for a significant mechanistic advance with regard to the molecular regulation of a relatively new receptor (ST2L) involved in sepsis. Results from these studies are intended to serve as the basis for strategies directed at the development of novel small molecule inhibitors of the IL-33/ST2L pathway to lessen the severity of sepsis-induced organ injury.

Public Health Relevance

Acute lung injury (ALI) is a cause of respiratory failure resulting from acute pulmonary inflammation. Almost half of patients with septic shock develop ALI. These studies will identify molecular mechanisms on how a new protein, termed F-box protein FBXL19, targets a pro-inflammatory cytokine receptor to mediate its degradation. These studies will be critical in developing a novel small molecule as potential therapeutics to lessen the severity of sepsis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL112791-01A1
Application #
8499556
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Sarkar, Rita
Project Start
2013-06-01
Project End
2017-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$357,952
Indirect Cost
$119,952
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Nan, Ling; Jacko, Anastasia M; Tan, Jiangning et al. (2016) Ubiquitin carboxyl-terminal hydrolase-L5 promotes TGFβ-1 signaling by de-ubiquitinating and stabilizing Smad2/Smad3 in pulmonary fibrosis. Sci Rep 6:33116
Zou, Chunbin; Synan, Matthew J; Li, Jin et al. (2016) LPS impairs oxygen utilization in epithelia by triggering degradation of the mitochondrial enzyme Alcat1. J Cell Sci 129:51-64
Nan, Ling; Wei, Jianxin; Jacko, Anastasia M et al. (2016) Cross-talk between lysophosphatidic acid receptor 1 and tropomyosin receptor kinase A promotes lung epithelial cell migration. Biochim Biophys Acta 1863:229-35
Zhao, Jing; Wei, Jianxin; Dong, Su et al. (2016) Destabilization of Lysophosphatidic Acid Receptor 1 Reduces Cytokine Release and Protects Against Lung Injury. EBioMedicine 10:195-203
Zhao, Jing; Wei, Jianxin; Weathington, Nathaniel et al. (2015) Lysophosphatidic acid receptor 1 antagonist ki16425 blunts abdominal and systemic inflammation in a mouse model of peritoneal sepsis. Transl Res 166:80-8
Wei, Jianxin; Zhao, Jing; Schrott, Valerie et al. (2015) Red Blood Cells Store and Release Interleukin-33. J Investig Med 63:806-10
Zhao, Jing; Wei, Jianxin; Bowser, Rachel K et al. (2015) Focal adhesion kinase-mediated activation of glycogen synthase kinase 3β regulates IL-33 receptor internalization and IL-33 signaling. J Immunol 194:795-802
Zhao, Jing; Zhao, Yutong (2015) Interleukin-33 and its Receptor in Pulmonary Inflammatory Diseases. Crit Rev Immunol 35:451-61
Liu, Y; Lear, T; Zhao, Y et al. (2015) F-box protein Fbxl18 mediates polyubiquitylation and proteasomal degradation of the pro-apoptotic SCF subunit Fbxl7. Cell Death Dis 6:e1630
Lendermon, Elizabeth A; Dodd-o, Jeffrey M; Coon, Tiffany A et al. (2015) CD8(+)IL-17(+) T Cells Mediate Neutrophilic Airway Obliteration in T-bet-Deficient Mouse Lung Allograft Recipients. Am J Respir Cell Mol Biol 52:622-33

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