CREB-binding protein (CBP) is a versatile histone acetyltransferase (HAT), which plays a crucial role in the regulation of pro-inflammatory cytokine gene transcription in inflammatory diseases including sepsis and lung disorders. Therefore, selectively modulating the availability of CBP can potentially suppress cytokine storm and lessen the severity of sepsis. The ubiquitin-proteasome system disposes of the vast majority of intracellular proteins, including CBP. Ubiquitination is a reversible reaction. De-ubiquitination i mediated by a group of de- ubiquitinating enzymes, which enhances protein stability by removing the degradation signal from the target proteins. However, the de-ubiquitination of CBP has not been previously investigated. Our preliminary data show that ubiquitin specific peptidase (USP)14 de-ubiquitinates CBP and enhances its stability, and that inhibition of USP14 attenuates LPS-increased CBP stability, histone acetylation, and cytokine release, thereby lessening both systemic and pulmonary inflammation. This is the first study to identify a de-ubiquitinating enzyme regulating stability and biological effects of a HAT. This study suggests that IU1, an inhibitor of USP14, is an anti-inflammatory small molecule potentially applicable in new medication for sepsis. Execution of these studies will lay the groundwork for a significant mechanistic advance for the molecular regulation of the innate immune response during severe infection.

Public Health Relevance

Sepsis is a life-threatening illness with high hospitalization and mortality rates caused by bacteria or other microbes. A cytokine storm is commonly seen in sepsis resulting in organ injury. These studies will be the first to elucidate that a de-ubiquitinating enzyme (USP14) regulates cytokine release by de-ubiquitinating and stabilizing a histone acetyltransferase, CBP. IU1, an inhibitor of USP14, suppresses infection-induced chromatin remodeling, cytokine storm, and thereby lessens the severity of sepsis. These studies will be critical in developing novel therapeutics by a small molecule inhibitor of USP14 to lessen the severity of sepsis.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM115389-04
Application #
9503736
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Dunsmore, Sarah
Project Start
2015-07-10
Project End
2020-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Li, Shuang; Zhao, Jing; Shang, Dong et al. (2018) Ubiquitination and deubiquitination emerge as players in idiopathic pulmonary fibrosis pathogenesis and treatment. JCI Insight 3:
Li, Shuang; Wang, Dan; Zhao, Jing et al. (2018) The deubiquitinating enzyme USP48 stabilizes TRAF2 and reduces E-cadherin-mediated adherens junctions. FASEB J 32:230-242
Wei, Jianxin; Dong, Su; Yao, Kangning et al. (2018) Histone acetyltransferase CBP promotes function of SCF FBXL19 ubiquitin E3 ligase by acetylation and stabilization of its F-box protein subunit. FASEB J 32:4284-4292
Cai, Junting; Wei, Jianxin; Schrott, Valerie et al. (2018) Induction of deubiquitinating enzyme USP50 during erythropoiesis and its potential role in the regulation of Ku70 stability. J Investig Med 66:1-6
Cai, Junting; Culley, Miranda K; Zhao, Yutong et al. (2018) The role of ubiquitination and deubiquitination in the regulation of cell junctions. Protein Cell 9:754-769
Wang, Dan; Zhao, Jing; Li, Shuang et al. (2018) Phosphorylated E2F1 is stabilized by nuclear USP11 to drive Peg10 gene expression and activate lung epithelial cells. J Mol Cell Biol 10:60-73
Li, Shuang; Liu, Jia; Tan, Jiangning et al. (2018) Inhibition of Raf1 ameliorates bleomycin-induced pulmonary fibrosis through attenuation of TGF-?1 signaling. Am J Physiol Lung Cell Mol Physiol 315:L241-L247
Suber, Tomeka L; Nikolli, Ina; O'Brien, Michael E et al. (2018) FBXO17 promotes cell proliferation through activation of Akt in lung adenocarcinoma cells. Respir Res 19:206
Suber, Tomeka; Wei, Jianxin; Jacko, Anastasia M et al. (2017) SCFFBXO17 E3 ligase modulates inflammation by regulating proteasomal degradation of glycogen synthase kinase-3? in lung epithelia. J Biol Chem 292:7452-7461
Wei, Jianxin; Dong, Su; Bowser, Rachel K et al. (2017) Regulation of the ubiquitylation and deubiquitylation of CREB-binding protein modulates histone acetylation and lung inflammation. Sci Signal 10:

Showing the most recent 10 out of 19 publications