2014
Liu, Yujie; Wang, Liqing; Han, Rongxiang; Beier, Ulf H; Akimova, Tatiana; Bhatti, Tricia; Xiao, Haiyan; Cole, Philip A; Brindle, Paul K; Hancock, Wayne W
Two histone/protein acetyltransferases, CBP and p300, are indispensable for Foxp3+ T-regulatory cell development and function Journal Article
In: Mol Cell Biol, vol. 34, no. 21, pp. 3993-4007, 2014, ISSN: 1098-5549.
Abstract | Links | BibTeX | Tags: Animals, Cell Survival, Colitis, CREB-Binding Protein, Cyclic AMP Response Element-Binding Protein, E1A-Associated p300 Protein, Epigenesis, Female, Forkhead Transcription Factors, GATA3 Transcription Factor, Genetic, Humans, Inbred C57BL, Male, Mice, Promoter Regions, Regulatory, Sequence Deletion, T-Lymphocytes
@article{1299979,
title = {Two histone/protein acetyltransferases, CBP and p300, are indispensable for Foxp3+ T-regulatory cell development and function},
author = {Yujie Liu and Liqing Wang and Rongxiang Han and Ulf H Beier and Tatiana Akimova and Tricia Bhatti and Haiyan Xiao and Philip A Cole and Paul K Brindle and Wayne W Hancock},
doi = {10.1128/MCB.00919-14},
issn = {1098-5549},
year = {2014},
date = {2014-11-01},
journal = {Mol Cell Biol},
volume = {34},
number = {21},
pages = {3993-4007},
abstract = {T-regulatory (Treg) cells are important to immune homeostasis, and Treg cell deficiency or dysfunction leads to autoimmune disease. A histone/protein acetyltransferase (HAT), p300, was recently found to be important for Treg function and stability, but further insights into the mechanisms by which p300 or other HATs affect Treg biology are needed. Here we show that CBP, a p300 paralog, is also important in controlling Treg function and stability. Thus, while mice with Treg-specific deletion of CBP or p300 developed minimal autoimmune disease, the combined deletion of CBP and p300 led to fatal autoimmunity by 3 to 4 weeks of age. The effects of CBP and p300 deletion on Treg development are dose dependent and involve multiple mechanisms. CBP and p300 cooperate with several key Treg transcription factors that act on the Foxp3 promoter to promote Foxp3 production. CBP and p300 also act on the Foxp3 conserved noncoding sequence 2 (CNS2) region to maintain Treg stability in inflammatory environments by regulating pCREB function and GATA3 expression, respectively. Lastly, CBP and p300 regulate the epigenetic status and function of Foxp3. Our findings provide insights into how HATs orchestrate multiple aspects of Treg development and function and identify overlapping but also discrete activities for p300 and CBP in control of Treg cells.},
keywords = {Animals, Cell Survival, Colitis, CREB-Binding Protein, Cyclic AMP Response Element-Binding Protein, E1A-Associated p300 Protein, Epigenesis, Female, Forkhead Transcription Factors, GATA3 Transcription Factor, Genetic, Humans, Inbred C57BL, Male, Mice, Promoter Regions, Regulatory, Sequence Deletion, T-Lymphocytes},
pubstate = {published},
tppubtype = {article}
}
T-regulatory (Treg) cells are important to immune homeostasis, and Treg cell deficiency or dysfunction leads to autoimmune disease. A histone/protein acetyltransferase (HAT), p300, was recently found to be important for Treg function and stability, but further insights into the mechanisms by which p300 or other HATs affect Treg biology are needed. Here we show that CBP, a p300 paralog, is also important in controlling Treg function and stability. Thus, while mice with Treg-specific deletion of CBP or p300 developed minimal autoimmune disease, the combined deletion of CBP and p300 led to fatal autoimmunity by 3 to 4 weeks of age. The effects of CBP and p300 deletion on Treg development are dose dependent and involve multiple mechanisms. CBP and p300 cooperate with several key Treg transcription factors that act on the Foxp3 promoter to promote Foxp3 production. CBP and p300 also act on the Foxp3 conserved noncoding sequence 2 (CNS2) region to maintain Treg stability in inflammatory environments by regulating pCREB function and GATA3 expression, respectively. Lastly, CBP and p300 regulate the epigenetic status and function of Foxp3. Our findings provide insights into how HATs orchestrate multiple aspects of Treg development and function and identify overlapping but also discrete activities for p300 and CBP in control of Treg cells.
0000
Cao, Jia; Peng, Jinghua; An, Hongying; He, Qiyi; Boronina, Tatiana; Guo, Shaodong; White, Morris F; Cole, Philip A; He, Ling
Endotoxemia-mediated activation of acetyltransferase P300 impairs insulin signaling in obesity Journal Article
In: Nat Commun, vol. 8, no. 1, pp. 131, 0000, ISSN: 2041-1723.
Abstract | Links | BibTeX | Tags: Animals, Cell Line, E1A-Associated p300 Protein, Endoplasmic Reticulum Stress, Endotoxemia, Gene Expression Profiling, Immunoblotting, Inbred C57BL, Insulin, Insulin Resistance, Lipopolysaccharides, Liver, Male, Membrane Proteins, Mice, Obese, Obesity, Protein-Serine-Threonine Kinases, Receptor, Signal Transduction, Tumor, X-Box Binding Protein 1
@article{1299941,
title = {Endotoxemia-mediated activation of acetyltransferase P300 impairs insulin signaling in obesity},
author = {Jia Cao and Jinghua Peng and Hongying An and Qiyi He and Tatiana Boronina and Shaodong Guo and Morris F White and Philip A Cole and Ling He},
doi = {10.1038/s41467-017-00163-w},
issn = {2041-1723},
journal = {Nat Commun},
volume = {8},
number = {1},
pages = {131},
abstract = {Diabetes and obesity are characterized by insulin resistance and chronic low-grade inflammation. An elevated plasma concentration of lipopolysaccharide (LPS) caused by increased intestinal permeability during diet-induced obesity promotes insulin resistance in mice. Here, we show that LPS induces endoplasmic reticulum (ER) stress and protein levels of P300, an acetyltransferase involved in glucose production. In high-fat diet fed and genetically obese ob/ob mice, P300 translocates from the nucleus into the cytoplasm of hepatocytes. We also demonstrate that LPS activates the transcription factor XBP1 via the ER stress sensor IRE1, resulting in the induction of P300 which, in turn, acetylates IRS1/2, inhibits its association with the insulin receptor, and disrupts insulin signaling. Pharmacological inhibition of P300 acetyltransferase activity by a specific inhibitor improves insulin sensitivity and decreases hyperglycemia in obese mice. We suggest that P300 acetyltransferase activity may be a promising therapeutic target for the treatment of obese patients.Elevated plasma LPS levels have been associated with insulin resistance. Here Cao et al. show that LPS induces ER stress and P300 activity via the XBP1/IRE1 pathway. P300 acetylates IRS1/2 and inhibits its binding with the insulin receptor. The consequent impairment of insulin signaling can be rescued by pharmacological inhibition of P300.},
keywords = {Animals, Cell Line, E1A-Associated p300 Protein, Endoplasmic Reticulum Stress, Endotoxemia, Gene Expression Profiling, Immunoblotting, Inbred C57BL, Insulin, Insulin Resistance, Lipopolysaccharides, Liver, Male, Membrane Proteins, Mice, Obese, Obesity, Protein-Serine-Threonine Kinases, Receptor, Signal Transduction, Tumor, X-Box Binding Protein 1},
pubstate = {published},
tppubtype = {article}
}
Diabetes and obesity are characterized by insulin resistance and chronic low-grade inflammation. An elevated plasma concentration of lipopolysaccharide (LPS) caused by increased intestinal permeability during diet-induced obesity promotes insulin resistance in mice. Here, we show that LPS induces endoplasmic reticulum (ER) stress and protein levels of P300, an acetyltransferase involved in glucose production. In high-fat diet fed and genetically obese ob/ob mice, P300 translocates from the nucleus into the cytoplasm of hepatocytes. We also demonstrate that LPS activates the transcription factor XBP1 via the ER stress sensor IRE1, resulting in the induction of P300 which, in turn, acetylates IRS1/2, inhibits its association with the insulin receptor, and disrupts insulin signaling. Pharmacological inhibition of P300 acetyltransferase activity by a specific inhibitor improves insulin sensitivity and decreases hyperglycemia in obese mice. We suggest that P300 acetyltransferase activity may be a promising therapeutic target for the treatment of obese patients.Elevated plasma LPS levels have been associated with insulin resistance. Here Cao et al. show that LPS induces ER stress and P300 activity via the XBP1/IRE1 pathway. P300 acetylates IRS1/2 and inhibits its binding with the insulin receptor. The consequent impairment of insulin signaling can be rescued by pharmacological inhibition of P300.
Hsiao, Po-Yuan; Kalin, Jay H; Sun, Im-Hong; Amin, Mohammed N; Lo, Ying-Chun; Chiang, Meng-Jung; Giddens, John; Sysa-Shah, Polina; Gabrielson, Kathleen; Wang, Lai-Xi; Powell, Jonathan D; Cole, Philip A
An Fc-Small Molecule Conjugate for Targeted Inhibition of the Adenosine 2A Receptor Journal Article
In: Chembiochem, vol. 17, no. 20, pp. 1951-1960, 0000, ISSN: 1439-7633.
Abstract | Links | BibTeX | Tags: Adenosine A2 Receptor Antagonists, Adenosine A2A, Animals, Female, Humans, Immunoglobulin Fab Fragments, Inbred C57BL, Knockout, Male, Mice, Models, Molecular, Molecular Structure, Receptor, Respiratory Tract Infections, Triazines, Triazoles, Vaccinia virus
@article{1299961,
title = {An Fc-Small Molecule Conjugate for Targeted Inhibition of the Adenosine 2A Receptor},
author = {Po-Yuan Hsiao and Jay H Kalin and Im-Hong Sun and Mohammed N Amin and Ying-Chun Lo and Meng-Jung Chiang and John Giddens and Polina Sysa-Shah and Kathleen Gabrielson and Lai-Xi Wang and Jonathan D Powell and Philip A Cole},
doi = {10.1002/cbic.201600337},
issn = {1439-7633},
journal = {Chembiochem},
volume = {17},
number = {20},
pages = {1951-1960},
abstract = {The adenosine A2A receptor (A2A R) is expressed in immune cells, as well as brain and heart tissue, and has been intensively studied as a therapeutic target for multiple disease indications. Inhibitors of the A2A R have the potential for stimulating immune response, which could be valuable for cancer immune surveillance and mounting a response against pathogens. One well-established potent and selective small molecule A2A R antagonist, ZM-241385 (ZM), has a short pharmacokinetic half-life and the potential for systemic toxicity due to A2A R effects in the brain and the heart. In this study, we designed an analogue of ZM and tethered it to the Fc domain of the immunoglobulin IgG3 by using expressed protein ligation. The resulting protein-small molecule conjugate, Fc-ZM, retained high affinity for two Fc receptors: FcγRI and the neonatal Fc receptor, FcRn. In addition, Fc-ZM was a potent A2A R antagonist, as measured by a cell-based cAMP assay. Cell-based assays also revealed that Fc-ZM could stimulate interferon γ production in splenocytes in a fashion that was dependent on the presence of A2A R. We found that Fc-ZM, compared with the small molecule ZM, was a superior A2A R antagonist in mice, consistent with the possibility that Fc attachment can improve pharmacokinetic and/or pharmacodynamic properties of the small molecule.},
keywords = {Adenosine A2 Receptor Antagonists, Adenosine A2A, Animals, Female, Humans, Immunoglobulin Fab Fragments, Inbred C57BL, Knockout, Male, Mice, Models, Molecular, Molecular Structure, Receptor, Respiratory Tract Infections, Triazines, Triazoles, Vaccinia virus},
pubstate = {published},
tppubtype = {article}
}
The adenosine A2A receptor (A2A R) is expressed in immune cells, as well as brain and heart tissue, and has been intensively studied as a therapeutic target for multiple disease indications. Inhibitors of the A2A R have the potential for stimulating immune response, which could be valuable for cancer immune surveillance and mounting a response against pathogens. One well-established potent and selective small molecule A2A R antagonist, ZM-241385 (ZM), has a short pharmacokinetic half-life and the potential for systemic toxicity due to A2A R effects in the brain and the heart. In this study, we designed an analogue of ZM and tethered it to the Fc domain of the immunoglobulin IgG3 by using expressed protein ligation. The resulting protein-small molecule conjugate, Fc-ZM, retained high affinity for two Fc receptors: FcγRI and the neonatal Fc receptor, FcRn. In addition, Fc-ZM was a potent A2A R antagonist, as measured by a cell-based cAMP assay. Cell-based assays also revealed that Fc-ZM could stimulate interferon γ production in splenocytes in a fashion that was dependent on the presence of A2A R. We found that Fc-ZM, compared with the small molecule ZM, was a superior A2A R antagonist in mice, consistent with the possibility that Fc attachment can improve pharmacokinetic and/or pharmacodynamic properties of the small molecule.