The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
John M Denu - One of the best experts on this subject based on the ideXlab platform.
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stoichiometry of site specific lysine acetylation in an entire proteome
Journal of Biological Chemistry, 2014Co-Authors: Josue Baeza, James A Dowell, Michael J Smallegan, Jing Fan, Daniel Amadornoguez, Zia Khan, John M DenuAbstract:Acetylation of lysine ϵ-amino groups influences many cellular processes and has been mapped to thousands of sites across many organisms. Stoichiometric information of acetylation is essential to accurately interpret biological significance. Here, we developed and employed a novel method for directly quantifying stoichiometry of site-specific acetylation in the entire proteome of Escherichia coli. By coupling isotopic labeling and a novel pairing algorithm, our approach performs an in silico enrichment of acetyl peptides, circumventing the need for immunoenrichment. We investigated the function of the sole NAD+-dependent Protein Deacetylase, CobB, on both site-specific and global acetylation. We quantified 2206 peptides from 899 Proteins and observed a wide distribution of acetyl stoichiometry, ranging from less than 1% up to 98%. Bioinformatic analysis revealed that metabolic enzymes, which either utilize or generate acetyl-CoA, and Proteins involved in transcriptional and translational processes displayed the highest degree of acetylation. Loss of CobB led to increased global acetylation at low stoichiometry sites and induced site-specific changes at high stoichiometry sites, and biochemical analysis revealed altered acetyl-CoA metabolism. Thus, this study demonstrates that sirtuin Deacetylase deficiency leads to both site-specific and global changes in Protein acetylation stoichiometry, affecting central metabolism.
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activation of the Protein Deacetylase sirt6 by long chain fatty acids and widespread deacylation by mammalian sirtuins
Journal of Biological Chemistry, 2013Co-Authors: Jessica L Feldman, Josue Baeza, John M DenuAbstract:Mammalian sirtuins (SIRT1 through SIRT7) are members of a highly conserved family of NAD+-dependent Protein Deacetylases that function in metabolism, genome maintenance, and stress responses. Emerging evidence suggests that some sirtuins display substrate specificity toward other acyl groups attached to the lysine ϵ-amine. SIRT6 was recently reported to preferentially hydrolyze long-chain fatty acyl groups over acetyl groups. Here we investigated the catalytic ability of all sirtuins to hydrolyze 13 different acyl groups from histone H3 peptides, ranging in carbon length, saturation, and chemical diversity. We find that long-chain deacylation is a general feature of mammalian sirtuins, that SIRT1 and SIRT2 act as efficient decrotonylases, and that SIRT1, SIRT2, SIRT3, and SIRT4 can remove lipoic acid. These results provide new insight into sirtuin function and a means for cellular removal of an expanding list of endogenous lysine modifications. Given that SIRT6 is a poor Deacetylase in vitro, but binds and prefers to hydrolyze long-chain acylated peptides, we hypothesize that binding of certain free fatty acids (FFAs) could stimulate deacetylation activity. Indeed, we demonstrate that several biologically relevant FFAs (including myristic, oleic, and linoleic acids) at physiological concentrations induce up to a 35-fold increase in catalytic efficiency of SIRT6 but not SIRT1. The activation mechanism is consistent with fatty acid inducing a conformation that binds acetylated H3 with greater affinity. Binding of long-chain FFA and myristoylated H3 peptide is mutually exclusive. We discuss the implications of discovering endogenous, small-molecule activators of SIRT6.
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activation of the Protein Deacetylase sirt6 by long chain fatty acids and widespread deacylation by mammalian sirtuins
Journal of Biological Chemistry, 2013Co-Authors: Jessica L Feldman, Josue Baeza, John M DenuAbstract:Mammalian sirtuins (SIRT1 through SIRT7) are members of a highly conserved family of NAD+-dependent Protein Deacetylases that function in metabolism, genome maintenance, and stress responses. Emerging evidence suggests that some sirtuins display substrate specificity toward other acyl groups attached to the lysine ϵ-amine. SIRT6 was recently reported to preferentially hydrolyze long-chain fatty acyl groups over acetyl groups. Here we investigated the catalytic ability of all sirtuins to hydrolyze 13 different acyl groups from histone H3 peptides, ranging in carbon length, saturation, and chemical diversity. We find that long-chain deacylation is a general feature of mammalian sirtuins, that SIRT1 and SIRT2 act as efficient decrotonylases, and that SIRT1, SIRT2, SIRT3, and SIRT4 can remove lipoic acid. These results provide new insight into sirtuin function and a means for cellular removal of an expanding list of endogenous lysine modifications. Given that SIRT6 is a poor Deacetylase in vitro, but binds and prefers to hydrolyze long-chain acylated peptides, we hypothesize that binding of certain free fatty acids (FFAs) could stimulate deacetylation activity. Indeed, we demonstrate that several biologically relevant FFAs (including myristic, oleic, and linoleic acids) at physiological concentrations induce up to a 35-fold increase in catalytic efficiency of SIRT6 but not SIRT1. The activation mechanism is consistent with fatty acid inducing a conformation that binds acetylated H3 with greater affinity. Binding of long-chain FFA and myristoylated H3 peptide is mutually exclusive. We discuss the implications of discovering endogenous, small-molecule activators of SIRT6. Background: Sirtuins regulate metabolism, genome maintenance, and stress responses. Results: Long-chain free fatty acids stimulate SIRT6 Deacetylase, and sirtuins display distinct but overlapping specificity for diverse acylated peptides. Conclusion: SIRT6 is activated by biologically relevant fatty acids, and long-chain deacylation is a general feature of sirtuins. Significance: Discovery of endogenous, small-molecule activators of SIRT6 demonstrates the therapeutic potential of compounds that promote SIRT6 function.
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where in the cell is sirt3 functional localization of an nad dependent Protein Deacetylase
Biochemical Journal, 2008Co-Authors: William C Hallows, Brittany N Albaugh, John M DenuAbstract:Sirtuins are NAD + -dependent enzymes that have been implicated in a wide range of cellular processes, including pathways that affect diabetes, cancer, lifespan and Parkinson9s disease. To understand their cellular function in these age-related diseases, identification of sirtuin targets and their subcellular localization is paramount. SIRT3 (sirtuin 3), a human homologue of Sir2 (silent information regulator 2), has been genetically linked to lifespan in the elderly. However, the function and localization of this enzyme has been keenly debated. A number of reports have indicated that SIRT3, upon proteolytic cleavage in the mitochondria, is an active Protein Deacetylase against a number of mitochondrial targets. In stark contrast, some reports have suggested that full-length SIRT3 exhibits nuclear localization and histone Deacetylase activity. Recently, a report comparing SIRT3 −/− and SIRT +/+ mice have provided compelling evidence that endogenous SIRT3 is mitochondrial and appears to be responsible for the majority of Protein deacetylation in this organelle. In this issue of the Biochemical Journal , Cooper et al. present additional results that address the mitochondrial and nuclear localization of SIRT3. Utilizing fluorescence microscopy and cellular fractionation studies, Cooper et al. have shown that SIRT3 localizes to the mitochondria and is absent in the nucleus. Thus this study provides additional evidence to establish SIRT3 as a proteolytically modified, mitochondrial Deacetylase.
Wayne W Hancock - One of the best experts on this subject based on the ideXlab platform.
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histone Protein Deacetylase inhibitor therapy for enhancement of foxp3 t regulatory cell function posttransplantation
American Journal of Transplantation, 2018Co-Authors: Liqing Wang, Satinder Dahiya, Rongxiang Han, Arabinda Samanta, Tatiana Akimova, U H Beier, Matthew H Levine, Wayne W HancockAbstract:T-regulatory (Treg) cells are like other cells present throughout the body in being subject to biochemical modifications in response to extracellular signals. An important component of these responses involves changes in post-translational modifications (PTMs) of histones and many non-histone Proteins, including phosphorylation/dephosphorylation, ubiquitination/deubiquitination and acetylation/deacetylation. Foxp3, the key transcription factor of Tregs, is constantly being rapidly turned over, and a number of these PTMs determine its level of expression and activity. Of interest in the transplant setting, modulation of the acetylation or deacetylation of key lysine residues in Foxp3 can promote the stability and function, leading to increased Treg production and increased Treg suppressive activity. This mini-review focuses on recent data concerning the roles that histone/Protein Deacetylases (HDACs) play in control of Treg function, and how small molecule HDAC inhibitors can be used to promote Treg-dependent allograft survival in experimental models. These data are discussed in the light of increasing interest in the identification and clinical evaluation of isoform-selective HDAC inhibitors, and their potential application as tools to modulate Foxp3+ Treg cell numbers and function in transplant recipients.
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foxp3 regulatory t cell development and function require histone Protein Deacetylase 3
Journal of Clinical Investigation, 2015Co-Authors: Liqing Wang, Ulf H Beier, Tatiana Akimova, Tricia R Bhatti, Mark I Greene, Scott W Hiebert, Wayne W HancockAbstract:Treg dysfunction is associated with a variety of inflammatory diseases. Treg populations are defined by expression of the oligomeric transcription factor FOXP3 and inability to produce IL-2, a cytokine required for T cell maintenance and survival. FOXP3 activity is regulated post-translationally by histone/Protein acetyltransferases and histone/Protein Deacetylases (HDACs). Here, we determined that HDAC3 mediates both the development and function of the two main Treg subsets, thymus-derived Tregs and induced Tregs (iTregs). We determined that HDAC3 and FOXP3 physically interact and that HDAC3 expression markedly reduces Il2 promoter activity. In murine models, conditional deletion of Hdac3 during thymic Treg development restored Treg production of IL-2 and blocked the suppressive function of Tregs. HDAC3-deficient mice died from autoimmunity by 4–6 weeks of age; however, injection of WT FOXP3+ Tregs prolonged survival. Adoptive transfer of Hdac3-deficient Tregs, unlike WT Tregs, did not control T cell proliferation in naive mice and did not prevent allograft rejection or colitis. HDAC3 also regulated the development of iTregs, as HDAC3-deficient conventional T cells were not converted into iTregs under polarizing conditions and produced large amounts of IL-2, IL-6, and IL-17. We conclude that HDAC3 is essential for the normal development and suppressive functions of thymic and peripheral FOXP3+ Tregs.
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sirtuin 1 targeting promotes foxp3 t regulatory cell function and prolongs allograft survival
Molecular and Cellular Biology, 2011Co-Authors: Ulf H Beier, Liqing Wang, Rongxiang Han, Tricia R Bhatti, Yujie Liu, Wayne W HancockAbstract:Sirtuin 1 (Sirt1), a class III histone/Protein Deacetylase, is central to cellular metabolism, stress responses, and aging, but its contributions to various host immune functions have been little investigated. To study the role of Sirt1 in T cell functions, we undertook targeted deletions by mating mice with a floxed Sirt1 gene to mice expressing CD4-cre or Foxp3-cre recombinase, respectively. We found that Sirt1 deletion left conventional T-effector cell activation, proliferation, and cytokine production largely unaltered. However, Sirt1 targeting promoted the expression of Foxp3, a key transcription factor in T-regulatory (Treg) cells, and increased Treg suppressive functions in vitro and in vivo. Consistent with these data, mice with targeted deletions of Sirt1 in either CD4 T cells or Foxp3 Treg cells exhibited prolonged survival of major histocompatibility complex (MHC)-mismatched cardiac allografts. Allografts in Sirt1-targeted recipients showed long-term preservation of myocardial histology and infiltration by Foxp3 Treg cells. Comparable results were seen in wild-type allograft recipients treated with Sirt1 inhibitors, such as EX-527 and splitomicin. Hence, Sirt1 may inhibit Treg functions, and its targeting may have therapeutic value in autoimmunity and transplantation.
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histone Protein Deacetylase inhibitors increase suppressive functions of human foxp3 tregs
Clinical Immunology, 2010Co-Authors: Tatiana Akimova, Liqing Wang, Tatiana N Golovina, Tatiana Mikheeva, James L Riley, Wayne W HancockAbstract:Histone/Protein Deacetylases (HDACs) decrease histone and Protein acetylation, typically leading to suppression of gene transcription and modulation of various Protein functions. We found significant differences in expression of HDAC before and after stimulation of human T regulatory (Treg) and T effector cells, suggesting the potential for future selective targeting of Tregs with HDAC inhibitors (HDACi). Use of various HDACi small molecules enhanced, by up to 4.5-fold (average 2-fold), the suppressive functions of both freshly isolated and expanded human Tregs, consistent with our previous murine data. HDACi use increased Treg expression of CTLA-4, a key negative regulator of immune response, and we found a direct and significant correlation between CTLA-4 expression and Treg suppression. Hence, HDACi compounds are promising pharmacologic tools to increase Treg suppressive functions, and this action may potentially be of use in patients with autoimmunity or post-transplantation.
Heng Zhu - One of the best experts on this subject based on the ideXlab platform.
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ycgc represents a new Protein Deacetylase family in prokaryotes
eLife, 2015Co-Authors: Shujuan Guo, Chengxi Liu, Hewei Jiang, Daniel M Czajkowsky, Chien Sheng Chen, Jiaoyu Deng, Yi Ming Zhou, Young Hoon Ahn, Philip A Cole, Heng ZhuAbstract:After Proteins have been made, they can be modified in several ways. For example, chemical tags called acetyl groups may be added to (and later removed from) the Protein to regulate cell activities such as aging and metabolism. Enzymes are Proteins that help catalyze the reactions that add or remove the acetyl tags on certain “substrate” Proteins. In the bacteria species Escherichia coli, many enzymes that help to add acetyl groups to Proteins have been discovered. However, only a single E. coli “Deacetylase” enzyme that removes the acetyl group has been identified. Now, Tu, Guo, Chen et al. have devised a technique to identify new Deacetylases, called the “clip-chip” approach. In this method, thousands of Proteins that are potential Deacetylases are arrayed on a glass slide, and substrate Proteins are immobilized on another slide. The two slides are then clipped together face-to-face, allowing the potential enzymes to transfer to the substrate slide and interact with the substrates. Using this approach, Tu, Guo, Chen et al. identified a Protein called YcgC as a Deacetylase in bacteria. Further characterization experiments revealed that YcgC works in a different way to other known Deacetylases, and that it targets different substrates to the previously known E. coli Deacetylase. Tu, Guo, Chen et al. found that the equivalents of YcgC in other bacteria species are also Deacetylases; these enzymes therefore represent a new Deacetylase family. In the future, the clip-chip approach could be used to discover new members of other enzyme families.
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ycgc represents a new Protein Deacetylase family in prokaryotes
eLife, 2015Co-Authors: Shujuan Guo, Chengxi Liu, Hewei Jiang, Daniel M Czajkowsky, Chien Sheng Chen, Jiaoyu Deng, Yi Ming Zhou, Young Hoon Ahn, Philip A Cole, Heng ZhuAbstract:Reversible lysine acetylation is one of the most important Protein posttranslational modifications that plays essential roles in both prokaryotes and eukaryotes. However, only a few lysine Deacetylases (KDACs) have been identified in prokaryotes, perhaps in part due to their limited sequence homology. Herein, we developed a 'clip-chip' strategy to enable unbiased, activity-based discovery of novel KDACs in the Escherichia coli proteome. In-depth biochemical characterization confirmed that YcgC is a serine hydrolase involving Ser200 as the catalytic nucleophile for lysine deacetylation and does not use NAD(+) or Zn(2+) like other established KDACs. Further, in vivo characterization demonstrated that YcgC regulates transcription by catalyzing deacetylation of Lys52 and Lys62 of a transcriptional repressor RutR. Importantly, YcgC targets a distinct set of substrates from the only known E. coli KDAC CobB. Analysis of YcgC's bacterial homologs confirmed that they also exhibit KDAC activity. YcgC thus represents a novel family of prokaryotic KDACs.
Shujuan Guo - One of the best experts on this subject based on the ideXlab platform.
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interplay between the bacterial Protein Deacetylase cobb and the second messenger c di gmp
The EMBO Journal, 2019Co-Authors: Hainan Zhang, Xingrun Zhang, Chengxi Liu, Hewei Jiang, Lili Qian, Daniel M Czajkowsky, Shujuan Guo, Shihua Wang, Bingbing Hao, Minjia TanAbstract:As a ubiquitous bacterial secondary messenger, c-di-GMP plays key regulatory roles in processes such as bacterial motility and transcription regulation. CobB is the Sir2 family Protein Deacetylase that controls energy metabolism, chemotaxis, and DNA supercoiling in many bacteria. Using an Escherichia coli proteome microarray, we found that c-di-GMP strongly binds to CobB. Further, Protein deacetylation assays showed that c-di-GMP inhibits the activity of CobB and thereby modulates the biogenesis of acetyl-CoA. Interestingly, we also found that one of the key enzymes directly involved in c-di-GMP production, DgcZ, is a substrate of CobB. Deacetylation of DgcZ by CobB enhances its activity and thus the production of c-di-GMP. Our work establishes a novel negative feedback loop linking c-di-GMP biogenesis and CobB-mediated Protein deacetylation.
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Protein Deacetylase cobb interplays with c di gmp
Social Science Research Network, 2018Co-Authors: Hainan Zhang, Xingrun Zhang, Chengxi Liu, Hewei Jiang, Lili Qian, Daniel M Czajkowsky, Shujuan Guo, Shihua Wang, Minjia Tan, Lei FengAbstract:As a ubiquitous bacterial secondary messenger, c-di-GMP plays key regulatory roles in processes such as bacterial motility and transcription regulation. CobB is the Sir2 family Protein Deacetylase that controls energy metabolism, chemotaxis and DNA supercoiling in many bacteria. Using an E.coli proteome microarray, we found that c-di-GMP strongly binds to CobB. Protein deacetylation assays showed that c-di-GMP inhibits CobB activity and thereby modulates the biogenesis of acetyl-CoA. Through mutagenesis studies, residues R8, R17 and E21 of CobB were shown to be required for c-di-GMP binding. Next, we found that CobB is an effective Deacetylase of YdeH, a major diguanylate cyclase (DGC) of E.coli that is endogenously acetylated. Mass spectrometry analysis identified YdeH K4 as the major site of acetylation, and it could be deacetylated by CobB. Interestingly, deacetylation of YdeH enhances its stability and cyclase activity in c-di-GMP production. Thus, our work establishes a novel negative feedback loop linking c-di-GMP biogenesis and CobB-mediated Protein deacetylation.
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ycgc represents a new Protein Deacetylase family in prokaryotes
eLife, 2015Co-Authors: Shujuan Guo, Chengxi Liu, Hewei Jiang, Daniel M Czajkowsky, Chien Sheng Chen, Jiaoyu Deng, Yi Ming Zhou, Young Hoon Ahn, Philip A Cole, Heng ZhuAbstract:After Proteins have been made, they can be modified in several ways. For example, chemical tags called acetyl groups may be added to (and later removed from) the Protein to regulate cell activities such as aging and metabolism. Enzymes are Proteins that help catalyze the reactions that add or remove the acetyl tags on certain “substrate” Proteins. In the bacteria species Escherichia coli, many enzymes that help to add acetyl groups to Proteins have been discovered. However, only a single E. coli “Deacetylase” enzyme that removes the acetyl group has been identified. Now, Tu, Guo, Chen et al. have devised a technique to identify new Deacetylases, called the “clip-chip” approach. In this method, thousands of Proteins that are potential Deacetylases are arrayed on a glass slide, and substrate Proteins are immobilized on another slide. The two slides are then clipped together face-to-face, allowing the potential enzymes to transfer to the substrate slide and interact with the substrates. Using this approach, Tu, Guo, Chen et al. identified a Protein called YcgC as a Deacetylase in bacteria. Further characterization experiments revealed that YcgC works in a different way to other known Deacetylases, and that it targets different substrates to the previously known E. coli Deacetylase. Tu, Guo, Chen et al. found that the equivalents of YcgC in other bacteria species are also Deacetylases; these enzymes therefore represent a new Deacetylase family. In the future, the clip-chip approach could be used to discover new members of other enzyme families.
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ycgc represents a new Protein Deacetylase family in prokaryotes
eLife, 2015Co-Authors: Shujuan Guo, Chengxi Liu, Hewei Jiang, Daniel M Czajkowsky, Chien Sheng Chen, Jiaoyu Deng, Yi Ming Zhou, Young Hoon Ahn, Philip A Cole, Heng ZhuAbstract:Reversible lysine acetylation is one of the most important Protein posttranslational modifications that plays essential roles in both prokaryotes and eukaryotes. However, only a few lysine Deacetylases (KDACs) have been identified in prokaryotes, perhaps in part due to their limited sequence homology. Herein, we developed a 'clip-chip' strategy to enable unbiased, activity-based discovery of novel KDACs in the Escherichia coli proteome. In-depth biochemical characterization confirmed that YcgC is a serine hydrolase involving Ser200 as the catalytic nucleophile for lysine deacetylation and does not use NAD(+) or Zn(2+) like other established KDACs. Further, in vivo characterization demonstrated that YcgC regulates transcription by catalyzing deacetylation of Lys52 and Lys62 of a transcriptional repressor RutR. Importantly, YcgC targets a distinct set of substrates from the only known E. coli KDAC CobB. Analysis of YcgC's bacterial homologs confirmed that they also exhibit KDAC activity. YcgC thus represents a novel family of prokaryotic KDACs.
Rongxiang Han - One of the best experts on this subject based on the ideXlab platform.
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histone Protein Deacetylase inhibitor therapy for enhancement of foxp3 t regulatory cell function posttransplantation
American Journal of Transplantation, 2018Co-Authors: Liqing Wang, Satinder Dahiya, Rongxiang Han, Arabinda Samanta, Tatiana Akimova, U H Beier, Matthew H Levine, Wayne W HancockAbstract:T-regulatory (Treg) cells are like other cells present throughout the body in being subject to biochemical modifications in response to extracellular signals. An important component of these responses involves changes in post-translational modifications (PTMs) of histones and many non-histone Proteins, including phosphorylation/dephosphorylation, ubiquitination/deubiquitination and acetylation/deacetylation. Foxp3, the key transcription factor of Tregs, is constantly being rapidly turned over, and a number of these PTMs determine its level of expression and activity. Of interest in the transplant setting, modulation of the acetylation or deacetylation of key lysine residues in Foxp3 can promote the stability and function, leading to increased Treg production and increased Treg suppressive activity. This mini-review focuses on recent data concerning the roles that histone/Protein Deacetylases (HDACs) play in control of Treg function, and how small molecule HDAC inhibitors can be used to promote Treg-dependent allograft survival in experimental models. These data are discussed in the light of increasing interest in the identification and clinical evaluation of isoform-selective HDAC inhibitors, and their potential application as tools to modulate Foxp3+ Treg cell numbers and function in transplant recipients.
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histone Protein Deacetylase 11 targeting promotes foxp3 treg function
Scientific Reports, 2017Co-Authors: Jianbing Huang, Liqing Wang, Satinder Dahiya, Ulf H Beier, Rongxiang Han, Arabinda Samanta, Joel A Bergman, Eduardo M Sotomayor, Edward Seto, Alan P KozikowskiAbstract:Current interest in Foxp3+ T-regulatory (Treg) cells as therapeutic targets in transplantation is largely focused on their harvesting pre-transplant, expansion and infusion post-transplantation. An alternate strategy of pharmacologic modulation of Treg function using histone/Protein Deacetylase inhibitors (HDACi) may allow more titratable and longer-term dosing. However, the effects of broadly acting HDACi vary, such that HDAC isoform-selective targeting is likely required. We report data from mice with constitutive or conditional deletion of HDAC11 within Foxp3+ Treg cells, and their use, along with small molecule HDAC11 inhibitors, in allograft models. Global HDAC11 deletion had no effect on health or development, and compared to WT controls, Foxp3+ Tregs lacking HDAC11 showed increased suppressive function, and increased expression of Foxp3 and TGF-β. Likewise, compared to WT recipients, conditional deletion of HDAC11 within Tregs led to long-term survival of fully MHC-mismatched cardiac allografts, and prevented development of transplant arteriosclerosis in an MHC class II-mismatched allograft model. The translational significance of HDAC11 targeting was shown by the ability of an HDAC11i to promote long-term allograft allografts in fully MHC-disparate strains. These data are powerful stimuli for the further development and testing of HDAC11-selective pharmacologic inhibitors, and may ultimately provide new therapies for transplantation and autoimmune diseases.
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class specific histone Protein Deacetylase inhibition protects against renal ischemia reperfusion injury and fibrosis formation
American Journal of Transplantation, 2015Co-Authors: Tricia R Bhatti, Matthew H Levine, Zhonglin Wang, Yanfeng Wang, David D Aufhauser, S Mcneal, Yujie Liu, Shayan Cheraghlou, Rongxiang HanAbstract:Renal ischemia-reperfusion injury (IRI) is a common cause of renal dysfunction and renal failure. Histone/ Protein Deacetylases (HDACs) regulate gene accessibility and higher order Protein structures and may alter cellular responses to a variety of stresses. We investigated whether use of pan- and class-specific HDAC inhibitors (HDACi) could improve IRI tolerance in the kidney. Using a model of unilateral renal IRI, we investigated early renal function after IRI, and calculated fibrosis after IRI using an automated scoring system. We found that pan-HDAC inhibition using trichostatin (TSA) yielded significant renal functional benefit at 24‐96hours (p<0.001). Treated mice developed significantly less fibrosis at 30 days (p<0.0004). Class I HDAC inhibition with MS-275 yielded similar effects. Protection from fibrosis formation was also noted in a cold ischemia transplant model (p<0.008) with a trend toward improved cold ischemic survival in TSA-treatedmice.Theseeffectswerenotaccompanied by induction of typical ischemic tolerance pathways or by priming of heat shock Protein expression. In fact, heat shock Protein 70 deletion or overexpression did not alter renal ischemia tolerance. Micro-RNA 21, known to be enhanced in vitro in renal tubular cells that survive stress, was enhanced by treatment with HDACi, pointing to possible mechanism.
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essential role of mitochondrial energy metabolism in foxp3 t regulatory cell function and allograft survival
The FASEB Journal, 2015Co-Authors: Ulf H Beier, Liqing Wang, Tatiana Akimova, Tricia R Bhatti, Yujie Liu, Alessia Angelin, Haiyan Xiao, Maya A Koike, Saege Hancock, Rongxiang HanAbstract:Conventional T (Tcon) cells and Foxp3+ T-regulatory (Treg) cells are thought to have differing metabolic requirements, but little is known of mitochondrial functions within these cell populations in vivo. In murine studies, we found that activation of both Tcon and Treg cells led to myocyte enhancer factor 2 (Mef2)-induced expression of genes important to oxidative phosphorylation (OXPHOS). Inhibition of OXPHOS impaired both Tcon and Treg cell function compared to wild-type cells but disproportionally affected Treg cells. Deletion of Pgc1α or Sirt3, which are key regulators of OXPHOS, abrogated Treg-dependent suppressive function and impaired allograft survival. Mef2 is inhibited by histone/Protein Deacetylase-9 (Hdac9), and Hdac9 deletion increased Treg suppressive function. Hdac9−/− Treg showed increased expression of Pgc1α and Sirt3, and improved mitochondrial respiration, compared to wild-type Treg cells. Our data show that key OXPHOS regulators are required for optimal Treg function and Treg-dependen...
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sirtuin 1 targeting promotes foxp3 t regulatory cell function and prolongs allograft survival
Molecular and Cellular Biology, 2011Co-Authors: Ulf H Beier, Liqing Wang, Rongxiang Han, Tricia R Bhatti, Yujie Liu, Wayne W HancockAbstract:Sirtuin 1 (Sirt1), a class III histone/Protein Deacetylase, is central to cellular metabolism, stress responses, and aging, but its contributions to various host immune functions have been little investigated. To study the role of Sirt1 in T cell functions, we undertook targeted deletions by mating mice with a floxed Sirt1 gene to mice expressing CD4-cre or Foxp3-cre recombinase, respectively. We found that Sirt1 deletion left conventional T-effector cell activation, proliferation, and cytokine production largely unaltered. However, Sirt1 targeting promoted the expression of Foxp3, a key transcription factor in T-regulatory (Treg) cells, and increased Treg suppressive functions in vitro and in vivo. Consistent with these data, mice with targeted deletions of Sirt1 in either CD4 T cells or Foxp3 Treg cells exhibited prolonged survival of major histocompatibility complex (MHC)-mismatched cardiac allografts. Allografts in Sirt1-targeted recipients showed long-term preservation of myocardial histology and infiltration by Foxp3 Treg cells. Comparable results were seen in wild-type allograft recipients treated with Sirt1 inhibitors, such as EX-527 and splitomicin. Hence, Sirt1 may inhibit Treg functions, and its targeting may have therapeutic value in autoimmunity and transplantation.
