Browsing by Author "Bicker, Kevin L."

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    Chemical Proteomic Platform To Identify Citrullinated Proteins
    Lewallen, Daniel M.; Bicker, Kevin L.; Subramanian, Venkataraman; Clancy, Kathleen W.; Slade, Daniel J.; Martell, Julianne; Dreyton, Christina J.; Sokolove, Jeremy; Weerapana, Eranthie; Thompson, Paul R. (2015-11-20)
    Anti-citrullinated protein antibodies (ACPAs) are a hallmark of rheumatoid arthritis (RA) and are routinely used for disease diagnosis. Protein citrullination is also increased in cancer and other autoimmune disorders, suggesting that citrullinated proteins may serve as biomarkers for diseases beyond RA. To identify these citrullinated proteins, we developed biotin-conjugated phenylglyoxal (biotin-PG). Using this probe and our platform technology, we identified >50 intracellular citrullinated proteins. More than 20 of these are involved in RNA splicing, suggesting, for the first time, that citrullination modulates RNA biology. Overall, this chemical proteomic platform will play a key role in furthering ourunderstanding of protein citrullination in rheumatoid arthritis and potentially a wider spectrum of inflammatory diseases.
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    Inhibition of PAD4 activity is sufficient to disrupt mouse and human NET formation
    Lewis, Huw D.; Liddle, John; Coote, Jim E.; Atkinson, Stephen J.; Barker, Michael D.; Bax, Benjamin D.; Bicker, Kevin L.; Bingham, Ryan P.; Campbell, Matthew; Chen, Yu Hua; Chung, Chun-wa; Craggs, Peter D.; Davis, Rob P.; Eberhard, Dirk; Joberty, Gerard; Lind, Kenneth E.; Locke, Kelly; Maller, Claire; Martinod, Kimberly; Patten, Chris; Polyakova, Oxana; Rise, Cecil E.; Rüdiger, Martin; Sheppard, Robert J.; Slade, Daniel J.; Thomas, Pamela; Thorpe, Jim; Yao, Gang; Drewes, Gerard; Wagner, Denisa D.; Thompson, Paul R.; Prinjha, Rab K.; Wilson, David M. (2015-03)
    PAD4 has been strongly implicated in the pathogenesis of autoimmune, cardiovascular and oncological diseases through clinical genetics and gene disruption in mice. New selective PAD4 inhibitors binding a calcium-deficient form of the PAD4 enzyme have validated the critical enzymatic role of human and mouse PAD4 in both histone citrullination and neutrophil extracellular trap formation for, to our knowledge, the first time. The therapeutic potential of PAD4 inhibitors can now be explored.
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    Peptidylarginine deiminase 2-catalyzed histone H3 arginine 26 citrullination facilitates estrogen receptor alpha target gene activation
    Zhang, Xuesen; Bolt, Michael; Guertin, Michael J.; Chen, Wei; Zhang, Sheng; Cherrington, Brian D.; Slade, Daniel J.; Dreyton, Christina J.; Subramanian, Venkataraman; Bicker, Kevin L.; Thompson, Paul R.; Mancini, Michael A.; Lis, John T.; Coonrod, Scott A. (2012-08-14)
    Cofactors for estrogen receptor α (ERα) can modulate gene activity by posttranslationally modifying histone tails at target promoters. Here, we found that stimulation of ERα-positive cells with 17β-estradiol (E2) promotes global citrullination of histone H3 arginine 26 (H3R26) on chromatin. Additionally, we found that the H3 citrulline 26 (H3Cit26) modification colocalizes with ERα at decondensed chromatin loci surrounding the estrogen-response elements of target promoters. Surprisingly, we also found that citrullination of H3R26 is catalyzed by peptidylarginine deiminase (PAD) 2 and not by PAD4 (which citrullinates H4R3). Further, we showed that PAD2 interacts with ERα after E2 stimulation and that inhibition of either PAD2 or ERα strongly suppresses E2-induced H3R26 citrullination and ERα recruitment at target gene promoters. Collectively, our data suggest that E2 stimulation induces the recruitment of PAD2 to target promoters by ERα, whereby PAD2 then citrullinates H3R26, which leads to local chromatin decondensation and transcriptional activation.