Regulation of E2F1 by PAD4 mediated citrullination

Peptidyl arginine deiminase (PAD) 4 is a nuclear enzyme that converts arginine residues to citrulline. PAD4 activity has been implicated in inflammatory disease and cancer, although its mechanism of action, particularly the identity of functionally relevant targets, remains unclear. Moreover, there are no known reader domains specifically recognising citrulline modifications. E2F transcription factors play a central role in regulating gene expression during cellular proliferation but in addition participate in diverse biological processes. Furthermore, it is known that arginine methylation provides an important level of control in dictating the biological consequence of E2F1 activity. Here, we show that E2F1 is citrullinated by PAD4 on functionally important arginine residues. Citrullination of E2F1 assists its chromatin association, specifically to cytokine genes in granulocyte cells, and regulates binding of the bromodomain reader BRD4 to an acetylated domain inE2F1. Accordingly, the combined inhibition of PAD4 and BRD4 impedes the chromatin association of E2F1 and the activation of cytokine gene expression. When administered as a combination therapy in the murine collagen-induced arthritis model, small molecule inhibitors of PAD4 and BRD4 provide an effective approach for preventing collagen-induced arthritis. Our results shed light on a new E2F-dependent pathway that mediates the inflammatory effect of PAD4 and, for the first time, establish the interplay between citrullination and acetylation as a regulatory interface for driving inflammatory gene expression. Moreover, the results highlight a novel therapeutic approach for treating chronic inflammatory diseases

Regulation of E2F1 by PAD4 mediated citrullination

Peptidyl arginine deiminase (PAD) 4 is a nuclear enzyme that converts arginine residues to citrulline. PAD4 activity has been implicated in inflammatory disease and cancer, although its mechanism of action, particularly the identity of functionally relevant targets, remains unclear. Moreover, there are no known reader domains specifically recognising citrulline modifications. E2F transcription factors play a central role in regulating gene expression during cellular proliferation but in addition participate in diverse biological processes. Furthermore, it is known that arginine methylation provides an important level of control in dictating the biological consequence of E2F1 activity. Here, we show that E2F1 is citrullinated by PAD4 on functionally important arginine residues. Citrullination of E2F1 assists its chromatin association, specifically to cytokine genes in granulocyte cells, and regulates binding of the bromodomain reader BRD4 to an acetylated domain inE2F1. Accordingly, the combined inhibition of PAD4 and BRD4 impedes the chromatin association of E2F1 and the activation of cytokine gene expression. When administered as a combination therapy in the murine collagen-induced arthritis model, small molecule inhibitors of PAD4 and BRD4 provide an effective approach for preventing collagen-induced arthritis. Our results shed light on a new E2F-dependent pathway that mediates the inflammatory effect of PAD4 and, for the first time, establish the interplay between citrullination and acetylation as a regulatory interface for driving inflammatory gene expression. Moreover, the results highlight a novel therapeutic approach for treating chronic inflammatory diseases

The Train of Universality of Human Rights on the Railway of Wittgenstein (from an Ideal language to a vague one)

The universality of (at least some of) moral norms was being challenged by many thinkers, philosophers, religious reformists, and even the political actors. Assuming that universality of the contemporary human rights as a morally justified as well as consistent system, the main task of this article is to appraise Wittgenstein`s ideas, once with regard to a Kantian contractual reading of human rights and then with an “in using” language approach, of course, not to question Universality of Human rights, rather to support a kind of universality. Finally, we shall explore the potentiality of Wittgenstein‘s thoughts to entertain a rather soft version of universality of human rights by revisiting his Tractatus and proposing the idea of “meaning in use” in his Philosophical Investigation

Development of Activity-Based Proteomic Probes for Protein Citrullination.

Protein arginine deiminases (PADs) catalyze the post-translational deimination of peptidyl arginine to form peptidyl citrulline. This modification is increased in multiple inflammatory diseases and in certain cancers. PADs regulate a variety of signaling pathways including apoptosis, terminal differentiation, and transcriptional regulation. Activity-based protein profiling (ABPP) probes have been developed to understand the role of the PADs in vivo and to investigate the effect of protein citrullination in various pathological conditions. Furthermore, these ABPPs have been utilized as a platform for high-throughput inhibitor discovery. This review will showcase the development of ABPPs targeting the PADs. In addition, it provides a brief overview of PAD structure and function along with recent advances in PAD inhibitor development