4 research outputs found
Citrullination of histone H3 drives IL-6 production by bone marrow mesenchymal stem cells in MGUS and multiple myeloma
Multiple myeloma (MM), an incurable plasma cell malignancy, requires localisation within the bone
marrow. This microenvironment facilitates crucial interactions between the cancer cells and stromal
cell types that permit the tumour to survival and proliferate. There is increasing evidence that the
bone marrow mesenchymal stem cell (BMMSC) is stably altered in patients with MM – a phenotype
also postulated to exist in patients with monoclonal gammopathy of undetermined significance
(MGUS) a benign condition that precedes MM. In this study, we describe a mechanism by which
increased expression of peptidyl arginine deiminase 2 (PADI2) by BMMSCs in patients with MGUS
and MM directly alters malignant plasma cell phenotype. We identify PADI2 as one of the most
highly upregulated transcripts in BMMSCs from both MGUS and MM patients, and that through its
enzymatic deimination of histone H3 arginine 26, PADI2 activity directly induces the upregulation of
interleukin-6 (IL-6) expression. This leads to the acquisition of resistance to the chemotherapeutic
agent, bortezomib, by malignant plasma cells. We therefore describe a novel mechanism by which
BMMSC dysfunction in patients with MGUS and MM directly leads to pro-malignancy signalling
through the citrullination of histone H3R26
Reduced glutathione as a physiological co-activator in the activation of peptidylarginine deiminase
Peptidyl arginine deiminase-4-deficient mice are protected against kidney and liver injury after renal ischemia and reperfusion
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