Chemical Proteomic Profiling of the Histaminylation Proteome in Cancer Cells Unveils Uncharted Epigenetic Marks on Core Histones
Ma, X.; Leaman, A. A.; Lin, Z.; Li, H.; Cai, Z.; Dalal, K.; Hossain, M. S.; Thirumalaikumar, V. P.; Wang, Z.; O'Brien, V. P.; Tao, W. A.; Zheng, Q.
Show abstract
Histamine is a key signaling molecule in pathophysiology that can exhibit significant regulatory roles in diverse health and disease status. Besides the well-studied noncovalent interactions between histamine and its receptors, protein histaminylation is a recently discovered mode of action, through which histamine regulates cellular signaling pathways in a covalent-interaction manner. Histaminylation is an emerging protein post-translational modification, where an isopeptide bond is formed between the histamine primary amine and {gamma}-carboxyl group of glutamine through a transamidation reaction catalyzed by transglutaminase 2 (TGM2). However, due to the lack of efficient pan-specific antibodies targeting histaminylated glutamine, the histaminylation proteome in cells remains poorly explored. Here, we report the design and development of a novel N{tau}-propargylated histamine probe as well as its successful application in chemical proteomic profiling of the histaminylation proteome in cancer cells. Notably, new TGM2-catalyzed epigenetic marks on core histones, e.g., H2AXQ84 and Q104 histaminylation, have been identified from cancer cells and verified in this study.
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