In the biological system, most of the important cellular events, such as growth, survival, apoptosis, differentiation and migration are regulated by post-translational modifications. Aside from phosphorylation, protein methylation has emerged over the last decade as one of the major control mechanisms in protein function. Notably, arginine methylation has been implicated in several key cytosolic and nuclear processes, including receptor signaling, protein transport and gene transcription and may represent the most common type of protein methylation in mammalian cells. In contrast, relatively few lysine-methylated proteins have been identified and those that have been characterized are associated with transcriptional regulation. The functional implications of lysine methylation of cytosolic proteins remain largely unclear.

Previously, we suggested a cytosolic role for the histone lysine methyltransferase (HKMT), Ezh2, in regulating lymphocyte activation (Su et al., Cell 2005, 121, 425-436). Our recent data further demonstrate that Ezh2 regulates adhesion dynamics and migration of leukocytes through direct methylation of the extra-nuclear protein, talin. Ezh2-mediated methylation of talin, a key regulatory molecule in cell migration, disrupts talin binding to F-actin and thereby promotes adhesion structure turnover (Gunawan et al., Nature Immunology 2015, 16: 505-516).

The physiological significance of this novel finding in leukocytes is further supported by two follow-up studies. The important role of cytosolic Ezh2 in governing Langerhans cell migration and tolerogenic dermal dendritic cell-mediated host protection against cutaneous allergy (Loh et al., iScience 2018,10: 23–39). Furthermore, the endogenous Ezh2-mediated talin methylation is demonstrated to be critical for neutrophil infiltration during peritonitis, suggesting a critical role of talin methylation in microbe induced sepsis (J Immunol 2018, 201: 3651-3661).

Interestingly, a significant role for cytoplasmic Ezh2 in neoplastic transformation is further demonstrated in a study led by Drs. Nandini Venkatesan & Jong Fu Wong. They have shown that disruption of Ezh2’s cytosolic function is sufficient to abolish Ezh2’s transforming capacity and cytoplasmic Ezh2 enriched cells are likely to represent a group of aggressive cancer stem cells (Oncogene 2018, 37: 461-477).

It is possible that Ezh2 and other lysine methyltransferases (KMTs) mediate the methylation of additional proteins to modulate various cytosolic signaling events. We have also identified several uncharacterized cytoplasmic KMTs that may be involved in regulating immune responses. Collectively, our studies aim to elucidate lysine-methylation-regulated signaling networks controlling various cellular functions in immune cells and cancers.