Phase Separation of a Novel form of Euchromatic Histone Methyltransferase1 (EHMT1N/C) into cytoplasmic RNA viral Inclusion bodies facilitates their coalescence, thereby enhancing viral replication

Protein lysine methyltransferases (PKMTs) methylate histone and non-histone proteins to regulate biological outcomes such as development and disease including viral infection. While PKMTs have been extensively studied for modulating the antiviral responses via host gene regulation, their role in methylation of proteins encoded by viruses and its impact on host-pathogen interactions remain poorly understood. In this study, we discovered a distinct nucleo-cytoplasmic form of Euchromatic Histone Methyltransferase1(EHMT1N/C), a PKMT, that phase separates into viral inclusion bodies (IBs) upon cytoplasmic RNA-virus infection (Sendai Virus). EHMT1N/C interacts with cytoplasmic EHMT2 and methylates SeV-Nucleoprotein upon infection. Elevated nucleoprotein methylation during infection correlated with coalescence of small IBs into large mature platforms for efficient replication. Inhibition of EHMT activity by pharmacological inhibitors or genetic depletion of EHMT1N/C reduced the size of IBs with a concomitant reduction in replication. Since IB formation is conserved among all cytoplasmic RNA-viruses, our study will have strong implications in understanding the mechanisms regulating IB formation, discerning RNA viral pathogenesis and designing therapeutic strategies.