mRNA cap 2'-O-methyltransferase (J3R) (J3R)

The J3R protein, also known as VP39, is a critical enzyme in the Mpox virus (MPXV) life cycle, functioning primarily as an mRNA cap 2'-O-methyltransferase. It is responsible for modifying the 5' cap of viral mRNA by transferring a methyl group from S-adenosyl-L-methionine (SAM) to the ribose 2'-O position of the first transcribed nucleotide. This modification is essential for the virus to mimic host mRNA, thereby evading detection by the host's innate immune sensors such as IFIT proteins and MDA5, which normally recognize unmethylated 'non-self' RNA. Beyond its methyltransferase activity, J3R also acts as a processivity factor for the viral poly(A) polymerase, ensuring the production of long poly(A) tails required for mRNA stability and translation. Due to its indispensable role in viral replication and immune suppression, J3R is considered a high-priority target for the development of novel anti-poxvirus therapeutics. Current research focuses on small-molecule inhibitors that occupy the SAM-binding pocket or the RNA-binding groove to block its enzymatic activity.

Other names

VP392'-O-methyltransferase VP39Poly(A) polymerase small subunitCap-specific mRNA (nucleoside-2'-O-)-methyltransferaseMPXV_gp115

Inhibition of the methyltransferase catalytic site prevents the 2'-O-methylation of the viral mRNA cap structure, leading to the recognition of viral RNA by host sensors like MDA5 and IFIT, thereby triggering an interferon-mediated immune response and inhibiting viral protein synthesis.