Arginine methylation of STAT1 modulates IFN alpha/beta-induced transcription

Transcriptional induction by interferons requires the tyrosine and serine p hosphorylation of STAT transcription factors. The N-terminal region is high ly homologous among the STAT proteins and surrounds a completely conserved arginine residue. Here we demonstrate arginine methylation of STAT1 by the protein arginine methyl-transferase PRMT1 as a novel requirement for IFN al pha/beta -induced transcription. Methylthioadenosine, a methyl-transferase inhibitor that accumulates in many transformed cells, inhibits STAT1-mediat ed IFN responses. This inhibition arises from impaired STAT1-DNA binding du e to an increased association of the STAT inhibitor PIAS1 with phosphorylat ed STAT1 dimers in the absence of arginine methylation. Thus, arginine meth ylation of STAT1 is an additional posttranslational modification regulating transcription factor function, and alteration of arginine methylation migh t be responsible for the lack of interferon responsiveness observed in many malignancies.