SETD3 functions beyond histidine methylation

SETD3 is a member of SET domain-containing proteins. It has been discovered as the first metazoan protein (actin) histidine methyltransferase. In addition to this well-characterized molecular function of SETD3, it has been clearly shown to be involved in multiple biological processes, such as cell differentiation, tumorigenesis and viral infection. Here, we summarize the current knowledge on the roles of SETD3 beyond its histidine methyltransferase activity, and outline its cellular and molecular modes of action, as well as the upstream regulation on SETD3, therefore providing insights for the molecular basis of how SETD3 fine regulates multiple physiological and pathological processes.