One of the prominent immunological abnormalities closely associated with SLE is upregulation of type I interferons (IFNs). Molecular and cellular mechanisms that lead to excessive production of type I IFNs in SLE has been a subject under extensive investigation and the research effort has focused on identifying factors and pathways that positively regulate IFNs expression. On the other hand, given their potential harmful effects, production of type I IFNs is under tight control by various inhibitory mechanisms that prevent overactivation of this pathway. We postulated that besides abnormal activation of positive IFN-inducing pathways, dysregulation of homeostatic inhibitory mechanisms also contributes to excessive IFN production seen in SLE and identified Hesl as a previously unappreciated negative regulator of IFN expression. In this application, we propose to investigate the molecular mechanisms by which Hesl inhibits the type I IFN pathway as well as the in vivo significance of Hesl regulation of IFNs in animal models of SLE. The proposed study will contribute to our understanding of IFN regulation in the context of SLE pathogenesis and shed light on designing novel therapeutic approaches targeting type I IFNs.