The interferon (IFN) signaling pathway is an important cellular defense mechanism against microorganism invasion. By sensing pathogen-associated molecular patterns (PAMPs) and transmitting signaling through the downstream cascades, IFN is robustly induced in expression and secreted to activate numerous genes’ expression in self and neighboring cells. Products of these induced genes then participate in restricting infection and modulating the immune system to further respond. This process needs to be properly regulated, for its aberrant activation under non-infectious conditions results in inflammation and onset of autoimmune diseases in the host. The correct recognition of “self” and “non-self” is the first step to control. Given the fact that nucleic acids of microorganisms are important immunogenic sources to the IFN signaling, the endogenous DNA/RNA metabolisms then must be faithfully conducted and strictly regulated. A series of enzymes, using them as substrates, work at different pathways to maintain this homeostasis. Intensive investigations on mechanisms of autoimmune diseases highlighted the protective role of these enzymes. Take Aicardi-Goutières syndrome (AGS) as an example, a monogenic type I interferonopathy, 9 mutated genes have been identified separately in patients so far, including DNA metabolism involved genes TREX1, RNASEH2A, RNASEH2B, RNASEH2C, and SAMHD1, RNA-related genes ADAR1 and IFIH1, and two recently identified genes, LSM11 and RNU7-1 whose correct activity is required for histone expression. Aberrant DNA metabolism or damaged histone expression activates IFN signaling through the cGAS-STING axis, while RNA errors sensitize the MDA5-MAVS axis. Thus, despite these 9 mutations all leading to the aberrant activation of IFN signaling, they can rely on different mechanisms, implicating that even having the same symptoms clinically the optimized treatment can be different. We thus argue the importance and necessity of diagnosing at the genetic level to the treatment of complicated symptoms and hope this review benefits the understanding of the pathogenesis of autoimmune diseases.