ENKD1 modulates innate immune responses through enhanced geranylgeranyl pyrophosphate synthase activity

Inflammation is a crucial element of immune responses, with pivotal roles in host defenses against pathogens. Comprehensive understanding of the molecular mechanisms underlying inflammation is imperative for developing effective strategies to combat infectious diseases. Here, we conducted a screening analysis and identified enkurin domain-containing protein 1 (ENKD1) as a promising regulator of inflammation. We observed that ENKD1 expression was significantly reduced on activation of multiple Toll-like receptor (TLR) molecules. Deletion of ENKD1 resulted in enhanced innate immune system activation and exacerbation of septic inflammation. Mechanistically, ENKD1 interacted with geranylgeranyl diphosphate synthase 1 (GGPS1) and modulated its enzymatic activity, thereby influencing geranylgeranyl diphosphate production. This interaction ultimately led to Ras-related C3 botulinum toxin substrate 1 (RAC1) inactivation and suppression of pro-inflammatory signaling pathways. Our findings establish ENKD1 as a critical regulator of innate immune cell activation, underscoring its significant role in septic inflammation.