The interferon signaling pathway is critical for host defense by serving diverse functions in both innate and adaptive immune responses. Here, we show that type I gamma phosphatidylinositol phosphate 5-kinase i5 (PIPKIγi5), an enzyme that synthesizes phosphatidylinositol-4,5-bisphosphate (PI4,5P₂), controls the sensitivity to interferon in both human and mouse cells. PIPKIγi5 directly binds to the interferon-gamma (IFN-γ) downstream effector signal transducer and activator of transcription 1 (STAT1), which suppresses the STAT1 dimerization, IFN-γ-induced STAT1 nuclear translocation, and transcription of IFN-γ-responsive genes. Depletion of PIPKIγi5 significantly enhances IFN-γ signaling and strengthens an antiviral response. In addition, PIPKIγi5-synthesized PI4,5P₂ can bind to STAT1 and promote the PIPKIγi5-STAT1 interaction. Similar to its interaction with STAT1, PIPKIγi5 is capable of interacting with other members of the STAT family, including STAT2 and STAT3, thereby suppressing the expression of genes mediated by these transcription factors. These findings identify the function of PIPKIγi5 in immune regulation.

干扰素信号通路通过在先天性和适应性免疫反应中发挥多种功能，对于宿主防御至关重要。在这里，我们发现 I 型 γ 磷脂酰肌醇磷酸 5-激酶 i5 (PIPKIγi5) 是一种合成磷脂酰肌醇-4,5-二磷酸 (PI4,5P ₂ ) 的酶，可控制人和小鼠细胞对干扰素的敏感性。 PIPKIγi5 直接与干扰素γ (IFN-γ) 下游效应信号转导器和转录激活子 1 (STAT1) 结合，抑制 STAT1 二聚化、IFN-γ 诱导的 STAT1 核转位和 IFN-γ 响应基因的转录。 PIPKIγi5 的消耗显着增强 IFN-γ 信号传导并增强抗病毒反应。此外，PIPKIγi5合成的PI4,5P ₂可以与STAT1结合并促进PIPKIγi5-STAT1相互作用。与与 STAT1 的相互作用类似，PIPKIγi5 能够与 STAT 家族的其他成员（包括 STAT2 和 STAT3）相互作用，从而抑制这些转录因子介导的基因表达。这些发现确定了 PIPKIγi5 在免疫调节中的功能。