Many viral proteases mediate the evasion of antiviral innate immunity by cleaving adapter proteins in the interferon (IFN) induction pathway. Host proteases are also involved in innate immunity and inflammation. Here, we report that the transmembrane protease hepsin (also known as TMPRSS1), which is predominantly present in hepatocytes, inhibited the induction of type I IFN during viral infections. Knocking out hepsin in mouse embryonic fibroblasts (MEFs) increased the viral infection–induced expression of Ifnb1, an Ifnb1 promoter reporter, and an IFN-sensitive response element promoter reporter. Ectopic expression of hepsin in cultured human hepatocytes and HEK293T cells suppressed the induction of IFNβ during viral infections by reducing the abundance of STING. These effects depended on the protease activity of hepsin. We identified a putative hepsin target site in STING and showed that mutating this site protected STING from hepsin-mediated cleavage. In addition to hepatocytes, several hepsin-producing prostate cancer cell lines showed reduced STING-mediated type I IFN induction and responses. These results reveal a role for hepsin in suppressing STING-mediated type I IFN induction, which may contribute to the vulnerability of hepatocytes to chronic viral infections.

许多病毒蛋白酶通过在干扰素 (IFN) 诱导途径中切割衔接蛋白来介导抗病毒先天免疫的逃避。宿主蛋白酶也参与先天免疫和炎症。在这里，我们报告主要存在于肝细胞中的跨膜蛋白酶 hepsin（也称为 TMPRSS1）在病毒感染期间抑制 I 型 IFN 的诱导。敲除小鼠胚胎成纤维细胞 (MEF) 中的 hepsin 可增加病毒感染诱导的Ifnb1表达，一种Ifnb1启动子报告基因和干扰素敏感反应元件启动子报告基因。hepsin 在培养的人肝细胞和 HEK293T 细胞中的异位表达通过降低 STING 的丰度来抑制病毒感染期间 IFNβ 的诱导。这些作用取决于 hepsin 的蛋白酶活性。我们在 STING 中鉴定了一个推定的 hepsin 靶位点，并表明突变该位点可以保护 STING 免受 hepsin 介导的切割。除肝细胞外，几种产生 hepsin 的前列腺癌细胞系表现出 STING 介导的 I 型 IFN 诱导和反应减少。这些结果揭示了 hepsin 在抑制 STING 介导的 I 型 IFN 诱导中的作用，这可能有助于肝细胞对慢性病毒感染的脆弱性。