Research ArticleImmunology

The transmembrane serine protease hepsin suppresses type I interferon induction by cleaving STING

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Science Signaling  15 Jun 2021:
Vol. 14, Issue 687, eabb4752
DOI: 10.1126/scisignal.abb4752

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Viral vulnerability in hepatocytes

Chronic viral infections of the liver can lead to organ dysfunction and hepatocellular carcinoma. Hsin et al. found that the transmembrane serine protease hepsin, which is abundant in the liver, suppressed the STING-mediated induction of type I IFNs in response to viral infection in mouse embryonic fibroblasts (MEFs) and human hepatocytes. Hepsin colocalized with STING at the endoplasmic reticulum and cleaved STING. This mechanism also appeared to account for the failure of prostate cancer cells, which also produce hepsin, to mount a STING-dependent type I IFN response to viral infection. Thus, hepsin makes hepatocytes vulnerable to viral infection and may contribute to the poor response of prostate cancer cells to immunotherapies that rely on STING activation.

Abstract

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.

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