Lin Chaohui, Kuffour Edmund Osei, Li Taolan, Gertzen Christoph G W, Kaiser Jesko, Luedde Tom, König Renate, Gohlke Holger, Münk Carsten
Clinic of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.
Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.
Viruses. 2024 Mar 22;16(4):485. doi: 10.3390/v16040485.
The innate immune response to viruses is formed in part by interferon (IFN)-induced restriction factors, including ISG15, p21, and SAMHD1. IFN production can be blocked by the ISG15-specific protease USP18. HIV-1 has evolved to circumvent host immune surveillance. This mechanism might involve USP18. In our recent studies, we demonstrate that HIV-1 infection induces USP18, which dramatically enhances HIV-1 replication by abrogating the antiviral function of p21. USP18 downregulates p21 by accumulating misfolded dominant negative p53, which inactivates wild-type p53 transactivation, leading to the upregulation of key enzymes involved in de novo dNTP biosynthesis pathways and inactivated SAMHD1. Despite the USP18-mediated increase in HIV-1 DNA in infected cells, it is intriguing to note that the cGAS-STING-mediated sensing of the viral DNA is abrogated. Indeed, the expression of USP18 or knockout of ISG15 inhibits the sensing of HIV-1. We demonstrate that STING is ISGylated at residues K224, K236, K289, K347, K338, and K370. The inhibition of STING K289-linked ISGylation suppresses its oligomerization and IFN induction. We propose that human USP18 is a novel factor that potentially contributes in multiple ways to HIV-1 replication.
机体对病毒的固有免疫反应部分由干扰素（IFN）诱导的限制因子形成，包括ISG15、p21和SAMHD1。IFN的产生可被ISG15特异性蛋白酶USP18阻断。HIV-1已经进化出规避宿主免疫监视的机制。这种机制可能涉及USP18。在我们最近的研究中，我们证明HIV-1感染会诱导USP18，USP18通过消除p21的抗病毒功能显著增强HIV-1复制。USP18通过积累错误折叠的显性负性p53来下调p21，显性负性p53会使野生型p53的反式激活失活，导致参与从头合成dNTP生物合成途径的关键酶上调以及SAMHD1失活。尽管USP18介导感染细胞中HIV-1 DNA增加，但值得注意的是，cGAS-STING介导的对病毒DNA的感知被消除。确实，USP18的表达或ISG15的敲除会抑制对HIV-1的感知。我们证明STING在K224、K236、K289、K347、K338和K370位点发生ISGylation修饰。抑制STING K289位点的ISGylation修饰会抑制其寡聚化和IFN诱导作用。我们提出，人USP18是一种新型因子，可能以多种方式促进HIV-1复制。
