1. The ISG15-Protease USP18 Is a Pleiotropic Enhancer of HIV-1 Replication.
- Author
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Lin C, Kuffour EO, Li T, Gertzen CGW, Kaiser J, Luedde T, König R, Gohlke H, and Münk C
- Subjects
- Humans, Cytokines metabolism, Cytokines genetics, Immunity, Innate, HIV Infections virology, HIV Infections genetics, Membrane Proteins metabolism, Membrane Proteins genetics, Cyclin-Dependent Kinase Inhibitor p21 metabolism, Cyclin-Dependent Kinase Inhibitor p21 genetics, Host-Pathogen Interactions, Tumor Suppressor Protein p53 metabolism, Tumor Suppressor Protein p53 genetics, Ubiquitin Thiolesterase metabolism, Ubiquitin Thiolesterase genetics, Virus Replication, HIV-1 physiology, HIV-1 genetics, Ubiquitins metabolism, Ubiquitins genetics
- Abstract
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.
- Published
- 2024
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