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The ISG15-Protease USP18 Is a Pleiotropic Enhancer of HIV-1 Replication.
- Source :
-
Viruses [Viruses] 2024 Mar 22; Vol. 16 (4). Date of Electronic Publication: 2024 Mar 22. - Publication Year :
- 2024
-
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.
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1999-4915
- Volume :
- 16
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Viruses
- Publication Type :
- Academic Journal
- Accession number :
- 38675828
- Full Text :
- https://doi.org/10.3390/v16040485