The ISG15-Protease USP18 Is a Pleiotropic Enhancer of HIV-1 Replication.
Viruses
; 16(4)2024 03 22.
Article
in En
| MEDLINE
| ID: mdl-38675828
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Virus Replication
/
Ubiquitins
/
HIV-1
/
Ubiquitin Thiolesterase
Limits:
Humans
Language:
En
Journal:
Viruses
Year:
2024
Document type:
Article
Affiliation country:
Alemania