| Title: |
Nef stabilizes actin to prevent HIV-1 sensing by RIG-I-like receptors |
| Authors: |
Kirchhoff, Frank; Laliberté, Alexandre; Bozzo, Caterina Prelli; Acharya, Dhiraj; De Luna, Aurora; Hirschenberger, Maximilian; Volcic, Meta; Stolp, Bettina; Fackler, Oliver; Gack, Michaela; Sparrer, Konstantin |
| Publisher Information: |
Springer Science and Business Media LLC |
| Publication Year: |
2025 |
| Description: |
Sensing of viral pathogens by RIG-I-like receptors (RLRs) requires their priming via dephosphorylation mediated by the protein phosphatase 1 regulatory subunit 12C (R12C), which is activated upon virus-induced actin rearrangements. Here, we show that the HIV-1 accessory protein Nef disrupts R12C-mediated RLR priming, thereby preventing efficient viral sensing. HIV-1 variants containing single point mutations in Nef (F/R191A) that ablate its ability to bind the actin-modulating kinase PAK2 trigger increased interferon (IFN) responses in primary CD4+ T cells, macrophages, and dendritic cells. Neutralization of IFN suppressed innate immune activation and enhanced the replication of Nef-mutated HIV-1. We further demonstrate that HIV-1 encoding Nef F/R191A is sensed by MDA5 after proviral integration in an R12C-dependent manner. Mechanistically, PAK2 binding by Nef prevents the re-localization of R12C to MDA5 and its subsequent dephosphorylation. Our data identify Nef as an antagonist of actin-R12C-mediated RLR priming, enabling HIV-1 to escape immune control. |
| Document Type: |
other/unknown material |
| Language: |
unknown |
| DOI: |
10.21203/rs.3.rs-6251290/v1 |
| Availability: |
https://doi.org/10.21203/rs.3.rs-6251290/v1; https://www.researchsquare.com/article/rs-6251290/v1; https://www.researchsquare.com/article/rs-6251290/v1.html |
| Rights: |
https://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.108F357F |
| Database: |
BASE |