Nef stabilizes actin to prevent HIV-1 sensing by RIG-I-like receptors
Sensing of viral pathogens by RIG-I-like receptors (RLRs) requires their priming via dephosphorylation mediated by the protein phosphatase 1 regulatory subunit 12 C (R12C), which is activated upon virus-induced actin rearrangements. Here, we show that the HIV-1 accessory protein Nef prevents R12C-me...
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| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
07 December 2025
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| In: |
Nature Communications
Year: 2025, Volume: 16, Pages: 1-15 |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-025-67028-5 |
| Online Access: | Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41467-025-67028-5 Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41467-025-67028-5 
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| Author Notes: | Alexandre Laliberté, Caterina Prelli Bozzo, Dhiraj Acharya, Aurora De Luna, Maximilian Hirschenberger, Junji Zhu, Meta Volcic, Bettina Stolp, Cristina M. Rodriguez-Quinteros, Oliver T. Fackler, Michaela U. Gack, Konstantin M.J. Sparrer & Frank Kirchhoff |
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| 520 | |a Sensing of viral pathogens by RIG-I-like receptors (RLRs) requires their priming via dephosphorylation mediated by the protein phosphatase 1 regulatory subunit 12 C (R12C), which is activated upon virus-induced actin rearrangements. Here, we show that the HIV-1 accessory protein Nef prevents R12C-mediated RLR priming, thereby suppressing 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 suppresses innate immune activation and enhances 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 promotes actin repair and stabilization, thereby preventing re-localization of R12C to MDA5 and RIG-I and their subsequent dephosphorylation. Our data identify Nef as an antagonist of actin-R12C-mediated RLR priming, enabling HIV-1 to escape immune control. | ||
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