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Nef stabilizes actin to prevent HIV-1 sensing by RIG-I-like receptors

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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: Laliberté, Alexandre (Author) , Prelli Bozzo, Caterina (Author) , Acharya, Dhiraj (Author) , De Luna, Aurora (Author) , Hirschenberger, Maximilian (Author) , Zhu, Junji (Author) , Volcic, Meta (Author) , Stolp-Rastätter, Bettina (Author) , Rodriguez Quinteros, Cristina (Author) , Fackler, Oliver Till (Author) , Gack, Michaela U. (Author) , Sparrer, Konstantin M. J. (Author) , Kirchhoff, Frank (Author)
Format: Article (Journal)
Language:English
Published: 07 December 2025
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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Summary: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.
Item Description:Online veröffentlicht: 07. Dezember 2025
Gesehen am 27.02.2026
Physical Description:Online Resource
ISSN:2041-1723
DOI:10.1038/s41467-025-67028-5

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