Home > Documents in Process > Nef stabilizes actin to prevent HIV-1 sensing by RIG-I-like receptors. > print

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024 7 _ |a 10.1038/s41467-025-67028-5
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037 _ _ |a DZNE-2025-01353
041 _ _ |a English
082 _ _ |a 500
100 1 _ |a Laliberté, Alexandre
|0 0000-0002-6526-4133
|b 0
245 _ _ |a Nef stabilizes actin to prevent HIV-1 sensing by RIG-I-like receptors.
260 _ _ |a [London]
|c 2025
|b Springer Nature
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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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650 _ 7 |a nef Gene Products, Human Immunodeficiency Virus
|2 NLM Chemicals
650 _ 7 |a Actins
|2 NLM Chemicals
650 _ 7 |a Receptors, Immunologic
|2 NLM Chemicals
650 _ 7 |a DEAD Box Protein 58
|0 EC 3.6.4.13
|2 NLM Chemicals
650 _ 7 |a nef protein, Human immunodeficiency virus 1
|2 NLM Chemicals
650 _ 7 |a p21-Activated Kinases
|0 EC 2.7.11.1
|2 NLM Chemicals
650 _ 7 |a RIGI protein, human
|0 EC 3.6.1.-
|2 NLM Chemicals
650 _ 7 |a Interferon-Induced Helicase, IFIH1
|0 EC 3.6.4.13
|2 NLM Chemicals
650 _ 7 |a PAK2 protein, human
|0 EC 2.7.11.1
|2 NLM Chemicals
650 _ 7 |a IFIH1 protein, human
|0 EC 3.6.1.-
|2 NLM Chemicals
650 _ 7 |a Protein Phosphatase 1
|0 EC 3.1.3.16
|2 NLM Chemicals
650 _ 7 |a Interferons
|0 9008-11-1
|2 NLM Chemicals
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a HIV-1: immunology
|2 MeSH
650 _ 2 |a HIV-1: genetics
|2 MeSH
650 _ 2 |a nef Gene Products, Human Immunodeficiency Virus: metabolism
|2 MeSH
650 _ 2 |a nef Gene Products, Human Immunodeficiency Virus: genetics
|2 MeSH
650 _ 2 |a nef Gene Products, Human Immunodeficiency Virus: immunology
|2 MeSH
650 _ 2 |a Actins: metabolism
|2 MeSH
650 _ 2 |a Receptors, Immunologic
|2 MeSH
650 _ 2 |a DEAD Box Protein 58: metabolism
|2 MeSH
650 _ 2 |a HIV Infections: immunology
|2 MeSH
650 _ 2 |a HIV Infections: virology
|2 MeSH
650 _ 2 |a HIV Infections: metabolism
|2 MeSH
650 _ 2 |a p21-Activated Kinases: metabolism
|2 MeSH
650 _ 2 |a Interferon-Induced Helicase, IFIH1: metabolism
|2 MeSH
650 _ 2 |a CD4-Positive T-Lymphocytes: immunology
|2 MeSH
650 _ 2 |a CD4-Positive T-Lymphocytes: virology
|2 MeSH
650 _ 2 |a HEK293 Cells
|2 MeSH
650 _ 2 |a Immunity, Innate
|2 MeSH
650 _ 2 |a Dendritic Cells: immunology
|2 MeSH
650 _ 2 |a Phosphorylation
|2 MeSH
650 _ 2 |a Macrophages: immunology
|2 MeSH
650 _ 2 |a Macrophages: virology
|2 MeSH
650 _ 2 |a Protein Phosphatase 1: metabolism
|2 MeSH
650 _ 2 |a Interferons: metabolism
|2 MeSH
650 _ 2 |a Interferons: immunology
|2 MeSH
650 _ 2 |a Virus Replication
|2 MeSH
700 1 _ |a Prelli Bozzo, Caterina
|b 1
700 1 _ |a Acharya, Dhiraj
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700 1 _ |a De Luna, Aurora
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700 1 _ |a Hirschenberger, Maximilian
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700 1 _ |a Zhu, Junji
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700 1 _ |a Volcic, Meta
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700 1 _ |a Stolp, Bettina
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700 1 _ |a Rodriguez-Quinteros, Cristina M
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700 1 _ |a Fackler, Oliver T
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700 1 _ |a Gack, Michaela U
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700 1 _ |a Sparrer, Konstantin M J
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700 1 _ |a Kirchhoff, Frank
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773 _ _ |a 10.1038/s41467-025-67028-5
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