| Title: |
The genetic driver of Acute Necrotizing Encephalopathy, RANBP2 , regulates the inflammatory response to Influenza A virus infection |
| Authors: |
Desgraupes, Sophie; Decorsière, Adrien; Perrin, Suzon; Gouy, Benoît; Wang, Yifan, E; Palazzo, Alexander, F; Munier, Sandie; Arhel, Nathalie, J |
| Contributors: |
Institut de Recherche en Infectiologie de Montpellier (IRIM); Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM); University of Toronto; Lyssavirus, épidémiologie et neuropathologie - Lyssavirus Epidemiology and Neuropathology; Institut Pasteur Paris (IP)-Université Paris Cité (UPCité); ANRS-MIE (ECTZ20941); ANR-23-CE15-0005,InflammaNUP,Rôle du composant du pore nucléaire RanBP2 dans les réponses inflammatoires aux infections virales(2023) |
| Source: |
https://hal.science/hal-05398660 ; 2025. |
| Publisher Information: |
CCSD |
| Publication Year: |
2025 |
| Collection: |
Université de Montpellier: HAL |
| Subject Terms: |
[SDV]Life Sciences [q-bio]; [SDV.IMM]Life Sciences [q-bio]/Immunology; [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology |
| Description: |
version 4 ; Influenza virus infections can cause severe complications such as Acute Necrotizing Encephalopathy (ANE), which is characterised by rapid onset pathological inflammation following febrile infection. Heterozygous dominant mutations in the nucleoporin RANBP2/Nup358 predispose to influenza-triggered ANE1. The aim of our study was to determine whether RANBP2 plays a role in IAV-triggered inflammatory responses. We found that the depletion of RANBP2 in a human airway epithelial cell line increased IAV genomic replication by favouring the import of the viral polymerase subunits, PB1, PB2 and PA following viral transcription and translation. Additionally, RANBP2 knockdown enhanced the cytoplasmic export of viral RNA (vRNA) and disrupted segment stoichiometry, which associated with elevated production of the pro-inflammatory chemokines CXCL8, CXCL10, CCL2, CCL3 and CCL4 in human primary macrophages. Using CRISPR-Cas9 knock-in for the ANE1 disease variant RANBP2-T585M, we further demonstrate that this point mutation causes a loss-of-localisation phenotype that excludes RANBP2 from the nuclear envelope, which phenocopies RANBP2 knockdown by increasing IAV replication and driving pro-inflammatory cytokine expression following infection. Together, our results reveal that RANBP2 regulates influenza RNA replication and nuclear export, thereby restraining virusinduced hyperinflammation, and further suggest that ANE1 pathogenesis results from the impaired localisation of RANBP2 at the nuclear envelope. . |
| Document Type: |
report |
| Language: |
English |
| DOI: |
10.1101/2025.03.23.644734 |
| Availability: |
https://hal.science/hal-05398660; https://hal.science/hal-05398660v1/document; https://hal.science/hal-05398660v1/file/Desgraupes%20Biorxiv_V2_2025.pdf; https://doi.org/10.1101/2025.03.23.644734 |
| Rights: |
http://creativecommons.org/licenses/by-nd/ ; info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.F2D273D9 |
| Database: |
BASE |