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| 001 | 302874 | ||
| 005 | 20250718114120.0 | ||
| 024 | 7 | _ | |a 10.1016/j.cellsig.2025.111973 |2 doi |
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| 037 | _ | _ | |a DKFZ-2025-01414 |
| 041 | _ | _ | |a English |
| 082 | _ | _ | |a 610 |
| 100 | 1 | _ | |a Wu, Guandi |0 P:(DE-He78)42ca8a4e67bf4367c45a3408c607937f |b 0 |e First author |u dkfz |
| 245 | _ | _ | |a High-throughput screening of E3 ubiquitin ligases identifies TRIM48 as a novel negative regulator of RIG-I signaling. |
| 260 | _ | _ | |a Amsterdam [u.a.] |c 2025 |b Elsevier Science |
| 336 | 7 | _ | |a article |2 DRIVER |
| 336 | 7 | _ | |a Output Types/Journal article |2 DataCite |
| 336 | 7 | _ | |a Journal Article |b journal |m journal |0 PUB:(DE-HGF)16 |s 1752749625_14020 |2 PUB:(DE-HGF) |
| 336 | 7 | _ | |a ARTICLE |2 BibTeX |
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| 336 | 7 | _ | |a Journal Article |0 0 |2 EndNote |
| 500 | _ | _ | |a #EA:D430#LA:D430# |
| 520 | _ | _ | |a The retinoic acid-inducible gene-I (RIG-I) signaling is crucial for cell-intrinsic innate antiviral immunity. Upon cytosolic detection of virus-associated RNA, it triggers a cascade inducing production of potent cytokines, mainly type I and III interferons (IFNs). While effective, dysregulated responses can harm the host, requiring tight pathway control. Here, we performed a comprehensive, systematic siRNA-based high-throughput screen across 616 established and putative E3 ubiquitin ligases for their impact on RIG-I signaling. We employed a fluorescence-based live-cell imaging assay in A549 cells to monitor nuclear translocation of IRF3 and NF-κB, two key transcription factors downstream of RIG-I. Candidate genes were validated in an orthogonal secondary screen, assessing their impact on the functional antiviral response to a Rift Valley Fever reporter virus. Fourteen hits showed consistent effects on RIG-I signaling across both screens. These genes were further validated and characterized by assessing IFN-β promoter reporter activity and IFNB1 mRNA levels upon dsRNA transfection. TRIM48 emerged as a highly robust negative regulator. Overexpression of TRIM48 suppressed RIG-I-mediated activation of IRF3 and NF-κB, reduced IFN and IFN-stimulated gene expression, and enhanced viral replication. Conversely, TRIM48 deficiency enhanced RIG-I signaling and inhibited viral replication. Notably, TRIM48 acts as an induced feedback regulator upon infection, and its effect depended on its enzymatic ubiquitin ligase activity. Our high-throughput screen provides an unbiased assessment of close to all E3 ubiquitin ligases for their regulatory effect in RIG-I signaling, and identified several interesting candidates for further investigation. TRIM48 was established as a negative feedback regulator of the RIG-I pathway. |
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| 650 | _ | 7 | |a E3 ubiquitin ligases |2 Other |
| 650 | _ | 7 | |a Innate antiviral immunity |2 Other |
| 650 | _ | 7 | |a RIG-I signaling |2 Other |
| 650 | _ | 7 | |a TRIM48 |2 Other |
| 650 | _ | 7 | |a siRNA screening |2 Other |
| 700 | 1 | _ | |a Frankish, Jamie |0 P:(DE-He78)f90105d3bdee431d11ce2f53fa15e1da |b 1 |
| 700 | 1 | _ | |a Willemsen, Joschka |0 P:(DE-He78)594b6e8e2b10f1beb53da1a5033ef2ad |b 2 |
| 700 | 1 | _ | |a Ricken, Dominik |0 P:(DE-He78)54a3727478fc2cd06f8a530458131a44 |b 3 |
| 700 | 1 | _ | |a Becker, Jonas |0 P:(DE-He78)45aa4fa7b16296bd3454cc3b68c33fc1 |b 4 |u dkfz |
| 700 | 1 | _ | |a Schweinoch, Darius |b 5 |
| 700 | 1 | _ | |a Beneke, Jürgen |b 6 |
| 700 | 1 | _ | |a Wüst, Sandra |0 P:(DE-He78)06a6077b0cfcb0f4890fb5f2543c43be |b 7 |u dkfz |
| 700 | 1 | _ | |a Beil, Nina |b 8 |
| 700 | 1 | _ | |a Matula, Petr |b 9 |
| 700 | 1 | _ | |a Rohr, Karl |b 10 |
| 700 | 1 | _ | |a Erfle, Holger |b 11 |
| 700 | 1 | _ | |a Kaderali, Lars |b 12 |
| 700 | 1 | _ | |a Binder, Marco |0 P:(DE-He78)2fb2bd9048a3777dddc4cb89b115c187 |b 13 |e Last author |u dkfz |
| 773 | _ | _ | |a 10.1016/j.cellsig.2025.111973 |g Vol. 134, p. 111973 - |0 PERI:(DE-600)1496718-2 |p 111973 |t Cellular signalling |v 134 |y 2025 |x 0898-6568 |
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