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000302874 1001_ $$0P:(DE-He78)42ca8a4e67bf4367c45a3408c607937f$$aWu, Guandi$$b0$$eFirst author$$udkfz
000302874 245__ $$aHigh-throughput screening of E3 ubiquitin ligases identifies TRIM48 as a novel negative regulator of RIG-I signaling.
000302874 260__ $$aAmsterdam [u.a.]$$bElsevier Science$$c2025
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000302874 520__ $$aThe 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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000302874 650_7 $$2Other$$aE3 ubiquitin ligases
000302874 650_7 $$2Other$$aInnate antiviral immunity
000302874 650_7 $$2Other$$aRIG-I signaling
000302874 650_7 $$2Other$$aTRIM48
000302874 650_7 $$2Other$$asiRNA screening
000302874 7001_ $$0P:(DE-He78)f90105d3bdee431d11ce2f53fa15e1da$$aFrankish, Jamie$$b1
000302874 7001_ $$0P:(DE-He78)594b6e8e2b10f1beb53da1a5033ef2ad$$aWillemsen, Joschka$$b2
000302874 7001_ $$0P:(DE-He78)54a3727478fc2cd06f8a530458131a44$$aRicken, Dominik$$b3
000302874 7001_ $$0P:(DE-He78)45aa4fa7b16296bd3454cc3b68c33fc1$$aBecker, Jonas$$b4$$udkfz
000302874 7001_ $$aSchweinoch, Darius$$b5
000302874 7001_ $$aBeneke, Jürgen$$b6
000302874 7001_ $$0P:(DE-He78)06a6077b0cfcb0f4890fb5f2543c43be$$aWüst, Sandra$$b7$$udkfz
000302874 7001_ $$aBeil, Nina$$b8
000302874 7001_ $$aMatula, Petr$$b9
000302874 7001_ $$aRohr, Karl$$b10
000302874 7001_ $$aErfle, Holger$$b11
000302874 7001_ $$aKaderali, Lars$$b12
000302874 7001_ $$0P:(DE-He78)2fb2bd9048a3777dddc4cb89b115c187$$aBinder, Marco$$b13$$eLast author$$udkfz
000302874 773__ $$0PERI:(DE-600)1496718-2$$a10.1016/j.cellsig.2025.111973$$gVol. 134, p. 111973 -$$p111973$$tCellular signalling$$v134$$x0898-6568$$y2025
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