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@ARTICLE{Wu:302874,
      author       = {G. Wu$^*$ and J. Frankish$^*$ and J. Willemsen$^*$ and D.
                      Ricken$^*$ and J. Becker$^*$ and D. Schweinoch and J. Beneke
                      and S. Wüst$^*$ and N. Beil and P. Matula and K. Rohr and
                      H. Erfle and L. Kaderali and M. Binder$^*$},
      title        = {{H}igh-throughput screening of {E}3 ubiquitin ligases
                      identifies {TRIM}48 as a novel negative regulator of
                      {RIG}-{I} signaling.},
      journal      = {Cellular signalling},
      volume       = {134},
      issn         = {0898-6568},
      address      = {Amsterdam [u.a.]},
      publisher    = {Elsevier Science},
      reportid     = {DKFZ-2025-01414},
      pages        = {111973},
      year         = {2025},
      note         = {#EA:D430#LA:D430#},
      abstract     = {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.},
      keywords     = {E3 ubiquitin ligases (Other) / Innate antiviral immunity
                      (Other) / RIG-I signaling (Other) / TRIM48 (Other) / siRNA
                      screening (Other)},
      cin          = {D430},
      ddc          = {610},
      cid          = {I:(DE-He78)D430-20160331},
      pnm          = {314 - Immunologie und Krebs (POF4-314)},
      pid          = {G:(DE-HGF)POF4-314},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40609779},
      doi          = {10.1016/j.cellsig.2025.111973},
      url          = {https://inrepo02.dkfz.de/record/302874},
}