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000300827 1001_ $$aLi, Teng-Feng$$b0
000300827 245__ $$aRBM39 shapes innate immunity by controlling the expression of key factors of the interferon response.
000300827 260__ $$aLausanne$$bFrontiers Media$$c2025
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000300827 520__ $$aThe contribution of innate immunity to clearance of viral infections of the liver, in particular sensing via Toll-like receptor 3 (TLR3), is incompletely understood. We aimed to identify the factors contributing to the TLR3 response in hepatocytes via CRISPR/Cas9 screening.A genome-wide CRISPR/Cas9 screen on the TLR3 pathway was performed in two liver-derived cell lines, followed by siRNA knockdown validation. SiRNA knockdown and indisulam treatment were used to study the role of RNA-binding motif protein 39 (RBM39) in innate immunity upon poly(I:C) or cytokine treatment and viral infections. Transcriptome, proteome, and alternative splicing were studied via RNA sequencing and mass spectrometry upon depletion of RBM39.Our CRISPR/Cas9 screen identified RBM39, which is highly expressed in hepatocytes, as an important regulator of the TLR3 pathway. Knockdown of RBM39 or treatment with indisulam, an aryl sulfonamide drug targeting RBM39 for proteasomal degradation, strongly reduced the induction of interferon-stimulated genes (ISGs) in response to double-stranded RNA (dsRNA) or viral infections. RNA sequencing (seq) and mass spectrometry identified that transcription and/or splicing of the key pathway components IRF3, RIG-I, and MDA5 were affected by RBM39 depletion, along with multiple other cellular processes identified previously. RBM39 knockdown further restrained type I and type III IFN pathways by reducing the expression of individual receptor subunits and STAT1/2. The function of RBM39 was furthermore not restricted to hepatocytes.We identified RBM39 as a regulatory factor of cell intrinsic innate immune signaling. Depletion of RBM39 impaired TLR3, RIG-I/MDA5, and IFN responses by affecting the basal expression of key pathway components.
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000300827 650_7 $$2Other$$aIFNs
000300827 650_7 $$2Other$$aIRF3
000300827 650_7 $$2Other$$aRBM39
000300827 650_7 $$2Other$$aSTAT1
000300827 650_7 $$2Other$$aSTAT2
000300827 650_7 $$2Other$$asplicing
000300827 650_7 $$2NLM Chemicals$$aRNA-Binding Proteins
000300827 650_7 $$2NLM Chemicals$$aToll-Like Receptor 3
000300827 650_7 $$09008-11-1$$2NLM Chemicals$$aInterferons
000300827 650_7 $$2NLM Chemicals$$aTLR3 protein, human
000300827 650_2 $$2MeSH$$aRNA-Binding Proteins: genetics
000300827 650_2 $$2MeSH$$aRNA-Binding Proteins: metabolism
000300827 650_2 $$2MeSH$$aRNA-Binding Proteins: immunology
000300827 650_2 $$2MeSH$$aImmunity, Innate: genetics
000300827 650_2 $$2MeSH$$aHumans
000300827 650_2 $$2MeSH$$aToll-Like Receptor 3: metabolism
000300827 650_2 $$2MeSH$$aToll-Like Receptor 3: genetics
000300827 650_2 $$2MeSH$$aToll-Like Receptor 3: immunology
000300827 650_2 $$2MeSH$$aHepatocytes: immunology
000300827 650_2 $$2MeSH$$aHepatocytes: metabolism
000300827 650_2 $$2MeSH$$aSignal Transduction
000300827 650_2 $$2MeSH$$aInterferons: immunology
000300827 650_2 $$2MeSH$$aInterferons: metabolism
000300827 650_2 $$2MeSH$$aGene Expression Regulation
000300827 650_2 $$2MeSH$$aCRISPR-Cas Systems
000300827 650_2 $$2MeSH$$aCell Line
000300827 7001_ $$aRothhaar, Paul$$b1
000300827 7001_ $$aLang, Arthur$$b2
000300827 7001_ $$aGrünvogel, Oliver$$b3
000300827 7001_ $$aColasanti, Ombretta$$b4
000300827 7001_ $$aUgarte, Santa Mariela Olivera$$b5
000300827 7001_ $$aTraut, Jannik$$b6
000300827 7001_ $$aPiras, Antonio$$b7
000300827 7001_ $$aAcosta-Rivero, Nelson$$b8
000300827 7001_ $$0P:(DE-He78)857fdd8f2ba2671be28c46a8c836dd42$$aGonçalves Magalhães, Vladimir$$b9$$udkfz
000300827 7001_ $$aSpringer, Emely$$b10
000300827 7001_ $$aBetz, Andreas$$b11
000300827 7001_ $$aHuang, Hao-En$$b12
000300827 7001_ $$0P:(DE-He78)92e094eac4fff11dc500bf29667bbc8e$$aPark, Jeongbin$$b13
000300827 7001_ $$aQiu, Ruiyue$$b14
000300827 7001_ $$aGnouamozi, Gnimah Eva$$b15
000300827 7001_ $$aMehnert, Ann-Kathrin$$b16
000300827 7001_ $$aThi, Viet Loan Dao$$b17
000300827 7001_ $$aUrban, Stephan$$b18
000300827 7001_ $$aMuckenthaler, Martina$$b19
000300827 7001_ $$0P:(DE-He78)f2a782242acf94a3114d75c45dc75b37$$aSchlesner, Matthias$$b20$$udkfz
000300827 7001_ $$aWohlleber, Dirk$$b21
000300827 7001_ $$0P:(DE-He78)2fb2bd9048a3777dddc4cb89b115c187$$aBinder, Marco$$b22$$udkfz
000300827 7001_ $$0P:(DE-He78)1d3968d2f0ff3eae55f6b2ea4c474387$$aBartenschlager, Ralf$$b23$$udkfz
000300827 7001_ $$aPichlmair, Andreas$$b24
000300827 7001_ $$aLohmann, Volker$$b25
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