A genome-wide RNA interference screen identifies caspase 4 as a factor required for tumor necrosis factor alpha signaling.
Tumor necrosis factor alpha (TNF-α) is a potent inflammatory cytokine secreted upon cellular stress as well as immunological stimuli and is implicated in the pathology of inflammatory diseases and cancer. The therapeutic potential of modifying TNF-α pathway activity has been realized in several diseases, and antagonists of TNF-α have reached clinical applications. While much progress in the understanding of signaling downstream of the TNF-α receptor complex has been made, the compendium of factors required for signal transduction is still not complete. In order to find novel regulators of proinflammatory signaling induced by TNF-α, we conducted a genome-wide small interfering RNA screen in human cells. We identified several new candidate modulators of TNF-α signaling, which were confirmed in independent experiments. Specifically, we show that caspase 4 is required for the induction of NF-κB activity, while it appears to be dispensable for the activation of the Jun N-terminal protein kinase signaling branch. Taken together, our experiments identify caspase 4 as a novel regulator of TNF-α-induced NF-κB signaling that is required for the activation of IκB kinase. We further provide the genome-wide RNA interference data set as a compendium in a format compliant with minimum information about an interfering RNA experiment (MAIRE).
German Cancer Research Center (DKFZ), Division of Signaling and Functional Genomics, and Heidelberg University, Department of Cell and Molecular Biology, Medical Faculty Mannheim, Heidelberg, Germany.
Dorothee
D
Nickles
Christina
C
Falschlehner
Marie
M
Metzig
Michael
M
Boutros
D053471:Caspases, Initiator / Q000235:genetics* / Q000276:immunology*; D023281:Genomics / Q000379:methods*; D057809:HEK293 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000276:immunology; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D034622:RNA Interference; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology*
D016328:NF-kappa B; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D051550:I-kappa B Kinase; C093516:CASP4 protein, human; D053471:Caspases, Initiator