A Genome-Wide RNA Interference Screen Identifies Caspase 4 as a Factor Required for Tumor Necrosis Factor Alpha Signaling

作者：Nickles Dorothee; Falschlehner Christina; Metzig Marie; Boutros Michael^*

来源：Molecular and Cellular Biology, 2012, 32(17): 3372-3381.

DOI：10.1128/MCB.06739-11

Tumor necrosis factor alpha (TNF-alpha) 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-alpha pathway activity has been realized in several diseases, and antagonists of TNF-alpha have reached clinical applications. While much progress in the understanding of signaling downstream of the TNF-alpha 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-alpha, we conducted a genome-wide small interfering RNA screen in human cells. We identified several new candidate modulators of TNF-alpha signaling, which were confirmed in independent experiments. Specifically, we show that caspase 4 is required for the induction of NF-kappa B 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-alpha-induced NF-kappa B signaling that is required for the activation of I kappa B 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).

• 出版日期2012-9