A genome-wide RNA interference screen identifies caspase 4 as a factor required for tumor necrosis factor alpha signaling.

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

SUBMITTER: Nickles D 

PROVIDER: S-EPMC3422000 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature