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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 dise...

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Bibliographic Details
Main Authors: Nickles, Dorothee (Author) , Oliver Metzig, Marie (Author) , Boutros, Michael (Author)
Format: Article (Journal)
Language:English
Published: 2012
In: Molecular and cellular biology
Year: 2012, Volume: 32, Issue: 17, Pages: 3372-3381
ISSN:1098-5549
DOI:10.1128/MCB.06739-11
Online Access:Verlag, kostenfrei, Volltext: http://dx.doi.org/10.1128/MCB.06739-11
Verlag, kostenfrei, Volltext: http://mcb.asm.org/content/32/17/3372
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Author Notes:Dorothee Nickles, Christina Falschlehner, Marie Metzig, and Michael Boutros

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520 |a 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). 
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