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.
Mol Cell Biol. 2012 Sep;32(17):3372-81. doi: 10.1128/MCB.06739-11. Epub 2012 Jun 25.
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).
肿瘤坏死因子-α（TNF-α）是一种在细胞应激以及免疫刺激时分泌的强效炎症细胞因子，与炎症性疾病和癌症的发病机制有关。通过改变 TNF-α 通路活性的治疗潜力已在多种疾病中得到证实，TNF-α 的拮抗剂已达到临床应用。尽管已经对 TNF-α 受体复合物下游的信号转导进行了大量研究，但信号转导所需的因素仍不完整。为了寻找 TNF-α 诱导的促炎信号的新调节因子，我们在人类细胞中进行了全基因组小干扰 RNA 筛选。我们鉴定了几种新的 TNF-α 信号转导候选调节剂，这些调节剂在独立实验中得到了验证。具体来说，我们发现半胱天冬酶 4 是诱导 NF-κB 活性所必需的，而它似乎对于 Jun N-末端蛋白激酶信号分支的激活是可有可无的。总之，我们的实验将半胱天冬酶 4 鉴定为一种新型 TNF-α 诱导的 NF-κB 信号转导调节剂，它对于 IκB 激酶的激活是必需的。我们进一步提供了符合小干扰 RNA 实验最小信息（MAIRE）格式的全基因组 RNA 干扰数据集。
