Abstract
Signaling via death receptor family members such as TNF-R1 mediates pleiotropic biological outcomes ranging from inflammation and proliferation to cell death. Pro-survival signaling is mediated via TNF-R1 complex I at the cellular plasma membrane. Cell death induction requires complex IIa/b or necrosome formation, which occurs in the cytoplasm. In many cell types, full apoptotic or necroptotic cell death induction requires the internalization of TNF-R1 and receptosome formation to properly relay the signal inside the cell. We interrogated the role of the enzyme A disintegrin and metalloprotease 17 (ADAM17)/TACE (TNF-α converting enzyme) in death receptor signaling in human hematopoietic cells, using pharmacological inhibition and genetic ablation. We show that in U937 and Jurkat cells the absence of ADAM17 does not abrogate, but rather increases TNF mediated cell death. Likewise, cell death triggered via DR3 is enhanced in U937 cells lacking ADAM17. We identified ADAM17 as the key molecule that fine-tunes death receptor signaling. A better understanding of cell fate decisions made via the receptors of the TNF-R1 superfamily may enable us, in the future, to more efficiently treat infectious and inflammatory diseases or cancer.
Highlights
Signaling via TNF-R1 evokes various biological outcomes, ranging from the induction of inflammation and gene transcription to the activation of different modes of cell death.Cell survival signaling via NFκB emanates from cell surface resident receptors, recruiting so-called TNF-R1 complex I
We recently showed that the absence of A disintegrin and metalloprotease 17 (ADAM17) resulted in reduced lung metastasis in a mouse model, due to a decrease in TNF mediated necroptosis in endothelial cells [11]
Signaling requires complex I formation at the plasma membrane, whereas cell death induction requires complex IIa/b or necrosome formation, resulting either in the induction of apoptosis or necroptosis, respectively [1]
Summary
Cell survival signaling via NFκB emanates from cell surface resident receptors, recruiting so-called TNF-R1 complex I. Cell death signaling requires complex II formation. The activation of TNF-R1 favors complex I formation, instead of cell death induction, in most cell types. The activation of apoptosis requires receptor internalization and complex II recruitment in the death domain of TNF receptors. Complex II can dissociate from the receptor and occurs as a soluble cytosolic complex. The mechanisms beyond this point are not fully understood. In contrast to apoptosis induction via complex II formation, necroptosis is a caspase-8 independent form of cell death.
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