Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.
Skip to main content

TNF is a primitive protein that has emerged from more than 550 million years of evolution. Our bioinformatics study of TNF from nine different taxa in vertebrates revealed several conserved regions in the TNF sequence. By screening overlapping peptides derived from human TNF to determine their role in three different TNF-induced processes--apoptosis, necrosis and NF-κB stimulation--we found that TNF conserved regions are mostly related to cell death rather than NF-κB stimulation. Among the most conserved regions, peptides (P)12, P13 and P1213 (comprising P12 and P13) induced apoptosis, whereas P14, P15, P16 and P1516 (comprising P15 and P16) induced necrosis. Cell death induced by these peptides was not through binding to the TNF receptor. P16-induced necrosis was mainly through disruption of the cell membrane, whereas P1213-induced apoptosis involved activation of TRADD followed by formation of complex II. Finally, using a monoclonal antibody and a mutant TNF protein, we show that TNF-induced apoptosis is determined by a conserved linear sequence that corresponds to that within P1213. Our results reveal the determinant sequence that is key to the TNF primitive function of inducing apoptosis.

Original publication

DOI

10.1242/jcs.175463

Type

Journal article

Journal

J Cell Sci

Publication Date

01/01/2016

Volume

129

Pages

108 - 120

Keywords

Apoptosis, Evolution, NF-κB, Necrosis, Overlapping peptides, TNF, Amino Acid Sequence, Animals, Caspase 8, Cell Membrane, Conserved Sequence, Evolution, Molecular, Fas-Associated Death Domain Protein, Humans, Jurkat Cells, Mice, Molecular Sequence Data, Nuclear Pore Complex Proteins, Peptides, RNA-Binding Proteins, Receptors, Tumor Necrosis Factor, Type I, TNF Receptor-Associated Death Domain Protein, Tumor Necrosis Factor-alpha, Vertebrates