RT Journal Article
SR Electronic
T1 Evolutionarily conserved primary TNF sequences relate to its primitive functions in cell death induction
JF Journal of Cell Science
JO J. Cell Sci.
FD The Company of Biologists Ltd
SP 108
OP 120
DO 10.1242/jcs.175463
VO 129
IS 1
A1 Lu, Wenshu
A1 Chen, Qiongyu
A1 Ying, Songmin
A1 Xia, Xiaobing
A1 Yu, Zhanru
A1 Lui, Yuan
A1 Tranter, George
A1 Jin, Boquan
A1 Song, Chaojun
A1 Seymour, Leonard W.
A1 Jiang, Shisong
YR 2016
UL http://jcs.biologists.org/content/129/1/108.abstract
AB 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.