Model-based dissection of CD95 signaling dynamics reveals both a pro- and antiapoptotic role of c-FLIPL.
Cellular FADD-like interleukin-1beta-converting enzyme inhibitory proteins (c-FLIPs; isoforms c-FLIP long [c-FLIP(L)], c-FLIP short [c-FLIP(S)], and c-FLIP Raji [c-FLIP(R)]) regulate caspase-8 activation and death receptor (DR)-induced apoptosis. In this study, using a combination of mathematical modeling, imaging, and quantitative Western blots, we present a new mathematical model describing caspase-8 activation in quantitative terms, which highlights the influence of c-FLIP proteins on this process directly at the CD95 death-inducing signaling complex. We quantitatively define how the stoichiometry of c-FLIP proteins determines sensitivity toward CD95-induced apoptosis. We show that c-FLIP(L) has a proapoptotic role only upon moderate expression in combination with strong receptor stimulation or in the presence of high amounts of one of the short c-FLIP isoforms, c-FLIP(S) or c-FLIP(R). Our findings resolve the present controversial discussion on the function of c-FLIP(L) as a pro- or antiapoptotic protein in DR-mediated apoptosis and are important for understanding the regulation of CD95-induced apoptosis, where subtle differences in c-FLIP concentrations determine life or death of the cells.
Fricker
Nicolai
N
Division of Immunogenetics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
Beaudouin
Joel
J
Richter
Petra
P
Eils
Roland
R
Krammer
Peter H
PH
Lavrik
Inna N
IN
D000465:Algorithms; D017209:Apoptosis; D015153:Blotting, Western; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism; D003198:Computer Simulation; D006367:HeLa Cells; D006801:Humans; D008954:Models, Biological; D020033:Protein Isoforms / Q000378:metabolism; D015398:Signal Transduction; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism*
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D020033:Protein Isoforms; D019014:fas Receptor; D053181:Caspase 8