Cellular FLICE-inhibitory Protein Splice Variants Inhibit Different Steps of Caspase-8 Activation at the CD95 Death-inducing Signaling Complex*

By A. Krueger, I. Schmitz, S. Baumann, P. Krammer, S. Kirchhoff. Journal of Biological Chemistry, 2001

625 citations recorded by the source corpus.

Upon stimulation, CD95 (APO-1/Fas) recruits the adapter molecule FADD/MORT1, procaspase-8, and the cellular FLICE-inhibitory proteins (c-FLIP) into the death-inducing signaling complex (DISC). According to the induced proximity model, procaspase-8 is activated in the DISC in an autoproteolytic manner by two subsequent cleavage steps. c-FLIP proteins exist as a long (c-FLIPL) and a short (c-FLIPS) splice variant, both of them capable of protecting cells from death receptor-mediated apoptosis. In stably transfected BJAB cells, both c-FLIPS and c-FLIPL block procaspase-8 activation at the DISC. However, cleavage is blocked at different steps. c-FLIPL allows the first cleavage step of procaspase-8, leading to the generation of the p10 subunit. In contrast, c-FLIPS completely inhibits cleavage of procaspase-8. Interestingly, p43-c-FLIPL lacking the p12 subunit also prevents cleavage of procaspase-8. In contrast, a nonprocessable mutant of c-FLIPL allows the first cleavage of procaspase-8. In conclusion, both c-FLIP proteins prevent caspase-8 activation at different levels of procaspase-8 processing at the DISC. Our results indicate that c-FLIPL induces a conformation of procaspase-8 that allows partial but not complete proteolytical processing, whereas in contrast c-FLIPS even prevents partial procaspase-8 activation at the DISC.

Subfields: Cell Biology, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/e16d1da70daa02c03858d832ab14d779d3dd5c19

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cell Biology

In Molecular Biology

In Oncology

Citations in the corpus

Cellular mechanisms controlling caspase activation and function. (2013, background): “In addition, it appears that the short isoform can completely prevent processing of DISC-bound caspase-8, whereas the long isoform appears to allow partial processing (Krueger et al. 2001).”
The CD95(APO-1/Fas) DISC and beyond (2003, background): “through the recruitment to and cleavage in the DISC, but because c-FLIPL is not an active protease, the cleavage is not reciprocated, resulting in the generation of two p10 subunits (one from caspase-8, the other from c-FLIPL) followed by no further cleavage and, therefore, an inactive caspase-8 mol”
Mechanisms of resistance to TRAIL-induced apoptosis in cancer (2005, background): “resulted in only the antiapoptotic effect being observed.(58,59) Expression of cFLIP was recently reported to correlate strongly with malignant potential in colonic adenocarcinomas, melanoma, and hepatocellular carcinoma.”
Life and death in peripheral T cells (2007, background): “cFLIP proteins are well-known inhibitors of the extrinsic apoptotic pathwa”
A decade of caspases (2003, background): “…the recruitment of caspase-8 into the DISC, and its presence in the DISC even stimulates the first cleavage step of caspase-8 zymogen, but blocks further processing (Krueger et al., 2001), resulting in local activation of caspase-8 within the DISC complex (Chang et al., 2002; Micheau et al., 2002).”