Abstract
Presentation Description :
Death receptor Fas signals extrinsic apoptosis by promoting caspase-8 dimerization and activation. Impaired Fas signaling causes unconventional lymphocytes to accumulate, and elicits autoimmune lymphoproliferative syndrome (ALPS) in humans and lymphoproliferative (LPR) disease in mice. Although caspase-8 homodimer-deficient mice (for example, Casp8D387A/D387A mice) exhibit reduced Fas-induced apoptosis, they do not develop LPR disease. Therefore, there must be sufficient residual caspase-8 activity to suppress LPR disease. We now show that this lingering caspase-8 activity is provided by heterodimers of caspase-8 and the Cflar-encoded pseudoprotease cFLIPL. Thus, besides suppressing MLKL-dependent necroptosis, heterodimers of caspase-8 and cFLIPL can also mediate extrinsic apoptosis and suppress LPR disease. Consistent with caspase-8 cleavage of cFLIPL enhancing heterodimer proteolytic activity, knock-in mice expressing non-cleavable cFLIPL exhibited impaired extrinsic apoptosis and less TNF toxicity. Our data highlight a role for cFLIPL in promoting caspase-8 proteolytic activity and altering cell survival.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.