New Roles for Caspase-8

Abstract

Investigation of two siblings with an autoimmune lymphoproliferative syndrome (ALPS) has resulted in the identification of novel functions for caspase-8. The caspases, a family of cysteine proteases, play a key role in executing apoptosis, a cell suicide process that counters cell proliferation to achieve a homeostatic balance. In lymphocytes, apoptosis is triggered by reorganization of inactive Fas complexes into the death-inducing signal complex (DISC) and the consequent release of active caspase-8. Chun et al. identified two siblings with an ALPS that, atypically, was accompanied by pronounced immunodeficiency. Their lymphocytes showed defects in apoptosis after Fas stimulation, but not after induction of the intrinsic pathway of mitochondrial apoptosis. Western analysis of cell lysates and DISC immunoprecipitates showed reduced levels of caspase-8 and lacked caspase-8 cleavage products, indicating loss of functional activity. Sequence analysis revealed a homozygous mutation in caspase-8. Mutant caspase-8 failed to cleave a reporter substrate, and, unlike wild-type caspase-8, could not restore Fas-induced apoptosis when expressed in a caspase-8-deficient cell line. T lymphocytes, B lymphocytes, and natural killer (NK) cells showed defects in various indicators of cell activation, including T cell receptor-stimulated release of interleukin-2, phytohemagglutinin-stimulated T cell proliferation, induction of T cell and NK cell-surface markers of activation, and B cell production of immunoglobulins μ and γ. Inactivating caspase-8 in normal human lymphocytes through RNA interference or through antisense constructs also reduced induction of cell-surface activation markers, whereas introducing active caspase-8 into lymphocytes from an ALPS sibling restored induction of cell surface activation markers. These data suggest that caspase-8 plays some role in lymphocyte activation, in addition to its well-known role in apoptosis. H. J. Chun, L. Zheng, M. Ahmed, J. Wang, C. K. Speirs, R. M. Siegel, J. K. Dale, J. Puck, J. Davis, C. G. Hall, S. Skoda-Smith, T. P. Atkinson, S. E. Straus, M. J. Lenardo, Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human deficiency. Nature 419 , 395-399 (2002). [Online Journal]