The protease caspase-8 functions in signaling from death-inducing receptors on the cell surface, but analysis of humans lacking the enzyme suggests that it must also play a role in signaling from antigen and Fc receptors on cells in the immune system. Su et al. show that activation of nuclear factor κB (NF-κB, a key player in immune responses) is defective in cells lacking caspase-8. Antigen or Fc receptors stimulate NF-κB through a process mediated by a molecular complex that contains numerous signaling proteins, and caspase-8 physically interacts with adaptor proteins that aid in the formation of these signaling clusters. When it signals cell death, caspase-8 undergoes autoproteolysis that generates a fragment with strong protease activity. After activation of antigen receptors, however, catalytic activity of caspase-8 was still required for signaling, but the enzyme remained intact, perhaps in a conformation with a more moderate proteolytic activity. These results help explain the range of physiological effects seen in patients after the loss of this single protein-degrading enzyme.
H. Su, N. Bidère, L. Zheng, A. Cubre, K. Sakai, J. Dale, L. Salmena, R. Hakem, S. Straus, M. Lenardo, Requirement for caspase-8 in NF-κB activation by antigen receptor. Science 307, 1465-1468 (2005). [Abstract] [Full Text]