A Life or Death Decision

Abstract

Stimulation of lymphocyte death receptors leads to activation of the cysteine protease caspase-8, which undergoes autoproteolysis to produce a mature form that cleaves effector caspases (such as caspase-3) as part of a proteolytic cascade that ends in apoptosis. In contrast, caspase-8 activation during antigenic stimulation, which involves its association with a complex that contains Bcl10 and MALT1, is required for lymphocyte proliferation. Kawadler et al . found that interleukin-2 (IL-2) production was reduced in activated human T cells (stimulated with antibodies directed against CD3 and a chimeric form of CD28) in which caspase-8 was knocked down with siRNA. Caspase-8 activated by antibody stimulation underwent limited autoproteolysis and failed to cleave substrate effector caspases appreciably. Activation of the transcription factor NF-κB in response to coexpression of MALT1 and Bcl10 was attenuated in Jurkat lymphoma cells lacking caspase-8; moreover, MALT1 knockdown prevented caspase-8 activation in primary human T cells. Noting that MALT1 contains a paracaspase domain (distantly related to the caspase proteolytic domain), the authors used a controlled heterodimerization system to show that heterodimerization of MALT1 and caspase-8 led to cleavage of the latter. The MALT1 paracaspase domain bound to the caspase-8 protease domain; however, mutational analysis established that caspase-8 cleavage was autoproteolytic and did not depend on MALT1 protease activity. MALT1 failed to stimulate caspase-8–mediated proteolysis of caspase-3, although it did stimulate proteolysis of the caspase homolog c-FLIP L . c-FLIP L was cleaved after antibody stimulation of lymphocytes, and its knockdown inhibited IL-2 production. Moreover, mutational analysis revealed that MALT1-dependent activation of caspase-8 and proteolysis of c-FLIP L were critical to NF-κB activation and IL-2 production. Thus, MALT1 appears to activate caspase-8 in a manner that affects its processing and substrate specificity, which leads to proliferative—rather than apoptotic—signaling. H. Kawadler, M. A. Gantz, J. L. Riley, X. Yang, The paracaspase MALT1 controls caspase-8 activation during lymphocyte proliferation. Mol. Cell 31 , 415-421 (2008). [PubMed]