The paracaspase MALT1 controls caspase-8 activation during lymphocyte proliferation.
Caspase-8, an initiator caspase involved in lymphocyte apoptosis, is paradoxically required for lymphocyte proliferation. It is not understood how caspase-8 is controlled during antigenic signaling to allow for activation while averting the triggering of apoptosis. Here, we show that caspase-8 undergoes limited activation upon antigenic stimulation, and this activation is dependent on the paracaspase MALT1. The paracaspase domain of MALT1, in a protease-independent manner, induces caspase-8 activation through direct association. MALT1 diminishes the activation of apoptotic effector caspases, but it does not alter the activity of caspase-8 toward c-FLIP(L), which is required for antigenic signaling. Mutants of MALT1 that fail to activate caspase-8 and permit c-FLIP(L) cleavage cannot facilitate NF-kappaB activation or IL-2 induction. Our results reveal a mechanism that utilizes a protease potentially deadly to the cell for proliferative signaling and demonstrate a functional connection between the caspase and paracaspase families to enable nonapoptotic processes.
Kawadler
Holli
H
Abramson Family Cancer Research Institute, Department of Cancer Biology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Gantz
Mary A
MA
Riley
James L
JL
Yang
Xiaolu
X
D000941:Antigens / Q000276:immunology; D017209:Apoptosis; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism; D053181:Caspase 8 / Q000737:chemistry / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism*; D049109:Cell Proliferation; D004789:Enzyme Activation; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D015398:Signal Transduction; D013379:Substrate Specificity; D013601:T-Lymphocytes / Q000166:cytology* / Q000201:enzymology*
D000941:Antigens; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D009363:Neoplasm Proteins; D011948:Receptors, Antigen, T-Cell; D053181:Caspase 8; D020169:Caspases; C400109:MALT1 protein, human; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein