Kawadler Holli, Gantz Mary A, Riley James L, Yang Xiaolu
Abramson Family Cancer Research Institute, Department of Cancer Biology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Mol Cell. 2008 Aug 8;31(3):415-21. doi: 10.1016/j.molcel.2008.06.008.
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.
半胱天冬酶-8是一种参与淋巴细胞凋亡的起始半胱天冬酶，却出人意料地是淋巴细胞增殖所必需的。目前尚不清楚在抗原信号传导过程中半胱天冬酶-8是如何被调控的，既能实现激活又能避免触发凋亡。在此，我们表明半胱天冬酶-8在抗原刺激后会发生有限的激活，且这种激活依赖于类半胱天冬酶MALT1。MALT1的类半胱天冬酶结构域以不依赖蛋白酶的方式通过直接结合诱导半胱天冬酶-8激活。MALT1减少了凋亡效应半胱天冬酶的激活，但不改变半胱天冬酶-8对c-FLIP(L)的活性，而c-FLIP(L)是抗原信号传导所必需的。无法激活半胱天冬酶-8并允许c-FLIP(L)裂解的MALT1突变体不能促进核因子κB激活或白细胞介素-2诱导。我们的结果揭示了一种利用对细胞可能致命的蛋白酶进行增殖信号传导的机制，并证明了半胱天冬酶家族和类半胱天冬酶家族之间的功能联系以实现非凋亡过程。
