Essential role for caspase-8 in toll-like receptors and NFκB signaling
Essential role for caspase-8 in toll-like receptors and NFκB signaling
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DOI：
10.1074/jbc.m606721200
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发表时间：
2007-03-09
影响因子：
4.8
通讯作者：
Hakem, Anne
中科院分区：
文献类型：
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作者：
Lemmers, Benedicte;Salmena, Leonardo;Hakem, Anne
除了其在死亡受体途径中的促凋亡功能之外，胱天蛋白酶-8在介导T细胞增殖、维持淋巴细胞稳态和抑制免疫缺陷中的作用已经变得明显。具有半胱天冬酶-8生殖系点突变的人在T细胞、B细胞和NK细胞中具有多种缺陷，最显著的是减弱的活化和免疫缺陷。通过产生具有B细胞特异性半胱天冬酶-8（bcasp 8（-/-））失活的小鼠，我们表明半胱天冬酶-8对于B细胞发育是不稳定的，但是其在B细胞中的损失导致体内病毒感染后抗体产生减弱。我们还报告了caspase-8在维持Toll样受体（TLR）2，-3和-4刺激后B细胞存活中的重要作用。响应于TLR 4刺激，caspase-8被募集到含有IKK α β的复合物中，并且其损失导致延迟的NF κ B核转位和受损的NF κ B转录活性。我们的研究支持caspase-8在凋亡和非凋亡功能中的双重作用，并证明了其对TLR信号传导和NF κ B B功能调节的需求。
In addition to its pro-apoptotic function in the death receptor pathway, roles for caspase-8 in mediating T-cell proliferation, maintaining lymphocyte homeostasis, and suppressing immunodeficiency have become evident. Humans with a germline point mutation of CASPASE-8 have multiple defects in T cells, B cells, and NK cells, most notably attenuated activation and immunodeficiency. By generating mice with B-cell-specific inactivation of caspase-8 (bcasp8(-/-)), we show that caspase-8 is dispensable for B-cell development, but its loss in B cells results in attenuated antibody production upon in vivo viral infection. We also report an important role for caspase-8 in maintaining B-cell survival following stimulation of the Toll-like receptor (TLR)2,-3, and -4. In response to TLR4 stimulation, caspase-8 is recruited to a complex containing IKK alpha beta, and its loss resulted in delayed NF kappa B nuclear translocation and impaired NF kappa B transcriptional activity. Our study supports dual roles for caspase-8 in apoptotic and nonapoptotic functions and demonstrates its requirement for TLR signaling and in the regulation of NF kappa B function.