Fernández Miriam, Segura Miguel F, Solé Carme, Colino Alicia, Comella Joan X, Ceña Valentín
Unidad Asociada Neurodeath, UCLM-CSIC, Departamento de Ciencias Médicas, Universidad de Castilla-La Mancha, Albacete, Spain.
J Neurochem. 2007 Oct;103(1):190-203. doi: 10.1111/j.1471-4159.2007.04767.x. Epub 2007 Jul 17.
Fas ligand (FasL)-receptor system plays an essential role in regulating cell death in the developing nervous system, and it has been implicated in neurodegenerative and inflammatory responses in the CNS. Lifeguard (LFG) is a protein highly expressed in the hippocampus and the cerebellum, and it shows a particularly interesting regulation by being up-regulated during postnatal development and in the adult. We show that over-expression of LFG protected cortical neurons from FasL-induced apoptosis and decreased caspase-activation. Reduction of endogenous LFG expression by small interfering RNA sensitized cerebellar granular neurons to FasL-induced cell death and caspase-8 activation, and also increased sensitivity of cortical neurons. In differentiated cerebellar granular neurons, protection from FasL-induced cell death could be attributed exclusively to LFG and appears to be independent of FLICE inhibitor protein. Thus, LFG is an endogenous inhibitor of FasL-mediated neuronal death and it mediates the FasL resistance of CNS differentiated neurons. Finally, we also demonstrate that LFG is detected in lipid rafts microdomains, where it may interact with Fas receptor and regulate FasL-activated signaling pathways.
Fas配体（FasL）-受体系统在发育中的神经系统调节细胞死亡过程中发挥着至关重要的作用，并且已被证明与中枢神经系统的神经退行性变和炎症反应有关。救生员（LFG）是一种在海马体和小脑中高度表达的蛋白质，它在出生后发育过程以及成年期呈现出特别有趣的上调调节。我们发现，LFG的过表达可保护皮层神经元免受FasL诱导的凋亡，并降低半胱天冬酶的激活。通过小干扰RNA降低内源性LFG表达会使小脑颗粒神经元对FasL诱导的细胞死亡和半胱天冬酶-8激活更加敏感，同时也增加了皮层神经元的敏感性。在分化的小脑颗粒神经元中，对FasL诱导的细胞死亡的保护作用完全可归因于LFG，并且似乎独立于FLICE抑制蛋白。因此，LFG是FasL介导的神经元死亡的内源性抑制剂，它介导中枢神经系统分化神经元对FasL的抗性。最后，我们还证明在脂筏微结构域中可检测到LFG，它可能在其中与Fas受体相互作用并调节FasL激活的信号通路。
