Lifeguard/neuronal membrane protein 35 regulates Fas ligand-mediated apoptosis in neurons via microdomain recruitment
Lifeguard/neuronal membrane protein 35 regulates Fas ligand-mediated apoptosis in neurons via microdomain recruitment
复制标题
DOI：
10.1111/j.1471-4159.2007.04767.x
复制
发表时间：
2007-10-01
影响因子：
4.7
通讯作者：
Cena, Valentin
中科院分区：
文献类型：
--
作者：
Fernandez, Miriam;Segura, Miguel F.;Cena, Valentin
Fas配体（FasL）受体系统在调节发育中的神经系统细胞死亡中起重要作用，并与中枢神经系统的神经退行性和炎症反应有关。救生员蛋白（Lifeguard， LFG）是一种在海马和小脑中高度表达的蛋白，在出生后发育和成人中被上调，表现出一种特别有趣的调控。我们发现，过表达LFG可以保护皮质神经元免受fasl诱导的凋亡，并降低caspase的激活。通过小干扰RNA降低内源性LFG的表达，使小脑颗粒神经元对fasl诱导的细胞死亡和caspase-8激活敏感，并增加皮质神经元的敏感性。在分化的小脑颗粒神经元中，对fasl诱导的细胞死亡的保护可能完全归因于LFG，似乎与FLICE抑制剂蛋白无关。因此，LFG是FasL介导的神经元死亡的内源性抑制剂，它介导了CNS分化神经元对FasL的抵抗。最后，我们还证明在脂筏微域中检测到LFG，在那里它可能与Fas受体相互作用并调节fasl激活的信号通路。
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 sitivity 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.