Cytoskeleton keratin regulation of FasR signaling through modulation of actin/ezrin interplay at lipid rafts in hepatocytes
Cytoskeleton keratin regulation of FasR signaling through modulation of actin/ezrin interplay at lipid rafts in hepatocytes
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DOI：
10.1007/s10495-012-0733-2
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发表时间：
2012-08-01
期刊：
影响因子：
7.2
通讯作者：
Marceau, Normand
中科院分区：
文献类型：
--
作者：
Gilbert, Stephane;Loranger, Anne;Marceau, Normand
Fas配体的刺激导致FasR微聚体的快速形成，通过与肌动蛋白和Ezrin的相互作用，这些微聚体成为信号蛋白寡聚转导结构(SPOTS)，这是一个与原aspase-8激活相关的触发死亡诱导信号复合体形成的结构步骤。在一些被命名为I型的细胞中，caspase 8直接激活效应caspase，而在另一些被称为II型的细胞中，caspase介导的死亡信号是通过线粒体放大的。角蛋白是上皮细胞的中间丝(IF)蛋白，以谱系/分化方式成对表达。肝细胞IF仅由角蛋白8/18(K8/K18)组成，角蛋白8/18是所有单纯上皮的标志。我们最近发现，与野生型(WT)小鼠肝细胞相比，K8缺失的小鼠肝细胞中K8/K18IFs的缺失导致了更有效的FasR介导的细胞凋亡，这与FasR死亡信号中的II型/I型开关有关。在这里，我们证明了发生在I型K8缺失的肝细胞中的凋亡过程与表面膜上加速的斑点形成以及FasR帽形成和内化的表现有关。此外，在K8缺失的肝细胞中，脂筏组织发生了变化。虽然脂筏抑制损害了WT和K8缺失的肝细胞中斑点的形成，但后者中K8/K18 IF的缺失使斑点对肌动蛋白解聚敏感，并扰乱了Ezrin的区域化。总之，结果表明，肝细胞中K8/K18IF的丢失通过Ezrin/肌动蛋白相互作用和脂筏组织的扰动改变了初始的FasR激活步骤，从而导致FasR-Death信号中的II型/I型转换。
FasR stimulation by Fas ligand leads to rapid formation of FasR microaggregates, which become signaling protein oligomerization transduction structures (SPOTS), through interactions with actin and ezrin, a structural step that triggers death-inducing signaling complex formation, in association with procaspase-8 activation. In some cells, designated as type I, caspase 8 directly activates effector caspases, whereas in others, known as type II, the caspase-mediated death signaling is amplified through mitochondria. Keratins are the intermediate filament (IF) proteins of epithelial cells, expressed as pairs in a lineage/differentiation manner. Hepatocyte IFs are made solely of keratins 8/18 (K8/K18), the hallmark of all simple epithelia. We have shown recently that in comparison to type II wild-type (WT) mouse hepatocytes, the absence of K8/K18 IFs in K8-null hepatocytes leads to more efficient FasR-mediated apoptosis, in link with a type II/type I-like switch in FasR-death signaling. Here, we demonstrate that the apoptotic process occurring in type I-like K8-null hepatocytes is associated with accelerated SPOTS elaboration at surface membrane, along with manifestation of FasR cap formation and internalization. In addition, the lipid raft organization is altered in K8-null hepatocytes. While lipid raft inhibition impairs SPOTS formation in both WT and K8-null hepatocytes, the absence of K8/K18 IFs in the latter sensitizes SPOTS to actin de-polymerization, and perturbs ezrin compartmentalization. Overall, the results indicate that the K8/K18 IF loss in hepatocytes alters the initial FasR activation steps through perturbation of ezrin/actin interplay and lipid raft organization, which leads to a type II/type I switch in FasR-death signaling.