Regulation of the extrinsic apoptotic pathway by the extracellular matrix glycoprotein EMILIN2
Regulation of the extrinsic apoptotic pathway by the extracellular matrix glycoprotein EMILIN2
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DOI：
10.1128/mcb.00696-07
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发表时间：
2007-10-01
影响因子：
5.3
通讯作者：
Colombatti, Alfonso
中科院分区：
文献类型：
--
作者：
Mongiat, Maurizio;Ligresti, Giovanni;Colombatti, Alfonso
弹性蛋白微库接口定位蛋白（EMILINs）构成细胞外基质（ECM）糖蛋白家族，其特征在于在N末端存在EMI结构域和在C末端存在gC1q结构域。EMILIN 1是该家族的原型分子，参与弹性蛋白生成和高血压病因学，而EMILIN 2的功能尚未得到解决。在这里，我们提供的证据表明，EMILIN 2的表达触发不同细胞系的凋亡。细胞死亡取决于EMILIN 2与TRAIL受体DR4结合后外源性凋亡途径的激活，并且在较小程度上与DR5结合。结合之后是受体聚集、与脂筏共定位、死亡诱导信号复合物组装和半胱天冬酶活化。通过模拟已知死亡受体配体活性的ECM分子直接激活死亡受体是新颖的。EMILIN 2的敲低增加了转化细胞的存活，而过度表达由于大量凋亡而损害了软琼脂中的克隆形成和天然基质中的三维生长。这些数据证明了ECM成分与死亡受体的意外的直接和功能性相互作用，并公开了ECM信号可以负面影响细胞存活的另外的机制。
Elastin microlibril interface-located proteins (EMILINs) constitute a family of extracellular matrix (ECM) glycoproteins characterized by the presence of an EMI domain at the N terminus and a gC1q domain at the C terminus. EMILIN1, the archetype molecule of the family, is involved in elastogenesis and hypertension etiology, whereas the function of EMILIN2 has not been resolved. Here, we provide evidence that the expression of EMILIN2 triggers the apoptosis of different cell lines. Cell death depends on the activation of the extrinsic apoptotic pathway following EMILIN2 binding to the TRAIL receptors DR4 and, to a lesser extent, DR5. Binding is followed by receptor clustering, colocalization with lipid rafts, death-inducing signaling complex assembly, and caspase activation. The direct activation of death receptors by an ECM molecule that mimics the activity of the known death receptor ligands is novel. The knockdown of EMILIN2 increases transformed cell survival, and overexpression impairs clonogenicity in soft agar and three-dimensional growth in natural matrices due to massive apoptosis. These data demonstrate an unexpected direct and functional interaction of an ECM constituent with death receptors and discloses an additional mechanism by which ECM cues can negatively affect cell survival.