靶向Vpr衍生肽进入线粒体，诱导表达αVβ3的内皮细胞凋亡。

Targeted Vpr-derived peptides reach mitochondria to induce apoptosis of alphaVbeta3-expressing endothelial cells.

作者信息

Borgne-Sanchez A, Dupont S, Langonné A, Baux L, Lecoeur H, Chauvier D, Lassalle M, Déas O, Brière J-J, Brabant M, Roux P, Péchoux C, Briand J-P, Hoebeke J, Deniaud A, Brenner C, Rustin P, Edelman L, Rebouillat D, Jacotot E

机构信息

Theraptosis Research Laboratory, THERAPTOSIS S.A., 28 rue du Dr. Roux, Paris cedex 15, France.

出版信息

Cell Death Differ. 2007 Mar;14(3):422-35. doi: 10.1038/sj.cdd.4402018. Epub 2006 Aug 4.

DOI:10.1038/sj.cdd.4402018

PMID:16888644

Abstract

The HIV-1 encoded apoptogenic protein Vpr induces mitochondrial membrane permeabilization (MMP) via interactions with the voltage-dependent anion channel (VDAC) and the adenine nucleotide translocator (ANT). We have designed a peptide, TEAM-VP, composed of two functional domains, one a tumor blood vessel RGD-like 'homing' motif and the other an MMP-inducing sequence derived from Vpr. When added to isolated mitochondria, TEAM-VP interacts with ANT and VDAC, reduces oxygen consumption and overcomes Bcl-2 protection to cause inner and outer MMP. TEAM-VP specifically recognizes cell-surface expressed alpha(V)beta(3) integrins, internalizes, temporarily localizes to lysosomes and progressively co-distributes with the mitochondrial compartment with no sign of lysosomal membrane permeabilization. Finally TEAM-VP reaches mitochondria of angiogenic endothelial cells to induce mitochondrial fission, dissipation of the mitochondrial transmembrane potential (DeltaPsi(m)), cytochrome c release and apoptosis hallmarks. Hence, this chimeric peptide constitutes the first example of a virus-derived mitochondriotoxic compound as a candidate to kill selectively tumor neo-endothelia.

摘要

人类免疫缺陷病毒1型（HIV-1）编码的促凋亡蛋白Vpr通过与电压依赖性阴离子通道（VDAC）和腺嘌呤核苷酸转位酶（ANT）相互作用诱导线粒体膜通透性改变（MMP）。我们设计了一种肽TEAM-VP，它由两个功能域组成，一个是肿瘤血管类RGD“归巢”基序，另一个是源自Vpr的MMP诱导序列。当添加到分离的线粒体中时，TEAM-VP与ANT和VDAC相互作用，降低氧气消耗并克服Bcl-2的保护作用，从而导致线粒体内外膜通透性改变。TEAM-VP能特异性识别细胞表面表达的α(V)β(3)整合素，内化后暂时定位于溶酶体，并逐渐与线粒体区室共同分布，没有溶酶体膜通透性改变的迹象。最后，TEAM-VP到达血管生成性内皮细胞的线粒体，诱导线粒体分裂、线粒体跨膜电位（ΔΨm）消散、细胞色素c释放及凋亡特征。因此，这种嵌合肽构成了首个病毒来源的线粒体毒性化合物的实例，可作为选择性杀伤肿瘤新生内皮细胞的候选药物。