Comparative proteomics of exosomes secreted by tumoral Jurkat T cells and normal human T cell blasts unravels a potential tumorigenic role for valosin-containing protein.
Comparative proteomics of exosomes secreted by tumoral Jurkat T cells and normal human T cell blasts unravels a potential tumorigenic role for valosin-containing protein.
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DOI：
10.18632/oncotarget.8678
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发表时间：
2016-05-17
期刊：
影响因子：
--
通讯作者：
Anel A
中科院分区：
文献类型：
--
作者：
Bosque A;Dietz L;Gallego-Lleyda A;Sanclemente M;Iturralde M;Naval J;Alava MA;Martínez-Lostao L;Thierse HJ;Anel A
我们之前已经鉴定了FasL和Apo2L/TRAIL以其生物活性形式储存在人类T细胞母细胞内，存在于多囊泡体中的腔内小泡中。当T细胞重新激活时，这些小泡以外切体的形式迅速释放到上清液中。在这项研究中，我们首次比较了正常人T细胞和肿瘤Jurkat细胞产生的外切体的蛋白质组学，目的是识别与肿瘤外切体相关的蛋白质，这些蛋白质可能在恶性肿瘤中具有先前未被认识的作用。我们已经在T细胞母细胞和Jurkat细胞的外切体中分别鉴定了359和418个蛋白质。有趣的是，只有145个(约40%)是常见的。在这两种情况下，主要的蛋白质是肌动蛋白和微管蛋白亚型，共同的相互作用节点对应于这些细胞骨架和相关蛋白，以及核糖体和mRNA颗粒蛋白。我们检测到14种膜蛋白，与T细胞母细胞相比，Jurkat细胞的外切体中有14种蛋白特别丰富。这些蛋白中含量最丰富的是Valosin-Holding Protein(VCP)，它是一种参与ER动态平衡和泛素化的膜ATPase。在这项工作中，我们还表明，白血病细胞比正常T细胞对VCP抑制剂DBeQ诱导的细胞死亡更敏感。此外，VCP抑制只在Jurkat细胞中阻止功能性外切体的分泌，而不是在T细胞母细胞中。这些结果表明，VCP靶向是一种新的选择性途径，可用于癌症治疗以防止肿瘤外切体的分泌。
We have previously characterized that FasL and Apo2L/TRAIL are stored in their bioactive form inside human T cell blasts in intraluminal vesicles present in multivesicular bodies. These vesicles are rapidly released to the supernatant in the form of exosomes upon re-activation of T cells. In this study we have compared for the first time proteomics of exosomes produced by normal human T cell blasts with those produced by tumoral Jurkat cells, with the objective of identify proteins associated with tumoral exosomes that could have a previously unrecognized role in malignancy. We have identified 359 and 418 proteins in exosomes from T cell blasts and Jurkat cells, respectively. Interestingly, only 145 (around a 40%) are common. The major proteins in both cases are actin and tubulin isoforms and the common interaction nodes correspond to these cytoskeleton and related proteins, as well as to ribosomal and mRNA granule proteins. We detected 14 membrane proteins that were especially enriched in exosomes from Jurkat cells as compared with T cell blasts. The most abundant of these proteins was valosin-containing protein (VCP), a membrane ATPase involved in ER homeostasis and ubiquitination. In this work, we also show that leukemic cells are more sensitive to cell death induced by the VCP inhibitor DBeQ than normal T cells. Furthermore, VCP inhibition prevents functional exosome secretion only in Jurkat cells, but not in T cell blasts. These results suggest VCP targeting as a new selective pathway to exploit in cancer treatment to prevent tumoral exosome secretion.
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影响因子：
12.4
作者：
Kim, SH;Bianco, N;Robbins, PD
通讯作者：
Robbins, PD
影响因子：
2.9
作者：
BLUM, H;BEIER, H;GROSS, HJ
通讯作者：
GROSS, HJ
影响因子：
20.3
作者：
Del-Rey, Manuel;Ruiz-Contreras, Jesus;Allende, Luis M.
通讯作者：
Allende, Luis M.
DOI：
10.1083/jcb.97.2.329
发表时间：
1983-08
期刊：
The Journal of cell biology
影响因子：
--
作者：
Harding C;Heuser J;Stahl P
通讯作者：
Stahl P
影响因子：
5.5
作者：
Bosque, A;Pardo, J;Anel, A
通讯作者：
Anel, A