Induction of cell membrane protrusions by the N-terminal glutaredoxin domain of a rare splice variant of human thioredoxin reductase 1
Induction of cell membrane protrusions by the N-terminal glutaredoxin domain of a rare splice variant of human thioredoxin reductase 1
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DOI：
10.1074/jbc.m708939200
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发表时间：
2008-02-01
影响因子：
4.8
通讯作者：
Arner, Elias S. J.
中科院分区：
文献类型：
--
作者：
Dammeyer, Pascal;Damdimopoulos, Anastasios E.;Arner, Elias S. J.
人硫氧还蛋白系统在细胞中具有广泛的功能，包括调节细胞增殖和分化、免疫系统调节、抗氧化防御、转录因子活性的氧化还原控制和促进癌症发展。该酶系统的一个关键组成部分是硒蛋白硫氧还蛋白还原酶1（TrxR 1），由TXNRD 1基因编码。TXNRD 1的转录涉及选择性剪接，导致许多转录本也编码TrxR 1的同种型，这些同种型在其N-末端结构域彼此不同。在这里，我们研究了TXNRD1_v3亚型含有一个非典型的N-末端谷氧还蛋白（Grx）结构域。该亚型的转录本主要在睾丸中表达，但也在卵巢、脾脏、心脏、肝脏、肾脏和胰腺中检测到。通过免疫组织化学分析，在人类睾丸与特异性的TXNRD1_v3的Grx结构域的抗体，该蛋白被发现主要表达在Leydig细胞。TXNRD1_v3转录物的表达也在几种癌细胞系（HCC 1937、H23、A549、U1810或H157）中发现，并且在HeLa细胞中，其由雌二醇或睾酮处理诱导。令人惊讶的是，绿色荧光蛋白与完整TXNRD 1_v3蛋白或仅与其Grx结构域的融合物定位于靠近肌动蛋白的不同细胞位点，并且此外，具有快速诱导细胞膜突起的有效能力。这些结构的分析表明，TXNRD 1_ v3的Grx结构域首先定位在新兴的突起，然后通过肌动蛋白和随后的微管蛋白进入突起。因此，所呈现的结果揭示TXNRD 1_ v3在人类细胞中具有独特且不同的表达模式，并表明该蛋白质可以指导与细胞膜重构相关的肌动蛋白聚合。
The human thioredoxin system has a wide range of functions in cells including regulation of cell proliferation and differentiation, immune system modulation, antioxidant defense, redox control of transcription factor activity, and promotion of cancer development. A key component of this enzymatic system is the selenoprotein thioredoxin reductase 1(TrxR1), encoded by the TXNRD1 gene. Transcription of TXNRD1 involves alternative splicing, leading to a number of transcripts also encoding isoforms of TrxR1 that differ from each other at their N-terminal domains. Here we have studied the TXNRD1_v3 isoform containing an atypical N-terminal glutaredoxin (Grx) domain. Expression of the transcript of this isoform was found predominantly in testis but was also detected in ovary, spleen, heart, liver, kidney, and pancreas. By immunohistochemical analysis in human testis with antibodies specific for the Grx domain of TXNRD1_v3, the protein was found to be predominantly expressed in the Leydig cells. Expression of the TXNRD1_v3 transcript was also found in several cancer cell lines (HCC1937, H23, A549, U1810, or H157), and in HeLa cells, it was induced by estradiol or testosterone treatments. Surprisingly, green fluorescent protein fusions with the complete TXNRD1_v3 protein or with only its Grx domain localized to distinct cellular sites in proximity to actin, and furthermore, had a potent capacity to rapidly induce cell membrane protrusions. Analyses of these structures suggested that the Grx domain of TXNRD1_ v3 localizes first in the emerging protrusion and is then followed into the protrusions by actin and subsequently by tubulin. The results presented thus reveal that TXNRD1_ v3 has a unique and distinct expression pattern in human cells and suggest that the protein can guide actin polymerization in relation to cell membrane restructuring.