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J. Biol. Chem., Vol. 283, Issue 5, 2814-2821, February 1, 2008

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Induction of Cell Membrane Protrusions by the N-terminal Glutaredoxin Domain of a Rare Splice Variant of Human Thioredoxin Reductase 1^*

Pascal Dammeyer, Anastasios E. Damdimopoulos¹, Tomas Nordman², Alberto Jiménez³, Antonio Miranda-Vizuete⁴, and Elias S. J. Arnér⁵

From the Medical Nobel Institute for Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm and the Department of Biosciences and Nutrition, Novum, Karolinska Institutet, SE-141 57 Huddinge, Sweden

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.

Received for publication, October 31, 2007 , and in revised form, November 26, 2007.

^* This study was supported by grants from the Swedish Cancer Society, the Swedish Research Council (Medicine), the Åke Wibergs Foundation and Karolinska Institutet. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains a supplemental movie.

This article was selected as a Paper of the Week.

¹ Present address: Dept. of Physiology, Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, 20520 Turku, Finland.

² Present address: Clinical Pathology and Cytology, Karolinska University Hospital, SE-141 86 Huddinge, Sweden.

³ Present address: Instituto de Microbiología Bioquímica and Departamento de Microbiología y Genética, CSIC/Universidad de Salamanca, Campus Miguel de Unamuno, 37007 Salamanca, Spain.

⁴ Present address: Centro Andaluz de Biología del Desarrollo (CABD-CSIC), Universidad Pablo de Olavide, Ctra. de Utrera, km. 1, 41013 Sevilla, Spain.

⁵ To whom correspondence should be addressed. Tel.: +46-8-5248 69 83; Fax: +46-8-31 15 51; E-mail: Elias.Arner{at}ki.se.

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