Journal of Biological Chemistry
Volume 283, Issue 50, 12 December 2008, Pages 34880-34886
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Transcription, Chromatin, and Epigenetics
Huntingtin Regulates RE1-silencing Transcription Factor/Neuron-restrictive Silencer Factor (REST/NRSF) Nuclear Trafficking Indirectly through a Complex with REST/NRSF-interacting LIM Domain Protein (RILP) and Dynactin p150Glued*

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Huntingtin has been reported to regulate the nuclear translocation of the transcriptional repressor RE1-silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF). The REST/NRSF-interacting LIM domain protein (RILP) has also been shown to regulate REST/NRSF nuclear translocation. Therefore, we were prompted to address the question of how two distinct proteins could have the same function. We initially used a yeast two-hybrid screen to look for an interaction between huntingtin and RILP. This screen identified dynactin p150Glued as an interacting protein. Coimmunoprecipitation of proteins in vitro expressed in a reticulocyte lysate system showed an interaction between REST/NRSF and RILP as well as between RILP and dynactin p150Glued. Coimmunoprecipitation analysis further showed a complex containing RILP, dynactin p150Glued, and huntingtin. Huntingtin did not interact directly with either REST/NRSF or RILP, but did interact with dynactin p150Glued. The N-terminal fragment of wild-type huntingtin did not affect the interaction between dynactin p150Glued and RILP; however, mutant huntingtin weakened this interaction. We further show that HAP1 (huntingtin-associated protein-1) prevents this complex from translocating REST/NRSF to the nucleus. Thus, this study suggests that REST/NRSF, dynactin p150Glued, huntingtin, HAP1, and RILP form a complex involved in the translocation of REST/NRSF into the nucleus and that HAP1 controls REST/NRSF cellular localization in neurons.

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This work was supported, in whole or in part, by National Institutes of Health Grant P20RR020171 from the National Center for Research Resources and Grant K01MH067123 from the National Institute of Mental Health. 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.