Cell Biology
Soluble syntaxin 3 functions as a transcriptional regulatorSyntaxin 3 as transcriptional regulator

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Syntaxins are a conserved family of SNARE proteins and contain C-terminal transmembrane anchors required for their membrane fusion activity. Here we show that Stx3 (syntaxin 3) unexpectedly also functions as a nuclear regulator of gene expression. We found that alternative splicing creates a soluble isoform that we termed Stx3S, lacking the transmembrane anchor. Soluble Stx3S binds to the nuclear import factor RanBP5 (RAN-binding protein 5), targets to the nucleus, and interacts physically and functionally with several transcription factors, including ETV4 (ETS variant 4) and ATF2 (activating transcription factor 2). Stx3S is differentially expressed in normal human tissues, during epithelial cell polarization, and in breast cancer versus normal breast tissue. Inhibition of endogenous Stx3S expression alters the expression of cancer-associated genes and promotes cell proliferation. Similar nuclear-targeted, soluble forms of other syntaxins were identified, suggesting that nuclear signaling is a conserved, novel function common among these membrane-trafficking proteins.

SNARE proteins
alternative splicing
signal transduction
membrane trafficking
transcription coregulator
membrane fusion
splice variant
syntaxin signaling
transcriptional regulator

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This work was supported by National Institutes of Health Grant DK095248 and DK62338 (to T. W.); NINDS, National Institutes of Health Grant 1R01NS054794 (to J. B. H.); and NHBLI, National Institutes of Health Grant 1R01HL097800 (to J. B. H.); funds from the California Cancer Research Coordinating Committee (to T. W.); and Postdoctoral Fellowships from the Cancer Center of Santa Barbara (to C. W.) and the Spanish Ministry of Education and Science (to E. R.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

This article contains Figs. S1–S4.

1

Both authors contributed equally to this work.

2

Present address: Biogen GmbH, 85737 Ismaning, Germany.

3

Present address: Dept. of Cell Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195.

4

Present address: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain.