Soluble syntaxin 3 functions as a transcriptional regulator.

Area of Science:

• Molecular Biology
• Cell Biology
• Cancer Research

Background:

• Syntaxins are essential SNARE proteins involved in membrane fusion, characterized by C-terminal transmembrane anchors.
• The canonical function of syntaxins is restricted to membrane trafficking pathways.

Purpose of the Study:

• To investigate the unexpected nuclear functions of syntaxin 3 (Stx3).
• To characterize a novel soluble isoform of Stx3 (Stx3S) and its role in gene regulation.

Main Methods:

• Identified a soluble Stx3 isoform (Stx3S) lacking a transmembrane anchor via alternative splicing.
• Investigated Stx3S nuclear localization and interaction with nuclear import factors (RanBP5) and transcription factors (ETV4, ATF2).
• Analyzed Stx3S expression patterns in human tissues and breast cancer, and assessed the impact of Stx3S inhibition on gene expression and cell proliferation.

Main Results:

• Discovered a soluble syntaxin 3 isoform (Stx3S) that translocates to the nucleus.
• Stx3S physically and functionally interacts with transcription factors ETV4 and ATF2, modulating gene expression.
• Stx3S expression is altered in breast cancer, and its inhibition affects cancer-associated gene expression and promotes proliferation.

Conclusions:

• Syntaxin 3 unexpectedly functions as a nuclear regulator of gene expression through its soluble isoform, Stx3S.
• Nuclear signaling represents a conserved, novel function for membrane-trafficking syntaxins.
• Stx3S dysregulation contributes to cancer-associated gene expression changes and cell proliferation.