AI Insight
This study investigated how glucocorticoid receptors (GR), which mediate the effects of widely-prescribed anti-inflammatory drugs, move from the cytoplasm into the nucleus of cells. Using pair correlation function analysis to track single fluorescent GR molecules in live cells, researchers found that GR monomers enter the nucleus through passive diffusion, while GR dimers use active transport via the microtubule-dynein machinery. The perinuclear vimentin network facilitates faster translocation by keeping actively transported dimers near nuclear pores, demonstrating that both monomeric and dimeric forms translocate through distinct mechanisms.
Why it matters
These findings resolve long-standing debates about GR nuclear import mechanisms and highlight the cytoskeleton as an important component of GR signaling. Understanding these transport mechanisms could inform the development of more effective glucocorticoid-based therapies with improved efficacy or reduced side effects.
⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Glucocorticoids are among the most widely prescribed drugs globally due to their potent anti-inflammatory and immunosuppressive actions. These effects are primarily mediated by the glucocorticoid receptor (GR), a ligand-activated transcription factor that translocates from the cytoplasm to the nucleus to regulate hundreds of genes. Although nuclear entry is a prerequisite for its genomic response, the mechanisms governing this process remain unresolved; specifically, whether the receptor translocates as a monomer or a dimer remains a subject of significant controversy. Here, we employed the pair correlation function (pCF) approach to quantify the nuclear translocation of single fluorescent GR molecules in live cells. This minimally invasive method identifies correlations between intensity fluctuations generated by molecules moving from the cytoplasm into the nucleus. Our results demonstrate that GR’s quaternary structure and conformation modulate GR transport. While GR monomers rely exclusively on passive diffusion, GR dimers also utilize the microtubule-dynein machinery for active transport, proving that dimerization can precede nuclear import. Furthermore, the perinuclear vimentin network facilitates faster translocation by constraining actively transported dimers near nuclear pores. Collectively, our work reconciles contradicting reports regarding GR stoichiometry during import by demonstrating that both monomers and dimers translocate, albeit through distinct mechanisms. Importantly, these results reopen the door for a microtubule-dependent, heterocomplex-independent model of GR translocation, suggesting that the cytoskeleton is an integral, yet overlooked, component of the GR signaling pathway.