The long noncoding RNA VIM-AS1 and nucleoporin Nup358/RanBP2 regulate SMAD nuclear accumulation during TGF-β signaling.
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Rodrigues-Junior DM, Ali MM, Itoh Y, Ferreira MS, Heldin J, Fu H, Hoelz A, Heldin CH, Moustakas A
Nucleic Acids Res. 54 (2) - [2026-01-14; online 2026-01-20]
The transforming growth factor β (TGF-β) pathway is a developmental signaling network that regulates tissue homeostasis and malfunctions in human diseases, including cancer. TGF-β signals via two receptors, which activate SMAD and alternative signaling pathways. We show that TGF-β induces the expression of the mammalian long noncoding RNA (lncRNA) VIM-AS1 (Vimentin antisense RNA1) variant-2 (v.2) via a transcriptional SMAD-GATA6-SPI1 complex. VIM-AS1 v.1 and v.2 localize in different cell compartments, including the nuclear border. Unbiased whole transcriptomic analysis and functional gain and loss of function assays establish that VIM-AS1 v.2 enhances TGF-β signaling. Mechanistically, VIM-AS1 v.2 interacts with the nucleoporin Nup358/RanBP2, contributing to the binding of Nup358/RanBP2 to SMAD2/3 and enhancing SMAD nuclear accumulation. In the context of cancer biology, VIM-AS1 did not affect the antiproliferative actions of TGF-β, yet had an impact on the epithelial-mesenchymal transition gene program, and increased the invasion and motility of tumor cells, whereas its silencing sensitized cancer cells to chemotherapeutic agents. The molecular mechanism highlights how a lncRNA can modulate the nuclear pore's capacity to import SMAD complexes, by facilitating their capture by Nup358/RanBP2 and thereby enhancing nuclear accumulation of SMADs with distinct isoform composition, thus promoting selectively TGF-β signaling responses.
NGI Uppsala (SNP&SEQ Technology Platform) [Service]
National Genomics Infrastructure [Service]
PubMed 41556346
DOI 10.1093/nar/gkaf1526
Crossref 10.1093/nar/gkaf1526
pmc: PMC12817083
pii: 8431143