SUMOylation mediates the disassembly of the Smad4 nuclear export complex via RanGAP1 in KELOIDS

J Cell Mol Med. 2023 Apr;27(8):1045-1055. doi: 10.1111/jcmm.17216. Epub 2023 Mar 14.

Abstract

Sentrin/small ubiquitin-like modifier (SUMO) has emerged as a powerful mediator regulating biological processes and participating in pathophysiological processes that cause human diseases, such as cancer, myocardial fibrosis and neurological disorders. Sumoylation has been shown to play a positive regulatory role in keloids. However, the sumoylation mechanism in keloids remains understudied. We proposed that sumoylation regulates keloids via a complex. RanGAP1 acted as a synergistic, functional partner of SUMOs in keloids. Nuclear accumulation of Smad4, a TGF-β/Smad pathway member, was associated with RanGAP1 after SUMO1 inhibition. RanGAP1*SUMO1 mediated the nuclear accumulation of Smad4 due to its impact on nuclear export and reduction in the dissociation of Smad4 and CRM1. We clarified a novel mechanism of positive regulation of sumoylation in keloids and demonstrated the function of sumoylation in Smad4 nuclear export. The NPC-associated RanGAP1*SUMO1 complex functions as a disassembly machine for the export receptor CRM1 and Smad4. Our research provides new perspectives for the mechanisms of keloids and nucleocytoplasmic transport.

Keywords: CRM1; RanGAP1*SUMO1; Smad4; nuclear export; nucleocytoplasmic transport; sumoylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Cell Nucleus / metabolism
  • GTPase-Activating Proteins* / metabolism
  • Humans
  • Keloid* / metabolism
  • Smad4 Protein* / genetics
  • Smad4 Protein* / metabolism
  • Sumoylation

Substances

  • GTPase-Activating Proteins
  • RANGAP1 protein, human
  • Smad4 Protein
  • SMAD4 protein, human