Frontiers in Immunology (Apr 2024)

O-GlcNAc transferase regulates collagen deposition and fibrosis resolution in idiopathic pulmonary fibrosis

  • Shia Vang,
  • Eric Scott Helton,
  • Yiming Guo,
  • Bailey Burpee,
  • Elex Rose,
  • Molly Easter,
  • Seth Bollenbecker,
  • Meghan June Hirsch,
  • Emma Lea Matthews,
  • Luke Isaac Jones,
  • Patrick Henry Howze,
  • Vasanthi Rajasekaran,
  • Rebecca Denson,
  • Phillip Cochran,
  • Isaac Kwame Attah,
  • Heather Olson,
  • Geremy Clair,
  • Girish Melkani,
  • Stefanie Krick,
  • Jarrod Wesley Barnes

DOI
https://doi.org/10.3389/fimmu.2024.1387197
Journal volume & issue
Vol. 15

Abstract

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BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic pulmonary disease that is characterized by an excessive accumulation of extracellular matrix (ECM) proteins (e.g. collagens) in the parenchyma, which ultimately leads to respiratory failure and death. While current therapies exist to slow the progression, no therapies are available to resolve fibrosis.MethodsWe characterized the O-linked N-Acetylglucosamine (O-GlcNAc) transferase (OGT)/O-GlcNAc axis in IPF using single-cell RNA-sequencing (scRNA-seq) data and human lung sections and isolated fibroblasts from IPF and non-IPF donors. The underlying mechanism(s) of IPF were further investigated using multiple experimental models to modulate collagen expression and accumulation by genetically and pharmacologically targeting OGT. Furthermore, we hone in on the transforming growth factor-beta (TGF-β) effector molecule, Smad3, by co-expressing it with OGT to determine if it is modified and its subsequent effect on Smad3 activation.ResultsWe found that OGT and O-GlcNAc levels are upregulated in patients with IPF compared to non-IPF. We report that the OGT regulates collagen deposition and fibrosis resolution, which is an evolutionarily conserved process demonstrated across multiple species. Co-expression of OGT and Smad3 showed that Smad3 is O-GlcNAc modified. Blocking OGT activity resulted in decreased phosphorylation at Ser-423/425 of Smad3 attenuating the effects of TGF-β1 induced collagen expression/deposition.ConclusionOGT inhibition or knockdown successfully blocked and reversed collagen expression and accumulation, respectively. Smad3 is discovered to be a substrate of OGT and its O-GlcNAc modification(s) directly affects its phosphorylation state. These data identify OGT as a potential target in pulmonary fibrosis resolution, as well as other diseases that might have aberrant ECM/collagen accumulation.

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