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

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

doi:10.3389/fimmu.2024.1387197

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

Journal Article · Thu Apr 11 00:00:00 EDT 2024 · Frontiers in Immunology

DOI:https://doi.org/10.3389/fimmu.2024.1387197· OSTI ID:2441429

Vang, Shia ^[1]; Helton, Eric Scott ^[1]; Guo, Yiming ^[1]; Burpee, Bailey ^[1]; Rose, Elex ^[1]; Easter, Molly ^[1]; Bollenbecker, Seth ^[1]; Hirsch, Meghan June ^[1]; Matthews, Emma Lea ^[1]; Jones, Luke Isaac ^[1]; Howze IV, Patrick Henry ^[1]; Rajasekaran, Vasanthi ^[1]; Denson, Rebecca ^[1]; Cochran, Phillip ^[1]; Attah, Isaac Kwame ^[2]; Olson, Heather ^[2]; Clair, Geremy ^[2]; Melkani, Girish ^[1]; Krick, Stefanie ^[1]; Barnes, Jarrod Wesley ^[1]

Univ. of Alabama, Birmingham, AL (United States)
Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)

Idiopathic 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. We 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. We 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. OGT 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.

View Accepted Manuscript (DOE)

Research Organization:: Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF)

Grant/Contract Number:: AC05-76RL01830

OSTI ID:: 2441429

Report Number(s):: PNNL-SA--202240

Journal Information:: Frontiers in Immunology, Journal Name: Frontiers in Immunology Vol. 15; ISSN 1664-3224

Publisher:: Frontiers Research FoundationCopyright Statement

Country of Publication:: United States

Language:: English

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59 BASIC BIOLOGICAL SCIENCES
IPF
Lung
O-GlcNAc
OGT
Smad3
collagen
fibrosis
proteomics

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

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