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Ubc9 overexpression and SUMO1 deficiency blunt inflammation after intestinal ischemia/reperfusion.

Publication ,  Journal Article
Karhausen, J; Bernstock, JD; Johnson, KR; Sheng, H; Ma, Q; Shen, Y; Yang, W; Hallenbeck, JM; Paschen, W
Published in: Lab Invest
June 2018

The intestinal epithelium constitutes a crucial defense to the potentially life-threatening effects of gut microbiota. However, due to a complex underlying vasculature, hypoperfusion and resultant tissue ischemia pose a particular risk to function and integrity of the epithelium. The small ubiquitin-like modifier (SUMO) conjugation pathway critically regulates adaptive responses to metabolic stress and is of particular significance in the gut, as inducible knockout of the SUMO-conjugating enzyme Ubc9 results in rapid intestinal epithelial disintegration. Here we analyzed the pattern of individual SUMO isoforms in intestinal epithelium and investigated their roles in intestinal ischemia/reperfusion (I/R) damage. Immunostaining revealed that epithelial SUMO2/3 expression was almost exclusively limited to crypt epithelial nuclei in unchallenged mice. However, intestinal I/R or overexpression of Ubc9 caused a remarkable enhancement of epithelial SUMO2/3 staining along the crypt-villus axis. Unexpectedly, a similar pattern was found in SUMO1 knockout mice. Ubc9 transgenic mice, but also SUMO1 knockout mice were protected from I/R injury as evidenced by better preserved barrier function and blunted inflammatory responses. PCR array analysis of microdissected villus-tip epithelia revealed a specific epithelial contribution to reduced inflammatory responses in Ubc9 transgenic mice, as key chemotactic signaling molecules such as IL17A were significantly downregulated. Together, our data indicate a critical role particularly of the SUMO2/3 isoforms in modulating responses to I/R and provide the first evidence that SUMO1 deletion activates a compensatory process that protects from ischemic damage.

Duke Scholars

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Published In

Lab Invest

DOI

EISSN

1530-0307

Publication Date

June 2018

Volume

98

Issue

6

Start / End Page

799 / 813

Location

United States

Related Subject Headings

  • Ubiquitins
  • Ubiquitin-Conjugating Enzymes
  • Small Ubiquitin-Related Modifier Proteins
  • SUMO-1 Protein
  • Reperfusion Injury
  • Pathology
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice
  • Laser Capture Microdissection
 

Citation

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Karhausen, J., Bernstock, J. D., Johnson, K. R., Sheng, H., Ma, Q., Shen, Y., … Paschen, W. (2018). Ubc9 overexpression and SUMO1 deficiency blunt inflammation after intestinal ischemia/reperfusion. Lab Invest, 98(6), 799–813. https://doi.org/10.1038/s41374-018-0035-6
Karhausen, Jörn, Joshua D. Bernstock, Kory R. Johnson, Huaxin Sheng, Qing Ma, Yuntian Shen, Wei Yang, John M. Hallenbeck, and Wulf Paschen. “Ubc9 overexpression and SUMO1 deficiency blunt inflammation after intestinal ischemia/reperfusion.Lab Invest 98, no. 6 (June 2018): 799–813. https://doi.org/10.1038/s41374-018-0035-6.
Karhausen J, Bernstock JD, Johnson KR, Sheng H, Ma Q, Shen Y, et al. Ubc9 overexpression and SUMO1 deficiency blunt inflammation after intestinal ischemia/reperfusion. Lab Invest. 2018 Jun;98(6):799–813.
Karhausen, Jörn, et al. “Ubc9 overexpression and SUMO1 deficiency blunt inflammation after intestinal ischemia/reperfusion.Lab Invest, vol. 98, no. 6, June 2018, pp. 799–813. Pubmed, doi:10.1038/s41374-018-0035-6.
Karhausen J, Bernstock JD, Johnson KR, Sheng H, Ma Q, Shen Y, Yang W, Hallenbeck JM, Paschen W. Ubc9 overexpression and SUMO1 deficiency blunt inflammation after intestinal ischemia/reperfusion. Lab Invest. 2018 Jun;98(6):799–813.

Published In

Lab Invest

DOI

EISSN

1530-0307

Publication Date

June 2018

Volume

98

Issue

6

Start / End Page

799 / 813

Location

United States

Related Subject Headings

  • Ubiquitins
  • Ubiquitin-Conjugating Enzymes
  • Small Ubiquitin-Related Modifier Proteins
  • SUMO-1 Protein
  • Reperfusion Injury
  • Pathology
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice
  • Laser Capture Microdissection