Ubc9 overexpression and SUMO1 deficiency blunt inflammation after intestinal ischemia/reperfusion.
Abstract
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.
Type
Journal articleSubject
Intestinal MucosaAnimals
Mice, Inbred C57BL
Mice, Knockout
Mice
Reperfusion Injury
Ubiquitin-Conjugating Enzymes
Ubiquitins
Small Ubiquitin-Related Modifier Proteins
SUMO-1 Protein
Chemokines
Laser Capture Microdissection
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https://hdl.handle.net/10161/23251Published Version (Please cite this version)
10.1038/s41374-018-0035-6Publication Info
Karhausen, Jörn; Bernstock, Joshua D; Johnson, Kory R; Sheng, Huaxin; Ma, Qing; Shen,
Yuntian; ... Paschen, Wulf (2018). Ubc9 overexpression and SUMO1 deficiency blunt inflammation after intestinal ischemia/reperfusion.
Laboratory investigation; a journal of technical methods and pathology, 98(6). pp. 799-813. 10.1038/s41374-018-0035-6. Retrieved from https://hdl.handle.net/10161/23251.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Jorn Karhausen
Adjunct Associate Professor in the Department of Anesthesiology
Qing Ma
Assistant Professor in Anesthesiology
This author no longer has a Scholars@Duke profile, so the information shown here reflects
their Duke status at the time this item was deposited.
Wulf Paschen
Professor in Anesthesiology
My research interests are understanding the mechanisms underlying induction of cell
death induced by a severe form of cellular stress. I am particularly interested in
the role of the endoplasmic reticulum in the pathological process induced by transient
cerebral ischemia and culminating in neuronal cell death. This pathological process
is associated with an irreversible suppression of protein synthese that limits the
ability of cells to withstand ischemia-induced impairment of endoplasmic r
Huaxin Sheng
Associate Professor in Anesthesiology
We have successfully developed various rodent models of brain and spinal cord injuries
in our lab, such as focal cerebral ischemia, global cerebral ischemia, head trauma,
subarachnoid hemorrhage, intracerebral hemorrhage, spinal cord ischemia and compression
injury. We also established cardiac arrest and hemorrhagic shock models for studying
multiple organ dysfunction. Our current studies focus on two projects. One is to
examine the efficacy of catalytic antioxidant in treating cerebral is
Wei Yang
Associate Professor in Anesthesiology
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