Small ubiquitin-like modifier 3-modified proteome regulated by brain ischemia in novel small ubiquitin-like modifier transgenic mice: putative protective proteins/pathways.
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Background and purposeSmall ubiquitin-like modifier (SUMO) conjugation is a post-translational modification associated with many human diseases. Characterization of the SUMO-modified proteome is pivotal to define the mechanistic link between SUMO conjugation and such diseases. This is particularly evident for SUMO2/3 conjugation, which is massively activated after brain ischemia/stroke, and is believed to be a protective response. The purpose of this study was to perform a comprehensive analysis of the SUMO3-modified proteome regulated by brain ischemia using a novel SUMO transgenic mouse.
MethodsTo enable SUMO proteomics analysis in vivo, we generated transgenic mice conditionally expressing tagged SUMO1-3 paralogues. Transgenic mice were subjected to 10 minutes forebrain ischemia and 1 hour of reperfusion. SUMO3-conjugated proteins were enriched by anti-FLAG affinity purification and analyzed by liquid chromatography-tandem mass spectrometry.
ResultsCharacterization of SUMO transgenic mice demonstrated that all 3 tagged SUMO paralogues were functionally active, and expression of exogenous SUMOs did not modify the endogenous SUMOylation machinery. Proteomics analysis identified 112 putative SUMO3 substrates of which 91 candidates were more abundant in the ischemia group than the sham group. Data analysis revealed processes/pathways with putative neuroprotective functions, including glucocorticoid receptor signaling, RNA processing, and SUMOylation-dependent ubiquitin conjugation.
ConclusionsThe identified proteins/pathways modulated by SUMOylation could be the key to understand the mechanisms linking SUMOylation to neuroprotection, and thus provide new promising targets for therapeutic interventions. The new transgenic mouse will be an invaluable platform for analyzing the SUMO-modified proteome in models of human disorders and thereby help to mechanistically link SUMOylation to the pathological processes.
Published Version (Please cite this version)
Yang, Wei, Huaxin Sheng, J Will Thompson, Shengli Zhao, Liangli Wang, Pei Miao, Xiaozhi Liu, M Arthur Moseley, et al. (2014). Small ubiquitin-like modifier 3-modified proteome regulated by brain ischemia in novel small ubiquitin-like modifier transgenic mice: putative protective proteins/pathways. Stroke, 45(4). pp. 1115–1122. 10.1161/strokeaha.113.004315 Retrieved from https://hdl.handle.net/10161/23276.
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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 ischemia and the other is to examine the efficacy of post-conditioning on outcome of subarachnoid hemorrhage induced cognitive dysfunction.
Dr. Thompson's research focuses on the development and deployment of proteomics and metabolomics mass spectrometry techniques for the analysis of biological systems. He served as the Assistant Director of the Proteomics and Metabolomics Shared Resource in the Duke School of Medicine from 2007-2021. He currently maintains collaborations in metabolomics and proteomics research at Duke, and develops new tools for chemical analysis as a Principal Scientist at 908 Devices in Carrboro, NC.
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 reticulum function. We are working on strategies to activate restoration of protein synthese by conditional gene expression. A new area of research interest is understanding the role of small ubiquitin-like modifier (SUMO) conjugation to target proteins in the fate of neurons exposed to transient interruption of blood supply. We found that SUMO conjugation is dramatically activated after ischemia. This process is particularly activated in neurons located at the border of infarcts where it induces translocation of SUMO conjugated proteins to the nucleus.
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