Cerebral ischemia/stroke and small ubiquitin-like modifier (SUMO) conjugation--a new target for therapeutic
Wei Yang1, Huaxin Sheng, H Mayumi Homi
1Multidisciplinary Neuroprotection Laboratories, Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Abstract:
Transient cerebral ischemia/stroke activates various post-translational protein modifications such as phosphorylation and ubiquitin conjugation that are believed to play a major role in the pathological process triggered by an interruption of blood supply and culminating in cell death. A new system of post-translational protein modification has been identified, termed as small ubiquitin-like modifier (SUMO) conjugation. Like ubiquitin, SUMO is conjugated to the lysine residue of target proteins in a complex process. This review summarizes observations from recent experiments focusing on the effect of cerebral ischemia on SUMO conjugation. Transient global and focal cerebral ischemia both induced a rapid, dramatic and long-lasting rise in levels of SUMO2/3 conjugation. After transient focal cerebral ischemia, SUMO conjugation was particularly prominent in neurons located at the border of the ischemic territory where SUMO-conjugated proteins translocated to the nucleus. Many SUMO conjugation target proteins are transcription factors and sumoylation has been shown to have a major impact on the activity, stability, and cellular localization of target proteins. The rise in levels of SUMO-conjugated proteins is therefore likely to have a major effect on the fate of post-ischemic neurons. The sumoylation process could provide an exciting new target for therapeutic intervention.
Insights
Transient cerebral ischemia rapidly increases small ubiquitin-like modifier (SUMO) conjugation, particularly SUMO2/3. This protein modification impacts neuronal fate after stroke and may offer new therapeutic targets.
Area of Science:
- Neuroscience
- Biochemistry
- Molecular Biology
Background:
- Cerebral ischemia/stroke triggers protein modifications like phosphorylation and ubiquitination.
- Small ubiquitin-like modifier (SUMO) conjugation is an emerging post-translational modification system.
- SUMOylation involves conjugating SUMO proteins to lysine residues on target proteins.
Purpose of the Study:
- To review experimental findings on the impact of cerebral ischemia on SUMO conjugation.
- To understand the role of SUMOylation in the pathological processes following stroke.
- To explore SUMOylation as a potential therapeutic target for stroke.
Main Methods:
- Review of recent experimental studies on cerebral ischemia and SUMO conjugation.
- Analysis of changes in SUMO conjugation levels following transient global and focal cerebral ischemia.
- Investigation of the cellular localization of SUMO-conjugated proteins.
Main Results:
- Transient global and focal cerebral ischemia induce a rapid, significant, and sustained increase in SUMO2/3 conjugation.
- Following focal ischemia, SUMO conjugation is pronounced in neurons at the ischemic border.
- SUMO-conjugated proteins translocate to the nucleus in affected neurons.
Conclusions:
- The observed rise in SUMO conjugation likely influences the survival of post-ischemic neurons.
- SUMOylation significantly affects the activity, stability, and localization of target proteins, including transcription factors.
- The SUMOylation pathway presents a promising new avenue for therapeutic interventions in stroke treatment.
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