Transient global cerebral ischemia induces a massive increase in protein sumoylation.
A new group of proteins, small ubiquitin-like modifier (SUMO) proteins, has recently been identified and protein sumoylation has been shown to play a major role in various signal transduction pathways. Here, we report that transient global cerebral ischemia induces a marked increase in protein sumoylation. Mice were subjected to 10 mins severe forebrain ischemia followed by 3 or 6 h of reperfusion. Transient cerebral ischemia induced a massive increase in protein sumoylation by SUMO2/3 both in the hippocampus and cerebral cortex. SUMO2/3 conjugation was associated with a decrease in levels of free SUMO2/3. After ischemia, protein levels of the SUMO-conjugating enzyme Ubc9 were transiently decreased in the cortex but not in the hippocampus. We also exposed HT22 cells to arsenite, a respiratory poison that impairs cytoplasmic function and induces oxidative stress. Arsenite exposure induced a marked rise in protein sumoylation, implying that impairment of cytoplasmic function and oxidative stress may be involved in the massive post-ischemic activation of SUMO conjugation described here. Sumoylation of transcription factors has been shown to block their activation, with some exceptions such as the heat-shock factor and the hypoxia-responsive factor, where sumoylation blocks their degradation, and the nuclear factor-kappaB (NF-kappaB) essential modulator where sumoylation leads to an activation of NF-kappaB. Because protein sumoylation is known to be involved in the regulation of various biologic processes, the massive post-ischemic increase in protein sumoylation may play a critical role in defining the final outcome of neurons exposed to transient ischemia.
Yang
Wei
W
Department of Anesthesiology, Multidisciplinary Neuroprotection Laboratories, Duke University Medical Center, Durham, North Carolina 27710, USA.
Sheng
Huaxin
H
Warner
David S
DS
Paschen
Wulf
W
D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases; D010450:Endopeptidases / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D002546:Ischemic Attack, Transient / Q000378:metabolism*; D008297:Male; D051379:Mice; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025841:Small Ubiquitin-Related Modifier Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000096:biosynthesis / Q000235:genetics; D014452:Ubiquitins / Q000378:metabolism; D000098843:Ubiquitin-Conjugating Enzyme UBC9
D012333:RNA, Messenger; C515972:SUMO2 protein, mouse; D025841:Small Ubiquitin-Related Modifier Proteins; C117908:Sumo3 protein, mouse; D014452:Ubiquitins; D044763:Ubiquitin-Conjugating Enzymes; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; C501974:Senp1 protein, mouse; D000098843:Ubiquitin-Conjugating Enzyme UBC9