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SUMO and Ischemic Tolerance

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Abstract

Hibernating squirrels slow blood flow to a crawl, but sustain no damage to brain or other tissues. This phenomenon provides an excellent model of natural tolerance to ischemia. Small ubiquitin-like modifier (SUMO) is a 100-residue peptide that modifies other proteins by being attached to the epsilon amino group of specific lysine residues. The discovery of massive SUMOylation (by both SUMO-1 and SUMO-2/3) occurring in the brains of 13-lined ground squirrels (Ictidomys tridecemlineatus) during hibernation torpor had opened the door to the studies on SUMO and ischemic tolerance reviewed here. Ischemic stress was shown to increase the levels of SUMO conjugation, especially SUMO-2/3, mostly during reperfusion in animal models and during restoration of oxygen and glucose in cell culture systems. Over-expression or depletion of SUMOs and/or Ubc9 (the SUMO E2 conjugating enzyme) increases or decreases (respectively) the levels of SUMO conjugates. Elevated global SUMO conjugations were shown to cytoprotect from ischemic insults; conversely, depressed SUMOylation sensitized cells. Global protein conjugation not only by SUMOs, but also by other ubiquitin-like modifiers (ULMs) including NEDD8, ISG15, UFM1 and FUB1 was shown to be significantly increased in the brains of hibernating ground squirrels during torpor. These increases in multiple ULM conjugations may orchestrate the cellular events in hibernating ground squirrels that induce a state of natural tolerance through their multipronged effects. Certain miRNAs such as the miR-200 family and the miR-182 family were shown, at least partly, to control the levels of these ULM conjugations. Lowering the levels of these miRNAs leads to an increase in global SUMOylation/ULM conjugation, thereby providing the tolerance to ischemia. This suggests that these miRNAs may be good targets for therapeutic intervention in stroke.

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Abbreviations

SUMO:

Small ubiquitin-like modifier

ULM:

Ubiquitin-like modifier

MCAO:

Middle cerebral artery occlusion

OGD:

Oxygen–glucose deprivation

ROG:

Restoration of oxygen and glucose

miR:

microRNA

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Acknowledgments

This research was supported by the Intramural Research Program of the NINDS/NIH. The authors thank to all colleagues and collaborators involved in this work including Shinichi Miyake, Hideaki Wakita, David McMullen, Yongshan Mou, Paola Castri, Dace Klimanis, Joliet Bembry, Dragan Maric, Kory Johnson, Sungyoung Auh, Yoshiaki Azuma, and Mary Dasso.

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  1. Stroke Branch, National Institute of Neurological Disease and Stroke, National Institutes of Health (NINDS/NIH), Bldg10/Rm5B06, MSC 1401, 10 Center Drive, Bethesda, MD, 20892, USA

    Yang-ja Lee & John M. Hallenbeck

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  1. Yang-ja Lee
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Correspondence to Yang-ja Lee.

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Lee, Yj., Hallenbeck, J.M. SUMO and Ischemic Tolerance. Neuromol Med 15, 771–781 (2013). https://doi.org/10.1007/s12017-013-8239-9

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