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Kidney Int. 2015 Jan;87(1):95-108. doi: 10.1038/ki.2014.217. Epub 2014 Jun 18.

High-mobility group box 1 is a novel deacetylation target of Sirtuin1.

Author information

1
Department of Medicine, New York Medical College, Valhalla, New York, USA.
2
1] Department of Medicine, New York Medical College, Valhalla, New York, USA [2] Department of Pharmacology, New York Medical College, Valhalla, New York, USA [3] Department of Physiology, New York Medical College, Valhalla, New York, USA.
3
1] Department of Medicine, New York Medical College, Valhalla, New York, USA [2] Department of Physiology, New York Medical College, Valhalla, New York, USA.

Abstract

High-mobility group box 1 (HMGB1) undergoes acetylation, nuclear-to-cytoplasmic translocation, and release from stressed kidneys, unleashing a signaling cascade of events leading to systemic inflammation. Here, we tested whether the deacetylase activity of Sirtuin1 (SIRT1) participates in regulating nuclear retention of HMGB1 to ultimately modulate damage signaling initiated by HMGB1 secretion during stress. When immunoprecipitated acetylated HMGB1 was incubated with SIRT1, HMGB1 acetylation decreased by 57%. Proteomic analysis showed that SIRT1 deacetylates HMGB1 at four lysine residues (55, 88, 90, and 177) within the proinflammatory and nuclear localization signal domains of HMGB1. Genetic ablation or pharmacological inhibition of SIRT1 in endothelial cells increased HMGB1 acetylation and translocation. In vivo, deletion of SIRT1 reduced nuclear HMGB1 while increasing its acetylation and release into circulation during basal and ischemic conditions, causing increased renal damage. Conversely, resveratrol pretreatment led to decreased HMGB1 acetylation, its nuclear retention, decreased systemic release, and reduced tubular damage. Thus, a vicious cycle is set into motion in which the inflammation-induced repression of SIRT1 disables deacetylation of HMGB1, facilitates its nuclear-to-cytoplasmic translocation, and systemic release, thereby maintaining inflammation.

PMID:
24940804
PMCID:
PMC4270955
DOI:
10.1038/ki.2014.217
[Indexed for MEDLINE]
Free PMC Article

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