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* Department of Pathology and Laboratory Medicine, Epithelial Pathobiology Unit, Emory University School of Medicine, Atlanta, GA 30322; and
Department of Pediatrics, Division of Pulmonary, Asthma, Cystic Fibrosis and Sleep, Emory University, School of Medicine, Atlanta, GA 30322
The human enteric flora plays a significant role in intestinal health and disease. Populations of enteric bacteria can inhibit the NF-
B pathway by blockade of IB-
ubiquitination, a process catalyzed by the E3-SCFβ-TrCP ubiquitin ligase. The activity of this ubiquitin ligase is regulated via covalent modification of the Cullin-1 subunit by the ubiquitin-like protein NEDD8. We previously reported that interaction of viable commensal bacteria with mammalian intestinal epithelial cells resulted in a rapid and reversible generation of reactive oxygen species (ROS) that modulated neddylation of Cullin-1 and resulted in suppressive effects on the NF-B pathway. Herein, we demonstrate that butyrate and other short chain fatty acids supplemented to model human intestinal epithelia in vitro and human tissue ex vivo results in loss of neddylated Cul-1 and show that physiological concentrations of butyrate modulate the ubiquitination and degradation of a target of the E3- SCFβ-TrCP ubiquitin ligase, the NF-B inhibitor IB-. Mechanistically, we show that physiological concentrations of butyrate induces reactive oxygen species that transiently alters the intracellular redox balance and results in inactivation of the NEDD8-conjugating enzyme Ubc12 in a manner similar to effects mediated by viable bacteria. Because the normal flora produces significant amounts of butyrate and other short chain fatty acids, these data provide a functional link between a natural product of the intestinal normal flora and important epithelial inflammatory and proliferative signaling pathways.
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1 This work was supported in part by National Institutes of Health Grants DK-71604 and AI-64462 (to A.S.N.).
2 Address correspondence and reprint requests to Dr. Andrew S. Neish, Department of Pathology, Emory University School of Medicine, Room 105F, Whitehead Building, 615 Michael Street, Atlanta, GA, 30322. E-mail address: aneish{at}emory.edu
3 Abbreviations used in this paper: SCFA, short chain fatty acid; Cul-1, cullin-1; MAMP, microbial-associated molecular pattern; ROS, reactive oxygen species; NAC, N-acetyl cysteine; DPI, diphenyleneiodonium; DCF, 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate acetyl ester; DHE, dihydroethidium; MOI, multiplicity of infection; IAA, iodoacetamide; HMM, high molecular mass; Eh, redox potential; Trx, Thioredoxin.
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  S. Lipinski, A. Till, C. Sina, A. Arlt, H. Grasberger, S. Schreiber, and P. Rosenstiel DUOX2-derived reactive oxygen species are effectors of NOD2-mediated antibacterial responses J. Cell Sci., October 1, 2009; 122(19): 3522 - 3530. [Abstract] [Full Text] [PDF]
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 E. Png, J.-K. Siak, J. Chew, and L. Tong Comment on "The Bacterial Fermentation Product Butyrate Influences Epithelial Signaling via Reactive Oxygen Species-Mediated Changes in Cullin-1 Neddylation" J. Immunol., October 1, 2009; 183(7): 4146 - 4146. [Full Text] [PDF]
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