Thioredoxin glycation: A novel posttranslational modification that inhibits its antioxidant and organ protective actions.
Thioredoxin (Trx) is an antioxidant and antiapoptotic molecule, and its activity is regulated by posttranslational modifications. Trx-1 has recently been reported to exert potent protective action against endotoxic liver injury. However, whether Trx-1 activity is affected by endotoxin has never been previously investigated. The aim of the present study was to determine endotoxic regulation of Trx-1, and the potential mechanism involved. In vitro coincubation of Trx-1 with lipopolysaccharide (LPS) inhibited Trx-1 activity in a dose- and time-dependent fashion. The core (polysaccharide containing) region of LPS had a greater inhibitory effect on Trx-1 activity than its Lipid A fragment, suggesting the involvement of sugar groups. Periodic acid-Schiff staining and fructosamine assay demonstrated that Trx-1 was rapidly glycated by LPS. Aminoguanidine, a competitive glycation-inhibitor, completely blocked the inhibitory effect of LPS on Trx-1. Moreover, Trx-1 activity was also significantly inhibited by in vitro ribose incubation. Finally, in vivo administration of Trx-1, but not glycated Trx-1, reduced LPS-induced hepatic injury. Taken together, these results demonstrated for the first time that Trx-1 is susceptible to glycative inactivation. This novel posttranslational Trx-1 modification contributes to LPS cytotoxicity, suggesting that blockading protein glycation might be a new therapeutic strategy against endotoxic organ injury.
Yuan
Yuexing
Y
Department of Emergency Medicine, Thomas Jefferson University, 1020 Sansom Street, Philadelphia, PA 19107, USA.
Jiao
Xiangying
X
Lau
Wayne Bond
WB
Wang
Yajing
Y
Christopher
Theodore A
TA
Lopez
Bernard L
BL
Ramachandrarao
Satish P
SP
Tao
Ling
L
Ma
Xin-Liang
XL
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D006031:Glycosylation; D006146:Guanidines / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008297:Male; D051379:Mice; D011499:Protein Processing, Post-Translational; D013879:Thioredoxins / Q000378:metabolism*
D000975:Antioxidants; D006146:Guanidines; D008070:Lipopolysaccharides; D013879:Thioredoxins; C004479:pimagedine