Oxidative stress-mediated aldehyde adduction of GRP78 in a mouse model of alcoholic liver disease: functional independence of ATPase activity and chaperone function

被引:39
作者
Galligan, James J. [1 ]
Fritz, Kristofer S. [2 ]
Backos, Donald S. [2 ]
Shearn, Colin T. [2 ]
Smathers, Rebecca L. [2 ]
Jiang, Hua [3 ]
MacLean, Kenneth N. [3 ]
Reigan, Philip R. [2 ]
Petersen, Dennis R. [2 ]
机构
[1] Univ Colorado, Dept Pharmacol, Aurora, CO 80045 USA
[2] Univ Colorado, Dept Pharmaceut Sci, Aurora, CO 80045 USA
[3] Univ Colorado, Dept Pediat, Aurora, CO 80045 USA
基金
美国国家卫生研究院;
关键词
4-HNE; 4-ONE; HSP; Electrophile; Alcoholic liver disease; Protein oxidation; Free radicals; ENDOPLASMIC-RETICULUM STRESS; UNFOLDED PROTEIN RESPONSE; PEROXIREDOXIN; 6; BINDING; CARBONYLATION; INHIBITION; EXPRESSION; BIP/GRP78; BIP; ER;
D O I
10.1016/j.freeradbiomed.2014.06.002
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Pathogenesis in alcoholic liver disease (ALD) is complicated and multifactorial but clearly involves oxidative stress and inflammation. Currently, conflicting reports exist regarding the role of endoplasmic reticulum (ER) stress in the etiology of ALD. The glucose-regulated protein 78 (GRP78) is the ER homolog of HSP70 and plays a critical role in the cellular response to ER stress by serving as a chaperone assisting protein folding and by regulating the signaling of the unfolded protein response (UPR). Comprising three functional domains, an ATPase, a peptide-binding, and a lid domain, GRP78 folds nascent polypeptides via the substrate-binding domain. Earlier work has indicated that the ATPase function of GRP78 is intrinsically linked and essential to its chaperone activity. Previous work in our laboratory has indicated that GRP78 and the UPR are not induced in a mouse model of ALD but that GRP78 is adducted by the lipid electrophiles 4-hydroxynonenal (4-HNE) and 4-oxononenal (4-ONE) in vivo. As impairment of GRP78 has the potential to contribute to pathogenesis in ALD, we investigated the functional consequences of aldehyde adduction on GRP78 function. Identification of 4-HNE and 4-ONE target residues in purified human GRP78 revealed a marked propensity for Lys and His adduction within the ATPase domain and a relative paucity of adduct formation within the peptide-binding domain. Consistent with these findings, we observed a concomitant dose-dependent decrease in ATP-binding and ATPase activity without any discernible impairment of chaperone function. Collectively, our data indicate that ATPase activity is not essential for GRP78-mediated chaperone activity and is consistent with the hypothesis that ER stress does not play a primary initiating role in the early stages of ALD. (C) 2014 Elsevier Inc. All rights reserved.
引用
收藏
页码:411 / 420
页数:10
相关论文
共 42 条
[1]   Alcohol, oxidative stress and free radical damage [J].
Albano, Emanuele .
PROCEEDINGS OF THE NUTRITION SOCIETY, 2006, 65 (03) :278-290
[2]   Posttranslational modification and regulation of glutamate-cysteine ligase by the α,β-unsaturated aldehyde 4-hydroxy-2-nonenal [J].
Backos, Donald S. ;
Fritz, Kristofer S. ;
Roede, James R. ;
Petersen, Dennis R. ;
Franklin, Christopher C. .
FREE RADICAL BIOLOGY AND MEDICINE, 2011, 50 (01) :14-26
[3]   Solution conformation of wild-type E. coli Hsp70 (DnaK) chaperone complexed with ADP and substrate [J].
Bertelsen, Eric B. ;
Chang, Lyra ;
Gestwicki, Jason E. ;
Zuiderweg, Erik R. P. .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2009, 106 (21) :8471-8476
[4]   CHARMM: The Biomolecular Simulation Program [J].
Brooks, B. R. ;
Brooks, C. L., III ;
Mackerell, A. D., Jr. ;
Nilsson, L. ;
Petrella, R. J. ;
Roux, B. ;
Won, Y. ;
Archontis, G. ;
Bartels, C. ;
Boresch, S. ;
Caflisch, A. ;
Caves, L. ;
Cui, Q. ;
Dinner, A. R. ;
Feig, M. ;
Fischer, S. ;
Gao, J. ;
Hodoscek, M. ;
Im, W. ;
Kuczera, K. ;
Lazaridis, T. ;
Ma, J. ;
Ovchinnikov, V. ;
Paci, E. ;
Pastor, R. W. ;
Post, C. B. ;
Pu, J. Z. ;
Schaefer, M. ;
Tidor, B. ;
Venable, R. M. ;
Woodcock, H. L. ;
Wu, X. ;
Yang, W. ;
York, D. M. ;
Karplus, M. .
JOURNAL OF COMPUTATIONAL CHEMISTRY, 2009, 30 (10) :1545-1614
[5]   Modification of heat shock protein 90 by 4-hydroxynonenal in a rat model of chronic alcoholic liver disease [J].
Carbone, DL ;
Doorn, JA ;
Kiebler, Z ;
Ickes, BR ;
Petersen, DR .
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2005, 315 (01) :8-15
[6]   Inhibition of Hsp72-mediated protein refolding by 4-hydroxy-2-nonenal [J].
Carbone, DL ;
Doorn, JA ;
Kiebler, Z ;
Sampey, BP ;
Petersen, DR .
CHEMICAL RESEARCH IN TOXICOLOGY, 2004, 17 (11) :1459-1467
[7]   Protein-Selective Capture to Analyze Electrophile Adduction of Hsp90 by 4-Hydroxynonenal [J].
Connor, Rebecca E. ;
Marnett, Lawrence J. ;
Liebler, Daniel C. .
CHEMICAL RESEARCH IN TOXICOLOGY, 2011, 24 (08) :1275-1282
[8]   Protein carbonylation in human diseases [J].
Dalle-Donne, I ;
Giustarini, D ;
Colombo, R ;
Rossi, R ;
Milzani, A .
TRENDS IN MOLECULAR MEDICINE, 2003, 9 (04) :169-176
[9]   CHEMISTRY AND BIOCHEMISTRY OF 4-HYDROXYNONENAL, MALONALDEHYDE AND RELATED ALDEHYDES [J].
ESTERBAUER, H ;
SCHAUR, RJ ;
ZOLLNER, H .
FREE RADICAL BIOLOGY AND MEDICINE, 1991, 11 (01) :81-128
[10]  
Eswar Narayanan, 2008, V426, P145, DOI 10.1007/978-1-60327-058-8_8