The citrullination of enolase by PAD (peptidylarginine deiminase) has emerged as an important post-translational modification in human disorders; however, the physiological function of citrullination remains unknown. In the present study, we report that citrullination diversely regulates the biological functions of ENO1 (α-enolase) and NSE (neuron-specific enolase). We developed three mouse IgG1 monoclonal antibodies with specificity to the following: (i) citrullination of Arg9 of ENO1 [ENO1Cit9; anti-CE1 (citrullinated enolase 1) antibody]; (ii) citrullination of Arg9 in ENO1 and NSE (ENO1Cit9/NSECit9; anti-CE1/2 antibody); and (iii) citrullination of Arg429 of NSE (NSECit429; anti-CE2 antibody). Regardless of the total protein expression level, the levels of ENO1Cit9 and NSECit429 were elevated, and their immunoreactivities were also increased in cortical neuronal cells or around blood vessels in the frontal cortex of patients with sporadic Creutzfeldt-Jakob disease and Alzheimer's disease compared with controls. In a time- and dose-dependent manner, PAD negatively regulated enolase activity via citrullination, and enolase in diseased patients was more inactive than in controls. Interestingly, the citrullination of enolase effectively promoted its proteolytic degradation by Ca2+-dependent calpain-1, and leupeptin (calpain inhibitor I) abrogated this degradation. Surprisingly, using an affinity assay, the citrullination of enolase enhanced its plasminogen-binding affinity, which was blocked by the lysine analogue ϵ-aminocaproic acid. These findings suggest that PAD-mediated citrullination regulates the diverse physiological activities of enolase and that CE may be a candidate diagnostic/prognostic factor for degenerative diseases.
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Research Article|
June 27 2012
Peptidylarginine deiminase modulates the physiological roles of enolase via citrullination: links between altered multifunction of enolase and neurodegenerative diseases
Byungki Jang;
Byungki Jang
*Ilsong Institute of Life Science, Hallym University, 1605-4 Gwanyang-Dong, Dongan-Gu, Anyang, Gyeonggi-do 432-060, Republic of Korea
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Yong-Chul Jeon;
Yong-Chul Jeon
*Ilsong Institute of Life Science, Hallym University, 1605-4 Gwanyang-Dong, Dongan-Gu, Anyang, Gyeonggi-do 432-060, Republic of Korea
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Jin-Kyu Choi;
Jin-Kyu Choi
*Ilsong Institute of Life Science, Hallym University, 1605-4 Gwanyang-Dong, Dongan-Gu, Anyang, Gyeonggi-do 432-060, Republic of Korea
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Mira Park;
Mira Park
*Ilsong Institute of Life Science, Hallym University, 1605-4 Gwanyang-Dong, Dongan-Gu, Anyang, Gyeonggi-do 432-060, Republic of Korea
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Jae-Il Kim;
Jae-Il Kim
†Department of Food Science and Nutrition, College of Fisheries Sciences, Pukyong National University, 599-1 Daeyeon-Dong, Nam-Gu, Busan 608-737, Republic of Korea
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Akihito Ishigami;
Akihito Ishigami
‡Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo 173-0015, Japan
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Naoki Maruyama;
Naoki Maruyama
‡Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo 173-0015, Japan
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Richard I. Carp;
Richard I. Carp
§New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, New York, NY 10314-6330, U.S.A.
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Yong-Sun Kim;
Yong-Sun Kim
*Ilsong Institute of Life Science, Hallym University, 1605-4 Gwanyang-Dong, Dongan-Gu, Anyang, Gyeonggi-do 432-060, Republic of Korea
∥Department of Microbiology, College of Medicine, Hallym University, 1 Hallymdaehak-Gil, Chuncheon, Gangwon-do 200-702, Republic of Korea
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Eun-Kyoung Choi
Eun-Kyoung Choi
1
*Ilsong Institute of Life Science, Hallym University, 1605-4 Gwanyang-Dong, Dongan-Gu, Anyang, Gyeonggi-do 432-060, Republic of Korea
1To whom correspondence should be addressed (email ekchoi@hallym.ac.kr).
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Publisher: Portland Press Ltd
Received:
January 03 2012
Revision Received:
April 30 2012
Accepted:
May 02 2012
Accepted Manuscript online:
May 02 2012
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2012 Biochemical Society
2012
Biochem J (2012) 445 (2): 183–192.
Article history
Received:
January 03 2012
Revision Received:
April 30 2012
Accepted:
May 02 2012
Accepted Manuscript online:
May 02 2012
Citation
Byungki Jang, Yong-Chul Jeon, Jin-Kyu Choi, Mira Park, Jae-Il Kim, Akihito Ishigami, Naoki Maruyama, Richard I. Carp, Yong-Sun Kim, Eun-Kyoung Choi; Peptidylarginine deiminase modulates the physiological roles of enolase via citrullination: links between altered multifunction of enolase and neurodegenerative diseases. Biochem J 15 July 2012; 445 (2): 183–192. doi: https://doi.org/10.1042/BJ20120025
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