NF-κB and Enhancer-binding CREB Protein Scaffolded by CREB-binding Protein (CBP)/p300 Proteins Regulate CD59 Protein Expression to Protect Cells from Complement Attack*
- Yiqun Du‡1,
- Xiaoyan Teng‡,§,¶1,
- Na Wang‡,
- Xin Zhang‡,§,
- Jianfeng Chen‡,§,
- Peipei Ding‡,§,
- Qian Qiao‡,§,
- Qingkai Wang‡,§,
- Long Zhang‡,§,
- Chaoqun Yang‖,
- Zhangmin Yang¶,
- Yiwei Chu**,
- Xiang Du‡‡,
- Xuhui Zhou‖2 and
- Weiguo Hu‡,§,**3
- From the ‡Cancer Institute, Collaborative Innovation Center of Cancer Medicine, Fudan University Shanghai Cancer Center and Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China,
- §Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China,
- ¶Department of Biochemistry and Molecular Biology, College of Life Sciences, Shaanxi Normal University, Xi'an 710062, Shaanxi, China,
- ‖Changzheng Hospital, Second Military Medical University, Shanghai 200003, China,
- **Department of Immunology, Shanghai Medical College, Fudan University, Shanghai 200032, China, and
- ‡‡Department of Pathology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- ↵2 To whom correspondence may be addressed. Tel: 86-21-81886999; Fax: 86-21-63520020; E-mail: xuhuizhou0522{at}163.com.
- ↵3 To whom correspondence may be addressed. Tel: 86-21-64175590; Fax: 86-21-64172585; E-mail: weiguohu{at}fudan.edu.cn.
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↵1 Both authors contributed equally to this work.
Abstract
The complement system can be activated spontaneously for immune surveillance or induced to clear invading pathogens, in which the membrane attack complex (MAC, C5b-9) plays a critical role. CD59 is the sole membrane complement regulatory protein (mCRP) that restricts MAC assembly. CD59, therefore, protects innocent host cells from attacks by the complement system, and host cells require the constitutive and inducible expression of CD59 to protect themselves from deleterious destruction by complement. However, the mechanisms that underlie CD59 regulation remain largely unknown. In this study we demonstrate that the widely expressed transcription factor Sp1 may regulate the constitutive expression of CD59, whereas CREB-binding protein (CBP)/p300 bridge NF-κB and CREB, which surprisingly functions as an enhancer-binding protein to induce the up-regulation of CD59 during in lipopolysaccharide (LPS)-triggered complement activation, thus conferring host defense against further MAC-mediated destruction. Moreover, individual treatment with LPS, TNF-α, and the complement activation products (sublytic MAC (SC5b-9) and C5a) could increase the expression of CD59 mainly by activating NF-κB and CREB signaling pathways. Together, our findings identify a novel gene regulation mechanism involving CBP/p300, NF-κB, and CREB; this mechanism suggests potential drug targets for controlling various complement-related human diseases.
Footnotes
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↵1 This work was supported by the National Natural Science Foundation of China (91029726, 81171910), the Major State Basic Research Development Program of China (2013CB910802), the Program for New Century Excellent Talents in University (NCET-11-0107), Ministry of Education of China, the Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning, the Program for Shanghai Pujiang Talent (11PJ1400500), and the Shanghai Committee of Science and Technology (12DZ2260100) (to W. H.).
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This article contains supplemental Tables 1–3 and Fig. S1.
- Received October 8, 2013.
- Revision received November 27, 2013.
- © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
