title: 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.
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.
authors: 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.
authors: Yiqun
authors: Y
authors: Du
authors: Xiaoyan
authors: X
authors: Teng
authors: Na
authors: N
authors: Wang
authors: Xin
authors: X
authors: Zhang
authors: Jianfeng
authors: J
authors: Chen
authors: Peipei
authors: P
authors: Ding
authors: Qian
authors: Q
authors: Qiao
authors: Qingkai
authors: Q
authors: Wang
authors: Long
authors: L
authors: Zhang
authors: Chaoqun
authors: C
authors: Yang
authors: Zhangmin
authors: Z
authors: Yang
authors: Yiwei
authors: Y
authors: Chu
authors: Xiang
authors: X
authors: Du
authors: Xuhui
authors: X
authors: Zhou
authors: Weiguo
authors: W
authors: Hu
mesh_terms: D018957:CD59 Antigens / Q000235:genetics / Q000378:metabolism*; D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism*; D003167:Complement Activation / Q000502:physiology*; D003165:Complement System Proteins / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D050881:E1A-Associated p300 Protein / Q000235:genetics / Q000378:metabolism*; D004742:Enhancer Elements, Genetic / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D016329:Sp1 Transcription Factor / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D020298:U937 Cells
chemical_list: D018957:CD59 Antigens; C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D008070:Lipopolysaccharides; D016328:NF-kappa B; D016329:Sp1 Transcription Factor; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C051590:CD59 protein, human; D003165:Complement System Proteins; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human
keywords: CBP; CREB; Complement System; NF-κB (NF-KB); p300