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

Background: CD59 is the sole membrane complement regulatory protein in restricting membrane attack complex assembly. Results:CD59 gene produces eight transcripts that share three transcriptional initiation sites but the same open reading frame. Conclusion: NF-B and CREB (as an enhancer-binding protein) bridged by CBP/p300 are responsible for the inducible expression of CD59. Significance:CD59 regulation mechanism suggests potential drug targets for controlling various complement-related human diseases. 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-B 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-, and the complement activation products (sublytic MAC (SC5b-9) and C5a) could increase the expression of CD59 mainly by activating NF-B and CREB signaling pathways. Together, our findings identify a novel gene regulation mechanism involving CBP/p300, NF-B, and CREB; this mechanism suggests potential drug targets for controlling various complement-related human diseases.