NF-{kappa}B and enhancer-binding CREB scaffolded by CBP/p300 regulate CD59 expression to protect cells from complement attack [Immunology]

December 12th, 2013 by Du, Y., Teng, X., Wang, N., Zhang, X., Chen, J., Ding, P., Qiao, Q., Wang, Q., Zhang, L., Yang, C., Yang, Z., Chu, Y., Du, X., Zhou, X., Hu, W.

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, while CBP/p300 bridge NF-κB and CREB that 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.