The novel complement inhibitor CMSD1 protein promotes Factor I-mediated degradation of C4b and C3b and inhibits MAC assembly and C9 polymerisation

Abstract

CUB and Sushi multiple domains 1 (CSMD1) is a transmembrane protein formed from 14 N-terminal CUB domains separated by single complement control protein (CCP) domains and followed by a tandem repeat of 15 CCP domains which are characteristic for complement inhibitors. Therefore, shares homology with a number of proteins involved in many cellular processes such as growth, cell adhesion, cancer progression and in controlling the complement system. It was firstly identified as a candidate tumour suppressor gene of unknown function. By using a panel of healthy adult human samples, Q-PCR data revealed that CSMD1 is mainly found in testis, cerebellum, cerebral cortex and brain white matter. A high expression profile was also observed in fetal brain tissue. We expressed a soluble protein containing CCP domains 17–21 together with Fc-tag. The expression of this construct significantly decreased deposition of C4b and C3b on transfected mammalian cells and showed cofactor activity to FI. Furthermore, CSMD1 CCP 17–21 Fc inhibited MAC formation at the level of C7 and the polymerisation of C9, both when self-polymerisation of C9 was studied but also on the surface of erythrocytes in the presence of human serum. Moreover, reduction of expression in the T47 breast cancer cell line that expresses endogenous CSMD1, significantly increased C3b deposition on the surface. Considering that CSMD1 is frequently deleted in cancer, loss of CSMD1 and consequently loss of local complement inhibition may lead to inflammation, thus providing an ideal environment for cancer development.