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The novel complement inhibitor human CUB and Sushi multiple domains 1 (CSMD1) protein promotes factor I‐mediated degradation of C4b and C3b and inhibits the membrane attack complex assembly
Author(s) -
EscuderoEsparza Astrid,
Kalchishkova Nikolina,
Kurbasic Emila,
Jiang Wen G.,
Blom Anna M.
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.13-230706
Subject(s) - decay accelerating factor , complement membrane attack complex , complement system , chinese hamster ovary cell , complement factor i , cd46 , factor h , biology , complement control protein , receptor , microbiology and biotechnology , alternative complement pathway , antibody , immunology , biochemistry
CUB and Sushi multiple domains 1 (CSMD1) is a transmembrane protein containing 15 consecutive complement control protein (CCP) domains, which are characteristic for complement inhibitors. We expressed a membrane‐bound fragment of human CSMD1 composed of the 15 C‐terminal CCP domains and demonstrated that it inhibits deposition of C3b by the classical pathway on the surface of Chinese hamster ovary cells by 70% at 6% serum and of C9 (component of membrane attack complex) by 90% at 1.25% serum. Furthermore, this fragment of CSMD1 served as a cofactor to factor I‐mediated degradation of C3b. In all functional assays performed, well‐characterized complement inhibitors were used as positive controls, whereas Coxsackie adenovirus receptor, a protein with no effect on complement, was a negative control. Moreover, attenuation of expression in human T47 breast cancer cells that express endogenous CSMD1 significantly increased C3b deposition on these cells by 45% at 8% serum compared with that for the controls. Furthermore, by expressing a soluble 17–21 CCP fragment of CSMD1, we found that CSMD1 inhibits complement by promoting factor I‐mediated C4b/C3b degradation and inhibition of MAC assembly at the level of C7. Our results revealed a novel complement inhibitor for the classical and lectin pathways.—Escudero‐Esparza, A., Kalchishkova, N., Kurbasic, E., Jiang, W. G., Blom, A. M., The novel complement inhibitor human CUB and Sushi multiple domains 1 (CSMD1) protein promotes factor I‐mediated degradation of C4b and C3b and inhibits the membrane attack complex assembly. FASEB J. 27, 5083–5093 (2013). www.fasebj.org