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

Escudero-Esparza, A., Kalchishkova, N., Kurbasic, E., Jiang, Wen Guo ORCID: https://orcid.org/0000-0002-3283-1111 and Blom, A. 2013. 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. The FASEB Journal 27 (12) , p. 5083. 10.1096/fj.13-230706

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Abstract

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 1721 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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	R Medicine > R Medicine (General) R Medicine > RZ Other systems of medicine
Uncontrolled Keywords:	Animals; Cell Line, Tumor; CHO Cells; Complement C3b; Complement C4b; Complement Factor I; Complement Membrane Attack Complex; Cricetinae; Cricetulus; Humans; Membrane Proteins; Protein Multimerization; Protein Structure, Tertiary
Publisher:	Federation of American Society of Experimental Biology
ISSN:	0892-6638
Date of Acceptance:	5 August 2013
Last Modified:	28 Oct 2022 10:01
URI:	https://orca.cardiff.ac.uk/id/eprint/76409

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