title: 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.
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 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.
authors: 1Department of Laboratory Medicine Malmö, Section of Medical Protein Chemistry, Skåne University Hospital, The Wallenberg Laboratory, Inga Marie Nilssons gata 53, 20502 Malmö, Sweden. anna.blom@med.lu.se.
authors: Astrid
authors: A
authors: Escudero-Esparza
authors: Nikolina
authors: N
authors: Kalchishkova
authors: Emila
authors: E
authors: Kurbasic
authors: Wen G
authors: WG
authors: Jiang
authors: Anna M
authors: AM
authors: Blom
mesh_terms: D000818:Animals; D016466:CHO Cells; D045744:Cell Line, Tumor; D003179:Complement C3b / Q000378:metabolism*; D015935:Complement C4b / Q000378:metabolism*; D017244:Complement Factor I / Q000378:metabolism*; D015938:Complement Membrane Attack Complex / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D025521:Tumor Suppressor Proteins
chemical_list: C477880:CSMD1 protein, human; D015938:Complement Membrane Attack Complex; D008565:Membrane Proteins; D025521:Tumor Suppressor Proteins; D003179:Complement C3b; D015935:Complement C4b; D017244:Complement Factor I
keywords: cancer progression; innate immunity