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Epithelial Tissues Expressed in the Central Nervous System And CSMD1 Is a Novel Multiple Domain Complement-Regulatory Protein Highly Expressed in the Central Nervous System and Epithelial Tissues This information is current as of September 25, 2021. Damian M. Kraus, Gary S. Elliott, Hilary Chute, Thomas Horan, Karl H. Pfenninger, Staci D. Sanford, Stephen Foster, Sheila Scully, Andrew A. Welcher and V. Michael Holers J Immunol 2006; 176:4419-4430; ; doi: 10.4049/jimmunol.176.7.4419 Downloaded from http://www.jimmunol.org/content/176/7/4419 References This article cites 50 articles, 23 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/176/7/4419.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 25, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2006 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology CSMD1 Is a Novel Multiple Domain Complement-Regulatory Protein Highly Expressed in the Central Nervous System and Epithelial Tissues1 Damian M. Kraus,* Gary S. Elliott,† Hilary Chute,† Thomas Horan,† Karl H. Pfenninger,‡ Staci D. Sanford,‡ Stephen Foster,† Sheila Scully,† Andrew A. Welcher,† and V. Michael Holers2* In this study, we describe the identification and in vitro functional activity of a novel multiple domain complement regulatory protein discovered based on its homology to short consensus repeat (SCR)-containing proteins of the regulators of complement activation (RCA) gene family. The rat cDNA encodes a predicted 388-kDa protein consisting of 14 N-terminal CUB domains that are separated from each other by a SCR followed by 15 tandem SCR domains, a transmembrane domain, and a short cytoplasmic Downloaded from tail. This protein is the homolog of the human protein of unknown function called the CUB and sushi multiple domains 1 (CSMD1) protein. A cloning strategy that incorporates the two C-terminal CUB-SCR domains and 12 of the tandem SCR repeats was used to produce a soluble rat CSMD1 protein. This protein blocked classical complement pathway activation in a comparable fashion with rat Crry but did not block alternative pathway activation. Analysis of CSMD1 mRNA expression by in situ hybridization and immunolabeling of neurons indicates that the primary sites of synthesis are the developing CNS and epithelial tissues. Of par- ticular significance is the enrichment of CSMD1 in the nerve growth cone, the amoeboid-leading edge of the growing neuron. These http://www.jimmunol.org/ results suggest that CSMD1 may be an important regulator of complement activation and inflammation in the developing CNS, and that it may also play a role in the context of growth cone function. The Journal of Immunology, 2006, 176: 4419–4430. he complement system consists of over 30 fluid phase and In addition to a protective role, activation of the complement cell membrane proteins that act independently or in con- pathway can also exacerbate inflammatory injury and cause exten- T cert to defend against invading pathogens. Foreign sub- sive damage to self-tissues. To avoid or reduce inadvertent injury, strates activate complement via the classical pathway involving C1 host cells are protected by complement regulatory molecules (C1q, C1r, C1s), C4, C2, and C3 or the alternative pathway in- present in the fluid phase and on cell membranes that inhibit both by guest on September 25, 2021 volving C3, factor B, factor D, and properdin (1, 2). These proteins classical and alternative pathway activation pathways at several form C3 convertases, C4bC2a of the classical pathway or C3bBb points in the cascade. The largest group of proteins responsible for of the alternative pathway, which cleave C3 to C3b. Bound C3b controlling the actions of complement are encoded by closely serves as a covalently attached opsonin that can be cleaved by linked genes present in a locus on chromosome 1 designated the factor I to generate additional C3 fragments. Opsonization by C3b regulators of complement activation (RCA3; Ref. 4). RCA genes fragments is required for recognition of pathogens and foreign Ags encode the soluble regulatory proteins factor H and C4b-binding by appropriate cell types and initiation of cellular processes that protein, as well as the membrane-bound proteins decay-accelerat- remove immune complexes and enhance the humoral immune re- ing factor, membrane cofactor protein, and murine Crry. Regula- sponse. Substrate-bound C3b molecules also serve as focal points tion of complement is achieved by dissociation of C3 and C5 con- for the formation of additional C3 convertases in addition to the C5 vertases or by binding to and inactivating C3b through factor I convertases, C4bC2aC3b of the classical pathway and C3bBbC3b proteolytic activity. of the alternative pathway. Once C5 convertases are formed, target Foreign Ags opsonized with complement allow host inflamma- organisms can be lysed following cleavage of C5 to C5b and as- tory cells and erythrocytes to bind immune complexes via the cell sembly of complement components C6, C7, C8, and C9 to gener- surface RCA complement receptors, CR1 and CR2 (5). CR1 binds ate the lytic membrane attack complex (3). activation fragments of C3, which facilitates the recognition and removal of immune complexes from the circulation and also can serve as a regulatory protein (6–8). CR1 has limited tissue distri- bution and is expressed on erythrocytes, phagocytic cells, T and B *Division of Rheumatology, University of Colorado Health Sciences Center, Denver, CO 80262; †Amgen, Thousand Oaks, CA 91320; and ‡Departments of Pediatrics and lymphocytes, and follicular dendritic cells. CR2 binds iC3b/C3d of Cell and Developmental Biology, University of Colorado Health Sciences Center, opsonized immune complexes (9) and also serves as a receptor for Aurora, CO 80045 EBV (10, 11). CR2 is expressed primarily on B lymphocytes and Received for publication July 25, 2005. Accepted for publication January 17, 2006. follicular dendritic cells where it serves as a link between the in- The costs of publication of this article were defrayed in part by the payment of page nate and acquired immune systems by enhancing induction of the charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 This work was supported by National Institutes of Health Grants R01 AI31105 (to 3 Abbreviations used in this paper: RCA, regulator of complement activation; CR, V.M.H.), R01 NS041029 (to K.H.P.), and by collaboration from Amgen. complement receptor; SCR, short consensus repeat; CSMD1, CUB-sushi multiple 2 Address correspondence and reprint requests to Dr. V. Michael Holers, Division of domain 1; EST, expressed sequence tag; rs, recombinant soluble; PSG, penicillin/ Rheumatology, University of Colorado Health Sciences Center, B-115, 4200 East 9th streptomycin/glutamine; EA, Ab-sensitized sheep erythrocyte; AD, Alzheimer’s dis- Avenue, Denver, CO 80262. E-mail address: [email protected] ease; MASP, mannose-binding lectin-associated serine protease. Copyright © 2006 by The American Association of Immunologists, Inc. 0022-1767/06/$02.00 4420 NOVEL MULTIPLE DOMAIN COMPLEMENT REGULATOR humoral immune response and the maintenance of immunological Table I. 5Ј RACE primers memory (12–16). Despite functional differences, the RCA proteins are homologs No. Primer Sequence and Designation of each other, each being composed of a tandem array of the ϳ 1 8949-GGTGCCAGGGTTTCCACAGGAC-8928 60-aa structural motif designated short consensus repeat (SCR; 2 8915-ACAGGCTGGACTCCTGACCAGG-8894 also known as sushi repeat or complement control module) (4, 17). 3 8007-GCTCCAGAGACCATTGGCCAAGC-7985 SCR domains have a multiple ␤-strand structure held together, in 4 7981-CCCGGACATGGGAGCCTACAAG-7959 part, by four conserved cysteine (Cys) residues that form disulfide 5 6206-GAGTGGTCACTATAGAAGCGGATG-5183 6178-TTTCATGTGTGGTGCTCAGCAGTG-6155 bonds between Cys 1 and Cys 3 and between Cys 2 and Cys 4. 6 7 5226-GCTGCACTGCGTGTCACTGGTG-5205 Unlike most extracellular proteins that have more than one type of 8 5197-CGGCTTGGTAGACGAAGTGGAAAC-5174 structural domain, each type being defined by a specific consensus 9 4820-CCTGTCACACACTCAATGGATGAG-4797 sequence, the RCA proteins do not contain any of the other widely 10 4786-TCTTGTAACCAGAGTCACATTGATAG-4761 occurring module types. Furthermore, no other domain besides the 11 4450-TCACCTTAATTCTCCAGTCACACTC-4426 12 4281-GGCTTGCCCTTGGAGCTGGTATC-4258 SCR has been identified in proteins with the capacity to regulate 13 3827-TCCGCCACACAGGAAGGCATAGG-3805 complement activation at the C3 and C5 convertase steps. Decay- 14 3717-CACAGTGTCTGTGAAGTGACCATC-3694 accelerating factor and membrane cofactor protein are each com- 15 3868-GTATGCGTCCTGATGTGGCTGC-3846 posed of 4 SCRs, the murine regulator Crry has 5 SCRs, factor H 16 3840-GAGACCACCACATTCCGCCACA-3819
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