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Gene Review

Cr1l  -  complement component (3b/4b) receptor 1-like

Mus musculus

Synonyms: Complement component receptor 1-like protein, Complement regulatory protein Crry, Crry, Cry, Mcp, ...
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Disease relevance of Crry

  • Here, we report on the use of a mouse model of intestinal ischemia/reperfusion injury to investigate the strategy of targeting complement inhibition to sites of complement activation by linking an iC3b/C3dg-binding fragment of mouse complement receptor 2 (CR2) to a mouse complement-inhibitory protein, Crry [1].
  • Furthermore, the minimum effective dose of Crry-Ig significantly enhanced susceptibility to infection in a mouse model of acute septic peritonitis, whereas the effect of CR2-Crry on susceptibility to infection was indistinguishable from that of PBS control [1].
  • DAF/Crry double deficiency in mice exacerbates nephrotoxic serum-induced proteinuria despite markedly reduced systemic complement activity [2].
  • To clarify the role of complement in lupus nephritis, MRL/lpr mice were given Crry as a recombinant protein (Crry-Ig) from 12 to 24 wk of age [3].
  • Complement inhibition with Crry as the recombinant protein Crry-Ig has been demonstrated to prevent MRL/MpJ-Tnfrsf6(lpr) (MRL/lpr) mice from developing proteinuria and renal failure [4].

High impact information on Crry

  • Complement activation at the fetomaternal interface caused the fetal loss because breeding to C3-/- mice rescued Crry-/- mice from lethality [5].
  • Complement receptor 1-related gene/protein y (Crry) is a potent murine membrane complement regulator that inhibits classical and alternative pathway C3 convertases [6].
  • To study the phenotypic effects of continuous complement pathway blockade, transgenic mice were created that express recombinant soluble (rs) Crry directed by the broadly active and heavy metal-inducible metallothionein-I promoter [6].
  • For example, Crry/p65 is expressed on a wide variety of murine cells, and when expressed on human K562 erythroleukemic cells, it prevents deposition of mouse C3 fragments on the cell surface during activation of either the classical or alternative complement pathway [7].
  • These data suggest that the rat counterpart of mouse Crry/p65 plays a vital role in vivo by preventing the activation of autologous complement on vascular endothelium [8].

Chemical compound and disease context of Crry

  • We used a recombinant soluble form of Crry fused to the hinge, CH2, and CH3 domains of mouse IgG1 (Crry-Ig) to determine whether inhibition of complement activation prevents and/or reverses mesenteric ischemia/reperfusion-induced injury in mice [9].
  • HN is induced by immunization with Fx1A in CFA, and proteinuria in HN is associated with subepithelial IgG and C3 deposition and infiltration of CD8(+) T-cytotoxic 1 (Tc1) cells and macrophages into glomeruli, as well as induction of Abs to Crry [10].

Biological context of Crry

  • The Crry gene consists of 10 separate exons [11].
  • DNA sequence analysis of the Crry-ps gene indicates that this sequence most likely represents a pseudogene resulting from a processed mRNA transcript from the Crry gene [11].
  • By crossing female DAF(-/-)/Crry(-/-)/C3(-/-) mice with male DAF(-/-)/Crry(+/-)/C3(+/-) mice, we circumvented maternal complement attack during fetal development and generated viable DAF(-/-)/Crry(-/-)/C3(+/-) mice to address the consequence of DAF/Crry double deficiency [2].
  • Complement receptor 1-related gene/protein y (Crry) is a murine membrane protein that regulates the activity of both classical and alternative complement pathways [9].
  • The synovium from Crry-Tg mice without CIA contained the mRNA for the Crry transgene, by RT-PCR, and the synovium from transgenic mice with CIA exhibited little deposition of C3 protein by immunohistological analysis [12].

Anatomical context of Crry

  • Complement-mediated clearance of erythrocytes: mechanism and delineation of the regulatory roles of Crry and DAF. Decay-accelerating factor [13].
  • Molecules involving in the conversion of C3b to iC3b and binding of iC3b were present in the human oviduct (factor I) and mouse preimplantation embryo (Crry and CR3), respectively [14].
  • The dual function of Crry as a complement regulatory protein and as a T cell costimulator illustrates the importance of complement regulatory proteins as links between innate and adaptive immunity [15].
  • A fraction of Crry is found consistently in the detergent-insoluble membrane fraction of Th1 or Th2 cells or CD4+ lymphoblasts [15].
  • The positive regulator properdin, as well as Crry and factor H, were found in adipose tissue [16].

Associations of Crry with chemical compounds

  • Three separate strategies were used to investigate the role of the complement system in this model of ARF: (1) Crry-Ig, a recombinant protein containing the potent murine complement C3 activation inhibitor Crry was injected at the same time as LPS (N = 8) [17].
  • Crry/p65 is a type I glycoprotein, which protects mouse T cells from complement attack [15].
  • Male Wistar rats were anesthetized with Nembutal and were intravenously injected with 1 mg/kg of F(ab')2 or Fab fraction of either monoclonal antibody 5I2, which inhibits the function of rat counterpart of mouse Crry/p65, or monoclonal antibody 6D1, which inhibits the rat counterpart of CD59 [8].
  • A recombinant soluble form of the mouse membrane complement inhibitor Crry (complement receptor-related gene y) fused to IgG1 hinge, CH2, and CH3 domains has been created and designated Crry-Ig [18].
  • Decay-accelerating factor (DAF) and complement receptor 1-related gene/protein y (Crry) are two membrane-bound complement regulators on murine erythrocytes that inhibit C3/C5 convertases [19].

Regulatory relationships of Crry

  • Embryonic cells express mRNA for Crry similarly to other cells but additionally express Cr2-transcripts not found in most adult cells [20].

Other interactions of Crry

  • The coding sequences of the Crry gene encompass over 25 kb of DNA, whereas the Crry-ps sequences are included within a single 5.6-kb Eco-R1 fragment [11].
  • CR2-Crry has a significantly shorter serum half-life than Crry-Ig and, unlike Crry-Ig, had no significant effect on serum complement activity at minimum effective therapeutic doses [1].
  • Crry costimulation induced clustering of lipid rafts, increasing their content in Crry, CD3epsilon, and p59-60 forms of p56lck, and caused actin polymerization close to the site of activation in Th2 cells [15].
  • Finally, we evaluated the relative importance of the Fc receptor versus the complement pathway in disposing antibody-opsonized DAF/Crry-deficient erythrocytes [13].
  • The fusion gene containing the mouse C receptor 1-related gene/protein y (Crry) and a single chain Ab fragment with specificity for mouse glycophorin A was placed under transcriptional control of a liver-specific promoter [21].

Analytical, diagnostic and therapeutic context of Crry


  1. Targeted complement inhibition by C3d recognition ameliorates tissue injury without apparent increase in susceptibility to infection. Atkinson, C., Song, H., Lu, B., Qiao, F., Burns, T.A., Holers, V.M., Tsokos, G.C., Tomlinson, S. J. Clin. Invest. (2005) [Pubmed]
  2. DAF/Crry double deficiency in mice exacerbates nephrotoxic serum-induced proteinuria despite markedly reduced systemic complement activity. Miwa, T., Zhou, L., Tudoran, R., Lambris, J.D., Madaio, M.P., Nangaku, M., Molina, H., Song, W.C. Mol. Immunol. (2007) [Pubmed]
  3. Administration of a soluble recombinant complement C3 inhibitor protects against renal disease in MRL/lpr mice. Bao, L., Haas, M., Kraus, D.M., Hack, B.K., Rakstang, J.K., Holers, V.M., Quigg, R.J. J. Am. Soc. Nephrol. (2003) [Pubmed]
  4. Excessive matrix accumulation in the kidneys of MRL/lpr lupus mice is dependent on complement activation. Bao, L., Zhou, J., Holers, V.M., Quigg, R.J. J. Am. Soc. Nephrol. (2003) [Pubmed]
  5. A critical role for murine complement regulator crry in fetomaternal tolerance. Xu, C., Mao, D., Holers, V.M., Palanca, B., Cheng, A.M., Molina, H. Science (2000) [Pubmed]
  6. Transgenic mice overexpressing the complement inhibitor crry as a soluble protein are protected from antibody-induced glomerular injury. Quigg, R.J., He, C., Lim, A., Berthiaume, D., Alexander, J.J., Kraus, D., Holers, V.M. J. Exp. Med. (1998) [Pubmed]
  7. Mouse complement regulatory protein Crry/p65 uses the specific mechanisms of both human decay-accelerating factor and membrane cofactor protein. Kim, Y.U., Kinoshita, T., Molina, H., Hourcade, D., Seya, T., Wagner, L.M., Holers, V.M. J. Exp. Med. (1995) [Pubmed]
  8. In vivo effects of monoclonal antibodies that functionally inhibit complement regulatory proteins in rats. Matsuo, S., Ichida, S., Takizawa, H., Okada, N., Baranyi, L., Iguchi, A., Morgan, B.P., Okada, H. J. Exp. Med. (1994) [Pubmed]
  9. Complement inhibitor, complement receptor 1-related gene/protein y-Ig attenuates intestinal damage after the onset of mesenteric ischemia/reperfusion injury in mice. Rehrig, S., Fleming, S.D., Anderson, J., Guthridge, J.M., Rakstang, J., McQueen, C.E., Holers, V.M., Tsokos, G.C., Shea-Donohue, T. J. Immunol. (2001) [Pubmed]
  10. Il-4 therapy prevents the development of proteinuria in active Heymann nephritis by inhibition of Tc1 cells. Spicer, S.T., Ha, H., Boyd, R.A., He, X.Y., Carter, N., Tran, G., Penny, M.J., Hodgkinson, S.J., Hall, B.M. J. Immunol. (2001) [Pubmed]
  11. The murine complement receptor gene family. III. The genomic and transcriptional complexity of the Crry and Crry-ps genes. Paul, M.S., Aegerter, M., Cepek, K., Miller, M.D., Weis, J.H. J. Immunol. (1990) [Pubmed]
  12. Prevention of collagen-induced arthritis in mice transgenic for the complement inhibitor complement receptor 1-related gene/protein y. Banda, N.K., Kraus, D.M., Muggli, M., Bendele, A., Holers, V.M., Arend, W.P. J. Immunol. (2003) [Pubmed]
  13. Complement-mediated clearance of erythrocytes: mechanism and delineation of the regulatory roles of Crry and DAF. Decay-accelerating factor. Molina, H., Miwa, T., Zhou, L., Hilliard, B., Mastellos, D., Maldonado, M.A., Lambris, J.D., Song, W.C. Blood (2002) [Pubmed]
  14. The embryotrophic activity of oviductal cell-derived complement C3b and iC3b, a novel function of complement protein in reproduction. Lee, Y.L., Lee, K.F., Xu, J.S., He, Q.Y., Chiu, J.F., Lee, W.M., Luk, J.M., Yeung, W.S. J. Biol. Chem. (2004) [Pubmed]
  15. Complement regulatory protein Crry/p65-mediated signaling in T lymphocytes: role of its cytoplasmic domain and partitioning into lipid rafts. Jiménez-Periañez, A., Ojeda, G., Criado, G., Sánchez, A., Pini, E., Madrenas, J., Rojo, J.M., Portolés, P. J. Leukoc. Biol. (2005) [Pubmed]
  16. Regulation of alternative pathway activation and C3a production by adipose cells. Choy, L.N., Spiegelman, B.M. Obes. Res. (1996) [Pubmed]
  17. Complement is activated in kidney by endotoxin but does not cause the ensuing acute renal failure. Cunningham, P.N., Holers, V.M., Alexander, J.J., Guthridge, J.M., Carroll, M.C., Quigg, R.J. Kidney Int. (2000) [Pubmed]
  18. Blockade of antibody-induced glomerulonephritis with Crry-Ig, a soluble murine complement inhibitor. Quigg, R.J., Kozono, Y., Berthiaume, D., Lim, A., Salant, D.J., Weinfeld, A., Griffin, P., Kremmer, E., Holers, V.M. J. Immunol. (1998) [Pubmed]
  19. Retrovirus-mediated over-expression of decay-accelerating factor rescues crry-deficient erythrocytes from acute alternative pathway complement attack. Kim, D.D., Miwa, T., Song, W.C. J. Immunol. (2006) [Pubmed]
  20. Early embryonic cells activate the alternative complement system. Kircheis, R., Kircheis, L., Oshima, H., Kohchi, C., Soma, G., Mizuno, D. In Vivo (1995) [Pubmed]
  21. Cutting edge: treatment of complement regulatory protein deficiency by retroviral in vivo gene therapy. Spitzer, D., Wu, X., Ma, X., Xu, L., Ponder, K.P., Atkinson, J.P. J. Immunol. (2006) [Pubmed]
  22. Mouse complement receptor-related gene y/p65-neutralized tumor vaccine induces antitumor activity in vivo. Ohta, R., Kondor, N., Dohi, N., Tomlinson, S., Imai, M., Holers, V.M., Okada, H., Okada, N. J. Immunol. (2004) [Pubmed]
  23. Expression of the murine complement regulatory protein crry by glial cells and neurons. Davoust, N., Nataf, S., Holers, V.M., Barnum, S.R. Glia (1999) [Pubmed]
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