complement c3b inactivator proteins

Summary

Summary: Endogenous proteins that inhibit or inactivate COMPLEMENT C3B. They include COMPLEMENT FACTOR H and COMPLEMENT FACTOR I (C3b/C4b inactivator). They cleave or promote the cleavage of C3b into inactive fragments, and thus are important in the down-regulation of COMPLEMENT ACTIVATION and its cytolytic sequence.

Top Publications

  1. Skerka C, Horstmann R, Zipfel P. Molecular cloning of a human serum protein structurally related to complement factor H. J Biol Chem. 1991;266:12015-20 pubmed
    ..These two clones represent new human members of the family of proteins structurally related to complement factor H. ..
  2. Leban N, Abarrategui Garrido C, Fariza Requejo E, Amiñoso Carbonero C, Pinto S, Chibani J, et al. Factor H and CFHR1 polymorphisms associated with atypical Haemolytic Uraemic Syndrome (aHUS) are differently expressed in Tunisian and in Caucasian populations. Int J Immunogenet. 2012;39:110-3 pubmed publisher
    ..These results suggest distinct contributions of factor H and CFHR1 polymorphisms to aHUS in Tunisian and Caucasian populations. ..
  3. Meri T, Blom A, Hartmann A, Lenk D, Meri S, Zipfel P. The hyphal and yeast forms of Candida albicans bind the complement regulator C4b-binding protein. Infect Immun. 2004;72:6633-41 pubmed
    ..It inhibits complement activation at the yeast surface and, in addition, mediates adhesion of C. albicans to host endothelial cells. ..
  4. Schmid Kubista K, Tosakulwong N, Wu Y, Ryu E, Hecker L, Baratz K, et al. Contribution of copy number variation in the regulation of complement activation locus to development of age-related macular degeneration. Invest Ophthalmol Vis Sci. 2009;50:5070-9 pubmed publisher
    ..Deletion of CFHR3 and CFHR1 protected against the development of AMD at least in part because the deletion tagged a protective haplotype and did not occur on the risk haplotype. ..
  5. Dieterich R, Hammerschmidt C, Richter D, Skerka C, Wallich R, Matuschka F, et al. Inadequate binding of immune regulator factor H is associated with sensitivity of Borrelia lusitaniae to human complement. Infect Immun. 2010;78:4467-76 pubmed publisher
    ..This finding suggests that a reduced binding capability of CFH is associated with an increased serum sensitivity of B. lusitaniae to human complement...
  6. Venables J, Strain L, Routledge D, Bourn D, Powell H, Warwicker P, et al. Atypical haemolytic uraemic syndrome associated with a hybrid complement gene. PLoS Med. 2006;3:e431 pubmed
    ..In this study we tested the hypothesis that nonallelic homologous recombination between low-copy repeats in the RCA cluster could result in the formation of a hybrid CFH/CFHL1 gene that predisposes to the development of aHUS...
  7. Brooks C, Vuppala S, Jett A, Alitalo A, Meri S, Akins D. Complement regulator-acquiring surface protein 1 imparts resistance to human serum in Borrelia burgdorferi. J Immunol. 2005;175:3299-308 pubmed
    ..burgdorferi. The combined data led us to conclude that CRASP-1 expression is necessary for B. burgdorferi to resist killing by human serum. ..
  8. Oliver M, Rojo J, Rodriguez de Cordoba S, Alberti S. Binding of complement regulatory proteins to group A Streptococcus. Vaccine. 2008;26 Suppl 8:I75-8 pubmed
    ..This article summarizes these data to provide a starting point for future research aimed at the characterization of additional mechanisms developed by GAS to evade the immune system. ..
  9. Kenedy M, Akins D. The OspE-related proteins inhibit complement deposition and enhance serum resistance of Borrelia burgdorferi, the lyme disease spirochete. Infect Immun. 2011;79:1451-7 pubmed publisher
    ..These data demonstrate that OspE proteins expressed on the surface of B. burgdorferi bind FH and protect the organism from complement deposition and subsequent serum-mediated destruction. ..

More Information

Publications62

  1. Martinez Barricarte R, Recalde S, Fernández Robredo P, Millan I, Olavarrieta L, Viñuela A, et al. Relevance of complement factor H-related 1 (CFHR1) genotypes in age-related macular degeneration. Invest Ophthalmol Vis Sci. 2012;53:1087-94 pubmed publisher
    ..The results support a relevant role of CFHR1 in the pathogenesis of AMD. ..
  2. Francis N, McNicholas B, Awan A, Waldron M, Reddan D, Sadlier D, et al. A novel hybrid CFH/CFHR3 gene generated by a microhomology-mediated deletion in familial atypical hemolytic uremic syndrome. Blood. 2012;119:591-601 pubmed publisher
  3. Kubista K, Tosakulwong N, Wu Y, Ryu E, Roeder J, Hecker L, et al. Copy number variation in the complement factor H-related genes and age-related macular degeneration. Mol Vis. 2011;17:2080-92 pubmed
    ..Combined deletion of CFHR3 and CFHR1 was associated with a decreased risk of developing AMD. Other deletions were not sufficiently common to have a statistically detectable impact on the risk of AMD, and duplications were not observed. ..
  4. Cordes F, Kraiczy P, Roversi P, Simon M, Brade V, Jahraus O, et al. Structure-function mapping of BbCRASP-1, the key complement factor H and FHL-1 binding protein of Borrelia burgdorferi. Int J Med Microbiol. 2006;296 Suppl 40:177-84 pubmed
    ..This work demonstrates that pathogens interact with complement regulators in ways that are distinct from the mechanisms used by the host and are thus obvious targets for drug design. ..
  5. Skerka C, Chen Q, Fremeaux Bacchi V, Roumenina L. Complement factor H related proteins (CFHRs). Mol Immunol. 2013;56:170-80 pubmed publisher
    ..Here we summarize the recent data about CFHR genes and proteins in order to better understand the role of CFHR proteins in complement activation and in complement associated diseases. ..
  6. Raychaudhuri S, Ripke S, Li M, Neale B, Fagerness J, Reynolds R, et al. Associations of CFHR1-CFHR3 deletion and a CFH SNP to age-related macular degeneration are not independent. Nat Genet. 2010;42:553-5; author reply 555-6 pubmed publisher
  7. Kraiczy P, Rossmann E, Brade V, Simon M, Skerka C, Zipfel P, et al. Binding of human complement regulators FHL-1 and factor H to CRASP-1 orthologs of Borrelia burgdorferi. Wien Klin Wochenschr. 2006;118:669-76 pubmed
    ..burgdorferi s.s. and thus may be helpful in the development of novel therapeutic strategies against Lyme borreliosis. ..
  8. Skerka C, Timmann C, Horstmann R, Zipfel P. Two additional human serum proteins structurally related to complement factor H. Evidence for a family of factor H-related genes. J Immunol. 1992;148:3313-8 pubmed
  9. Wallich R, Pattathu J, Kitiratschky V, Brenner C, Zipfel P, Brade V, et al. Identification and functional characterization of complement regulator-acquiring surface protein 1 of the Lyme disease spirochetes Borrelia afzelii and Borrelia garinii. Infect Immun. 2005;73:2351-9 pubmed
  10. Fritsche L, Lauer N, Hartmann A, Stippa S, Keilhauer C, Oppermann M, et al. An imbalance of human complement regulatory proteins CFHR1, CFHR3 and factor H influences risk for age-related macular degeneration (AMD). Hum Mol Genet. 2010;19:4694-704 pubmed publisher
    ..Our findings allude to a critical balance between the complement regulators CFHR3, CFHR1 and factor H and further emphasize the central role of complement regulation in AMD pathology. ..
  11. Malik T, Lavin P, Goicoechea de Jorge E, Vernon K, Rose K, Patel M, et al. A hybrid CFHR3-1 gene causes familial C3 glomerulopathy. J Am Soc Nephrol. 2012;23:1155-60 pubmed publisher
    ..In addition to identifying an association between these genetic observations and complement-mediated kidney disease, these results provide insight into the protective role of the combined deletion of CFHR3 and CFHR1 in IgA nephropathy. ..
  12. Haupt K, Kraiczy P, Wallich R, Brade V, Skerka C, Zipfel P. Binding of human factor H-related protein 1 to serum-resistant Borrelia burgdorferi is mediated by borrelial complement regulator-acquiring surface proteins. J Infect Dis. 2007;196:124-33 pubmed
    ..For the pathogen, this type of surface decoration and specific acquisition of different host plasma proteins allows fine-tuning of the host immune attack. ..
  13. Sim E, Palmer M, Puklavec M, Sim R. Monoclonal antibodies against the complement control protein factor H (beta 1 H). Biosci Rep. 1983;3:1119-31 pubmed
    ..There was no precipitation from sera of cow, pig, sheep, chick, or rabbit. Using a radioimmunoassay with radiolabelled monoclonal MRC OX 23, the concentration of Factor H in human plasma was determined. ..
  14. Estaller C, Schwaeble W, Dierich M, Weiss E. Human complement factor H: two factor H proteins are derived from alternatively spliced transcripts. Eur J Immunol. 1991;21:799-802 pubmed
    ..8-kb mRNA the 43-kDa factor H polypeptide. The identity of the two cDNA in a region of 1400 nucleotides suggests that the two factor H-related transcripts are derived from one gene by a process of alternative splicing. ..
  15. Kraiczy P, Hanssen Hübner C, Kitiratschky V, Brenner C, Besier S, Brade V, et al. Mutational analyses of the BbCRASP-1 protein of Borrelia burgdorferi identify residues relevant for the architecture and binding of host complement regulators FHL-1 and factor H. Int J Med Microbiol. 2009;299:255-68 pubmed publisher
    ..The elucidation of BbCRASP-1 structure - function may allow development of novel therapeutic strategies against Lyme disease. ..
  16. Abarrategui Garrido C, Martinez Barricarte R, Lopez Trascasa M, de Cordoba S, Sanchez Corral P. Characterization of complement factor H-related (CFHR) proteins in plasma reveals novel genetic variations of CFHR1 associated with atypical hemolytic uremic syndrome. Blood. 2009;114:4261-71 pubmed publisher
    ..In summary, our comprehensive analyses of the CFHR proteins have improved our understanding of these proteins and provided further insights into aHUS pathogenesis. ..
  17. Kraiczy P, Hellwage J, Skerka C, Becker H, Kirschfink M, Simon M, et al. Complement resistance of Borrelia burgdorferi correlates with the expression of BbCRASP-1, a novel linear plasmid-encoded surface protein that interacts with human factor H and FHL-1 and is unrelated to Erp proteins. J Biol Chem. 2004;279:2421-9 pubmed
    ..is the key molecule of the complement resistance of spirochetes, and (iii). is distinct from the Erp protein family. Thus, BbCRASP-1 most likely contributes to persistence of B. burgdorferi and to pathogenesis of Lyme disease. ..
  18. von Lackum K, Miller J, Bykowski T, Riley S, Woodman M, Brade V, et al. Borrelia burgdorferi regulates expression of complement regulator-acquiring surface protein 1 during the mammal-tick infection cycle. Infect Immun. 2005;73:7398-405 pubmed
    ..Comparisons of CRASP-1 expression patterns with those of other infection-associated B. burgdorferi proteins, including the OspC, OspA, and Erp proteins, indicated that each protein is regulated through a unique mechanism. ..
  19. Gharavi A, Kiryluk K, Choi M, Li Y, Hou P, Xie J, et al. Genome-wide association study identifies susceptibility loci for IgA nephropathy. Nat Genet. 2011;43:321-7 pubmed publisher
  20. Zipfel P, Edey M, Heinen S, Jozsi M, Richter H, Misselwitz J, et al. Deletion of complement factor H-related genes CFHR1 and CFHR3 is associated with atypical hemolytic uremic syndrome. PLoS Genet. 2007;3:e41 pubmed
    ..The identification of CFHR1/CFHR3 deficiency in aHUS patients may lead to the design of new diagnostic approaches, such as enhanced testing for these genes. ..
  21. Moore I, Strain L, Pappworth I, Kavanagh D, Barlow P, Herbert A, et al. Association of factor H autoantibodies with deletions of CFHR1, CFHR3, CFHR4, and with mutations in CFH, CFI, CD46, and C3 in patients with atypical hemolytic uremic syndrome. Blood. 2010;115:379-87 pubmed publisher
    ..In 5 patients mutations were identified: 1 in CFH, 1 in CFI, 1 in CD46, and 2 in C3. The latter observation emphasizes that multiple concurrent factors may be necessary in individual patients for disease manifestation. ..
  22. Spencer K, Hauser M, Olson L, Schmidt S, Scott W, Gallins P, et al. Deletion of CFHR3 and CFHR1 genes in age-related macular degeneration. Hum Mol Genet. 2008;17:971-7 pubmed
    ..The presence of protective haplotypes in CFH that do not carry the deletion, suggests that other protective variants in this region have yet to be discovered. ..
  23. Heinen S, Hartmann A, Lauer N, Wiehl U, Dahse H, Schirmer S, et al. Factor H-related protein 1 (CFHR-1) inhibits complement C5 convertase activity and terminal complex formation. Blood. 2009;114:2439-47 pubmed publisher
    ..These findings provide new insights into complement regulation on the cell surface and biosurfaces and likely define the role of CFHR1 in human diseases. ..
  24. Kraiczy P, Wurzner R. Complement escape of human pathogenic bacteria by acquisition of complement regulators. Mol Immunol. 2006;43:31-44 pubmed
    ..Further studies on the utilization of host complement regulatory proteins will likely have a marked impact on a more efficient and specific clinical treatment. ..
  25. Dragon Durey M, Blanc C, Marliot F, Loirat C, Blouin J, Sautes Fridman C, et al. The high frequency of complement factor H related CFHR1 gene deletion is restricted to specific subgroups of patients with atypical haemolytic uraemic syndrome. J Med Genet. 2009;46:447-50 pubmed publisher
    ..These results suggest that the CFHR1 deletion plays a secondary role in susceptibility to aHUS. ..
  26. Tortajada A, Yébenes H, Abarrategui Garrido C, Anter J, García Fernández J, Martínez Barricarte R, et al. C3 glomerulopathy-associated CFHR1 mutation alters FHR oligomerization and complement regulation. J Clin Invest. 2013;123:2434-46 pubmed
    ..In summary, our identification and characterization of a unique CFHR1 mutation provides insights into the biology of the FHRs and contributes to our understanding of the pathogenic mechanisms underlying C3G. ..
  27. Jozsi M, Licht C, Strobel S, Zipfel S, Richter H, Heinen S, et al. Factor H autoantibodies in atypical hemolytic uremic syndrome correlate with CFHR1/CFHR3 deficiency. Blood. 2008;111:1512-4 pubmed
    ..Screening for both factors is obviously relevant for HUS patients as reduction of CFH autoantibody levels represents a therapeutic option. ..
  28. Siegel C, Schreiber J, Haupt K, Skerka C, Brade V, Simon M, et al. Deciphering the ligand-binding sites in the Borrelia burgdorferi complement regulator-acquiring surface protein 2 required for interactions with the human immune regulators factor H and factor H-like protein 1. J Biol Chem. 2008;283:34855-63 pubmed publisher
    ..Collectively, we mapped a structurally sensitive CFH/CFHL1 binding site within borrelial BbCRASP-2 and identified single amino acid residues potentially involved in the interaction with both complement regulators...
  29. Cordes F, Roversi P, Kraiczy P, Simon M, Brade V, Jahraus O, et al. A novel fold for the factor H-binding protein BbCRASP-1 of Borrelia burgdorferi. Nat Struct Mol Biol. 2005;12:276-7 pubmed
    ..Here we report the atomic structure for the key FHL-1- and FH-binding protein BbCRASP-1 and reveal a homodimer that presents a novel target for drug design. ..
  30. Kraiczy P, Skerka C, Brade V, Zipfel P. Further characterization of complement regulator-acquiring surface proteins of Borrelia burgdorferi. Infect Immun. 2001;69:7800-9 pubmed
    ..The characterization of the individual CRASPs on the molecular level is expected to identify new virulence factors and potential vaccine candidates. ..
  31. Hovis K, Jones J, Sadlon T, Raval G, Gordon D, Marconi R. Molecular analyses of the interaction of Borrelia hermsii FhbA with the complement regulatory proteins factor H and factor H-like protein 1. Infect Immun. 2006;74:2007-14 pubmed
    ..The data presented here expand our understanding of the pathogenic mechanisms of the relapsing fever spirochetes and of the molecular nature of the interaction between FH/FHL-1 and FhbA. ..
  32. Lappin D, Guc D, Hill A, McShane T, Whaley K. Effect of interferon-gamma on complement gene expression in different cell types. Biochem J. 1992;281 ( Pt 2):437-42 pubmed
    ..They also show that the degree of change in synthesis rates in response to IFN-gamma in each of the cell types often varies due to differences in transcriptional response, sometimes in association with changes in mRNA stability. ..
  33. Sfyroera G, Katragadda M, Morikis D, Isaacs S, Lambris J. Electrostatic modeling predicts the activities of orthopoxvirus complement control proteins. J Immunol. 2005;174:2143-51 pubmed
  34. van Burgel N, Kraiczy P, Schuijt T, Zipfel P, van Dam A. Identification and functional characterisation of Complement Regulator Acquiring Surface Protein-1 of serum resistant Borrelia garinii OspA serotype 4. BMC Microbiol. 2010;10:43 pubmed publisher
    ..All recombinant CspA orthologs from B. garinii ST4 PBi can bind CFH from different animal origins. This partly explains the wide variety of animals that can be infected by B. garinii. ..
  35. Eyler S, Meyer N, Zhang Y, Xiao X, Nester C, Smith R. A novel hybrid CFHR1/CFH gene causes atypical hemolytic uremic syndrome. Pediatr Nephrol. 2013;28:2221-5 pubmed publisher
  36. Luo S, Blom A, Rupp S, Hipler U, Hube B, Skerka C, et al. The pH-regulated antigen 1 of Candida albicans binds the human complement inhibitor C4b-binding protein and mediates fungal complement evasion. J Biol Chem. 2011;286:8021-9 pubmed publisher
    ..In summary, Candida Pra1 represents the first fungal C4BP-binding surface protein. Pra1, via binding to C4BP, mediates human complement control, thereby favoring the immune and complement evasion of C. albicans. ..
  37. Moseley H, Whaley K. Evidence for glomerular modulation of complement activation. J Clin Lab Immunol. 1979;2:9-13 pubmed
    ..Thus, in tissues undergoing complement-mediated tissue damage, the extent of complement activation is controlled by the normal regulatory mechanisms. ..
  38. Alsenz J, Avila D, Huemer H, Esparza I, Becherer J, Kinoshita T, et al. Phylogeny of the third component of complement, C3: analysis of the conservation of human CR1, CR2, H, and B binding sites, concanavalin A binding sites, and thiolester bond in the C3 from different species. Dev Comp Immunol. 1992;16:63-76 pubmed
    ..abstract truncated at 250 words) ..
  39. Gan W, Wu J, Lu L, Xiao X, Huang H, Wang F, et al. Associations of CFH polymorphisms and CFHR1-CFHR3 deletion with blood pressure and hypertension in Chinese population. PLoS ONE. 2012;7:e42010 pubmed publisher
    ..259). In conclusion, our results suggest that genetic variations in CFH and its related genes may contribute to hypertension risk in Chinese Hans. ..
  40. Cantsilieris S, White S, Richardson A, Guymer R, Baird P. Comprehensive analysis of Copy Number Variation of genes at chromosome 1 and 10 loci associated with late age related macular degeneration. PLoS ONE. 2012;7:e35255 pubmed publisher
    ..95 1.38-41.8). This is the first report of a phenotype specific association of a CNV for a major subtype of AMD and potentially allows for pre-diagnostic identification of individuals most likely to proceed to this end stage of disease. ..
  41. Sjoholm A. Inherited complement deficiency states: implications for immunity and immunological disease. APMIS. 1990;98:861-74 pubmed
    ..Notably, complement deficiency has not been reported in classical rheumatoid arthritis. Considerations of this kind would be refuted or modified by findings of complement deficiency in single patients. ..
  42. Harder M, Anliker M, Höchsmann B, Simmet T, Huber Lang M, Schrezenmeier H, et al. Comparative Analysis of Novel Complement-Targeted Inhibitors, MiniFH, and the Natural Regulators Factor H and Factor H-like Protein 1 Reveal Functional Determinants of Complement Regulation. J Immunol. 2016;196:866-76 pubmed publisher
    ..Unrestricted availability of FH CCPs 19-20 and an optimal spatial orientation between the N- and C-terminal FH regions are key. ..
  43. Boyer O, Balzamo E, Charbit M, Biebuyck Gouge N, Salomon R, Dragon Durey M, et al. Pulse cyclophosphamide therapy and clinical remission in atypical hemolytic uremic syndrome with anti-complement factor H autoantibodies. Am J Kidney Dis. 2010;55:923-7 pubmed publisher
    ..Cyclophosphamide pulses with PE may lead to a prolonged decrease in CFH antibody titers and a favorable outcome of atypical hemolytic uremic syndrome and kidney function. ..
  44. Timmann C, Leippe M, Horstmann R. Two major serum components antigenically related to complement factor H are different glycosylation forms of a single protein with no factor H-like complement regulatory functions. J Immunol. 1991;146:1265-70 pubmed
  45. Kozel T, Wilson M, Pfrommer G, Schlageter A. Activation and binding of opsonic fragments of C3 on encapsulated Cryptococcus neoformans by using an alternative complement pathway reconstituted from six isolated proteins. Infect Immun. 1989;57:1922-7 pubmed
  46. Schulz T, Schwäble W, Stanley K, Weiss E, Dierich M. Human complement factor H: isolation of cDNA clones and partial cDNA sequence of the 38-kDa tryptic fragment containing the binding site for C3b. Eur J Immunol. 1986;16:1351-5 pubmed
    ..The region coding for the epitope recognized by one of our monoclonal antibodies was localized by subcloning restriction fragments of H-19 into the expression plasmid and testing for the expression of this epitope. ..
  47. Kraiczy P, Skerka C, Kirschfink M, Zipfel P, Brade V. Immune evasion of Borrelia burgdorferi: insufficient killing of the pathogens by complement and antibody. Int J Med Microbiol. 2002;291 Suppl 33:141-6 pubmed
    ..These antigens may include the recently detected CRASPs. ..
  48. Strobel S, Abarrategui Garrido C, Fariza Requejo E, Seeberger H, Sanchez Corral P, Jozsi M. Factor H-related protein 1 neutralizes anti-factor H autoantibodies in autoimmune hemolytic uremic syndrome. Kidney Int. 2011;80:397-404 pubmed publisher
    ..Thus, exogenous CFHR1 provided during plasma exchange therapy may neutralize anti-factor H autoantibodies and help in the treatment of autoimmune atypical HUS. ..
  49. Shahid R, Mushtaq A, Maqsood M. Plate fixation of clavicle fractures: a comparative study between Reconstruction Plate and Dynamic Compression Plate. Acta Orthop Belg. 2007;73:170-4 pubmed
    ..4 months for the DCP group. Eight of the DCP group complained of plate prominence requiring plate removal. Recon plates should be used in preference to DCP whenever clavicular fracture fixation is indicated. ..
  50. Le Quintrec M, Zuber J, Noel L, Thervet E, Fremeaux Bacchi V, Niaudet P, et al. Anti-Factor H autoantibodies in a fifth renal transplant recipient with atypical hemolytic and uremic syndrome. Am J Transplant. 2009;9:1223-9 pubmed publisher
    ..This exceptional case suggests that early, specific management based on immunosuppressive therapy and plasma exchanges monitored by anti-FH IgG titer may result in long-term graft survival. ..
  51. Foltyn Zadura A, Zipfel P, Bokarewa M, Sturfelt G, Jönsen A, Nilsson S, et al. Factor H autoantibodies and deletion of Complement Factor H-Related protein-1 in rheumatic diseases in comparison to atypical hemolytic uremic syndrome. Arthritis Res Ther. 2012;14:R185 pubmed publisher
    ..Autoantibodies against FH are not specific for aHUS but are present at a significant frequency in rheumatic diseases where they could be involved in pathophysiological mechanisms. ..
  52. Hofer J, Janecke A, Zimmerhackl L, Riedl M, Rosales A, Giner T, et al. Complement factor H-related protein 1 deficiency and factor H antibodies in pediatric patients with atypical hemolytic uremic syndrome. Clin J Am Soc Nephrol. 2013;8:407-15 pubmed publisher
    ..Initial presentation of Shiga toxin-negative HUS with severe thrombocytopenia and no central nervous system complications in pediatric patients is especially suspicious for CFH antibody aHUS. ..
  53. Wywial E, Haven J, Casjens S, Hernandez Y, Singh S, Mongodin E, et al. Fast, adaptive evolution at a bacterial host-resistance locus: the PFam54 gene array in Borrelia burgdorferi. Gene. 2009;445:26-37 pubmed publisher