Functional and Expressional Analyses Reveal the Distinct Role of Complement Factor I in Regulating Complement System Activation During GCRV Infection in

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2022 Oct 14

PMID 36232671

Authors

Yi Liu

Zhao Lv

Tiaoyi Xiao

Xuewen Zhang

Chunhua Ding

Beibei Qin

Baohong Xu

Qiaolin Liu

Affiliations

Soon will be listed here.

Abstract

Complement factor I (CFI), a complement inhibitor, is well known for regulating the complement system activation by degrading complement component 3b (C3b) in animal serum, thus becoming involved in innate defense. Nevertheless, the functional mechanisms of CFI in the complement system and in host-pathogen interactions are far from being clarified in teleost fish. In the present study, we cloned and characterized the CFI gene, CiCFI, from grass carp () and analyzed its function in degrading serum C3b and expression changes after grass carp reovirus (GCRV) infection. The open reading frame of CiCFI was found to be 2121 bp, encoding 706 amino acids with a molecular mass of 79.06 kDa. The pairwise alignments showed that CiCFI shared the highest identity (66.9%) with CFI from and the highest similarity (78.7%) with CFI from . The CiCFI protein was characterized by a conserved functional core Tryp_SPc domain with the catalytic triad and substrate binding sites. Phylogenetic analysis indicated that CiCFI and the homologs CFIs from other teleost fish formed a distinct evolutionary branch. Similar with the CFIs reported in mammals, the recombinant CiCFI protein could significantly reduce the C3b content in the serum, demonstrating the conserved function of CiCFI in the complement system in the grass carp. CiCFI mRNA and protein showed the highest expression level in the liver. After GCRV infection, the mRNA expressions of CiCFI were first down-regulated, then up-regulated, and then down-regulated to the initial level, while the protein expression levels maintained an overall downward trend to the late stage of infection in the liver of grass carps. Unexpectedly, the protein levels of CiCFI were also continuously down-regulated in the serum of grass carps during GCRV infection, while the content of serum C3b proteins first increases and then returns to the initial level, suggesting a distinct role of CiCFI in regulating complement activation and fish-virus interaction. Combining our previous results that complement factor D, a complement enhancer, shows continuously up-regulated expression levels in grass carps during GCRV infection, and this study may provide the further essential data for the full picture of complex complement regulation mechanism mediated by Df and CFI of the grass carp during pathogen infection.

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References

Chen D, Li J, Yao Y, Zhang Y . Aeromonas hydrophila suppresses complement pathways via degradation of complement C3 in bony fish by metalloprotease. Fish Shellfish Immunol. 2019; 94:739-745. DOI: 10.1016/j.fsi.2019.09.057. View

Morris K, Aden D, Knowles B, Colten H . Complement biosynthesis by the human hepatoma-derived cell line HepG2. J Clin Invest. 1982; 70(4):906-13. PMC: 370299. DOI: 10.1172/jci110687. View

Tsiftsoglou S, Willis A, Li P, Chen X, Mitchell D, Rao Z . The catalytically active serine protease domain of human complement factor I. Biochemistry. 2005; 44(16):6239-49. DOI: 10.1021/bi047680t. View

de Vries S, Bootsma H . Differential gene expression of Moraxella catarrhalis upon exposure to human serum. Genom Data. 2015; 2:312-3. PMC: 4536000. DOI: 10.1016/j.gdata.2014.09.008. View

Zimmer J, Hobkirk J, Mohamed F, Browning M, Stover C . On the Functional Overlap between Complement and Anti-Microbial Peptides. Front Immunol. 2015; 5:689. PMC: 4298222. DOI: 10.3389/fimmu.2014.00689. View

Coulthard L, Woodruff T . Is the complement activation product C3a a proinflammatory molecule? Re-evaluating the evidence and the myth. J Immunol. 2015; 194(8):3542-8. DOI: 10.4049/jimmunol.1403068. View

Ding C, Xiao T, Qin B, Xu B, Lv Z, Wang H . Functional Identification of Complement Factor D and Analysis of Its Expression during GCRV Infection in Grass Carp ( ). Int J Mol Sci. 2021; 22(21). PMC: 8584590. DOI: 10.3390/ijms222112011. View

Ullman C, Haris P, Smith K, Sim R, Emery V, Perkins S . Beta-sheet secondary structure of an LDL receptor domain from complement factor I by consensus structure predictions and spectroscopy. FEBS Lett. 1995; 371(2):199-203. DOI: 10.1016/0014-5793(95)00916-w. View

Lambris J, Lao Z, Oglesby T, Atkinson J, Hack C, Becherer J . Dissection of CR1, factor H, membrane cofactor protein, and factor B binding and functional sites in the third complement component. J Immunol. 1996; 156(12):4821-32. View

10.

Ullman C, Perkins S . The Factor I and follistatin domain families: the return of a prodigal son. Biochem J. 1997; 326 ( Pt 3):939-41. PMC: 1218754. DOI: 10.1042/bj3260929v. View

11.

Roversi P, Johnson S, Caesar J, McLean F, Leath K, Tsiftsoglou S . Structural basis for complement factor I control and its disease-associated sequence polymorphisms. Proc Natl Acad Sci U S A. 2011; 108(31):12839-44. PMC: 3150940. DOI: 10.1073/pnas.1102167108. View

12.

Ricklin D, Reis E, Mastellos D, Gros P, Lambris J . Complement component C3 - The "Swiss Army Knife" of innate immunity and host defense. Immunol Rev. 2016; 274(1):33-58. PMC: 5427221. DOI: 10.1111/imr.12500. View

13.

Corvillo F, Okroj M, Nozal P, Melgosa M, Sanchez-Corral P, Lopez-Trascasa M . Nephritic Factors: An Overview of Classification, Diagnostic Tools and Clinical Associations. Front Immunol. 2019; 10:886. PMC: 6491685. DOI: 10.3389/fimmu.2019.00886. View

14.

Fraczek L, Martin B . Transcriptional control of genes for soluble complement cascade regulatory proteins. Mol Immunol. 2010; 48(1-3):9-13. DOI: 10.1016/j.molimm.2010.08.016. View

15.

Nilsson S, Sim R, Lea S, Fremeaux-Bacchi V, Blom A . Complement factor I in health and disease. Mol Immunol. 2011; 48(14):1611-20. DOI: 10.1016/j.molimm.2011.04.004. View

16.

Lachmann P . The story of complement factor I. Immunobiology. 2019; 224(4):511-517. DOI: 10.1016/j.imbio.2019.05.003. View

17.

Nakao M, Miura C, Itoh S, Nakahara M, Okumura K, Mutsuro J . A complement C3 fragment equivalent to mammalian C3d from the common carp (Cyprinus carpio): generation in serum after activation of the alternative pathway and detection of its receptor on the lymphocyte surface. Fish Shellfish Immunol. 2004; 16(2):139-49. DOI: 10.1016/S1050-4648(03)00057-3. View

18.

Nonaka M . Evolution of the complement system. Subcell Biochem. 2014; 80:31-43. DOI: 10.1007/978-94-017-8881-6_3. View

19.

Del Tordello E, Vacca I, Ram S, Rappuoli R, Serruto D . Neisseria meningitidis NalP cleaves human complement C3, facilitating degradation of C3b and survival in human serum. Proc Natl Acad Sci U S A. 2013; 111(1):427-32. PMC: 3890809. DOI: 10.1073/pnas.1321556111. View

20.

Hirsch R . The complement system: its importance in the host response to viral infection. Microbiol Rev. 1982; 46(1):71-85. PMC: 373211. DOI: 10.1128/mr.46.1.71-85.1982. View