Membrane protein Crry maintains homeostasis of the complement system.
Complement activation is tightly regulated to avoid excessive inflammatory and immune responses. Crry(-/-) is an embryonic lethal phenotype secondary to the maternal complement alternative pathway (AP) attacking a placenta deficient in this inhibitor. In this study, we demonstrate that Crry(-/-) mice could be rescued on a partial as well as on a complete factor B (fB)- or C3-deficient maternal background. The C3 and fB protein concentrations in Crry(-/-)C3(+/-) and Crry(-/-)fB(+/-) mice were substantially reduced for gene dosage secondary to enhanced AP turnover. Based on these observations, a breeding strategy featuring reduced maternal AP-activating capacity rescued the lethal phenotype. It led to a novel, stable line of Crry SKO mice carrying normal alleles for C3 and fB. Crry SKO mice also had accelerated C3 and fB turnover and therefore reduced AP- activating potential. These instructive results represent an example of a membrane regulatory protein being responsible for homeostasis of the complement system. They imply that there is constant turnover on cells of the AP pathway which functions as an immune surveillance system for pathogens and altered self.
Wu
Xiaobo
X
Department of Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Spitzer
Dirk
D
Mao
Dailing
D
Peng
Stanford L
SL
Molina
Hector
H
Atkinson
John P
JP
D000818:Animals; D002460:Cell Line; D003176:Complement C3 / Q000096:biosynthesis / Q000172:deficiency / Q000378:metabolism; D011415:Complement Factor B / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D003170:Complement Pathway, Alternative / Q000235:genetics / Q000276:immunology*; D020964:Embryo Loss / Q000235:genetics / Q000276:immunology; D005260:Female; D005838:Genotype; D006706:Homeostasis / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011951:Receptors, Complement / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017463:Receptors, Complement 3b
D003176:Complement C3; C081470:Cr1l protein, mouse; D008565:Membrane Proteins; D011951:Receptors, Complement; D017463:Receptors, Complement 3b; D011415:Complement Factor B