Ligation of erythrocyte CR1 induces its clustering in complex with scaffolding protein FAP-1.
The primary identified function of complement receptor 1 (CR1/CD35) on primate erythrocytes is to bind complement-tagged inflammatory particles including microbes and immune complexes. When erythrocytes circulate through liver and spleen, sinusoidal phagocytes remove CR1-adherent particles and erythrocytes return to the circulation. This process of immune adherence clearance is important for host defense and prevention of autoimmunity. CR1 was previously described as clustered in the human erythrocyte membrane, which was thought to be necessary for binding complement-opsonized particles. In contrast, we demonstrate that on erythrocytes CR1 is not clustered, but dispersed, and able to bind complement-tagged particles. When fresh erythrocytes are solubilized by nonionic detergent, CR1 partitions to the cytoskeleton fraction. Using a PDZ-peptide array, CR1's cytoplasmic tail, which contains 2 PDZ-motifs, binds PDZ domains 2, 3, and 5 of Fas-associated phosphatase 1 (FAP-1), a scaffolding protein. We show that FAP-1, not previously recognized as an erythroid protein, is expressed on circulating erythrocytes. CR1 and FAP-1 coimmunoprecipitate, which confirms their molecular association. Disperse CR1 on erythrocytes may be advantageous for capturing immune-complexes, while ligation-induced CR1 clustering may prevent ingestion of the erythrocyte during the immune-complex transfer to the macrophages by keeping the opsonic stimulus localized thus preventing phagocyosis.
Ghiran
Ionita
I
Divisions of Allergy/Inflammation and Infectious Diseases, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Glodek
Aleksandra M
AM
Weaver
Gregory
G
Klickstein
Lloyd B
LB
Nicholson-Weller
Anne
A
D020816:Amino Acid Motifs; D015551:Autoimmunity; D002448:Cell Adhesion; D016000:Cluster Analysis; D003432:Cross-Linking Reagents / Q000737:chemistry; D003599:Cytoskeleton / Q000378:metabolism; D004912:Erythrocytes / Q000378:metabolism*; D006801:Humans; D007107:Immune System; D008264:Macrophages / Q000378:metabolism; D040081:Protein Array Analysis; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D054595:Protein Tyrosine Phosphatase, Non-Receptor Type 13 / Q000378:metabolism*; D017463:Receptors, Complement 3b / Q000378:metabolism*
C509991:CR1 protein, human; D003432:Cross-Linking Reagents; D017463:Receptors, Complement 3b; C516742:PTPN13 protein, human; D054595:Protein Tyrosine Phosphatase, Non-Receptor Type 13