C1q binds phosphatidylserine and likely acts as a multiligand-bridging molecule in apoptotic cell recognition.
Efficient apoptotic cell clearance is critical for maintenance of tissue homeostasis, and to control the immune responses mediated by phagocytes. Little is known about the molecules that contribute "eat me" signals on the apoptotic cell surface. C1q, the recognition unit of the C1 complex of complement, also senses altered structures from self and is a major actor of immune tolerance. HeLa cells were rendered apoptotic by UV-B treatment and a variety of cellular and molecular approaches were used to investigate the nature of the target(s) recognized by C1q. Using surface plasmon resonance, C1q binding was shown to occur at early stages of apoptosis and to involve recognition of a cell membrane component. C1q binding and phosphatidylserine (PS) exposure, as measured by annexin V labeling, proceeded concomitantly, and annexin V inhibited C1q binding in a dose-dependent manner. As shown by cosedimentation, surface plasmon resonance, and x-ray crystallographic analyses, C1q recognized PS specifically and avidly (K(D) = 3.7-7 x 10(-8) M), through multiple interactions between its globular domain and the phosphoserine group of PS. Confocal microscopy revealed that the majority of the C1q molecules were distributed in membrane patches where they colocalized with PS. In summary, PS is one of the C1q ligands on apoptotic cells, and C1q-PS interaction takes place at early stages of apoptosis, in newly organized membrane patches. Given its versatile recognition properties, these data suggest that C1q has the unique ability to sense different markers which collectively would provide strong eat me signals, thereby allowing efficient apoptotic cell removal.
Païdassi
Helena
H
Laboratoire d'Enzymologie Moléculaire, Institut de Biologie Structurale Jean-Pierre Ebel, 41 Rue Jules Horowitz, Grenoble Cedex 1, France.
Tacnet-Delorme
Pascale
P
Garlatti
Virginie
V
Darnault
Claudine
C
Ghebrehiwet
Berhane
B
Gaboriaud
Christine
C
Arlaud
Gérard J
GJ
Frachet
Philippe
P
D017209:Apoptosis / Q000276:immunology*; D015922:Complement C1q / Q000737:chemistry / Q000378:metabolism*; D018360:Crystallography, X-Ray; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D010718:Phosphatidylserines / Q000378:metabolism*; D011485:Protein Binding / Q000276:immunology; D017434:Protein Structure, Tertiary; D020349:Surface Plasmon Resonance
D008024:Ligands; D010446:Peptide Fragments; D010718:Phosphatidylserines; D015922:Complement C1q