Annexin A2 and A5 serve as new ligands for C1Q on apoptotic cells.

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Annexin A2 and A5 serve as new ligands for C1Q on apoptotic cells. / Martin, Myriam; Leffler, Jonatan; Blom, Anna.

In: Journal of Biological Chemistry, Vol. 287, No. 40, 2012, p. 33733-33744.

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T1 - Annexin A2 and A5 serve as new ligands for C1Q on apoptotic cells.

AU - Martin, Myriam

AU - Leffler, Jonatan

AU - Blom, Anna

PY - 2012

Y1 - 2012

N2 - C1q is the initiator of the classical complement pathway and opsonizes apoptotic cells to facilitate phagocytosis. Deficiency of C1q is the strongest known risk factor for development of systemic lupus erythematosus (SLE)a, which appears to be related to ensuing impaired clearance of apoptotic material. The objective of the current study was to investigate new ligands for C1q on the surface of apoptotic cells. We revealed that the two phospholipid-binding proteins annexin A2 and A5 are, beside DNA, significant C1q ligands. We furthermore demonstrated that C1q binds directly to histones exposed on the surface of dying cells but we did not detect significant interaction with phosphatidylserine. The complement inhibitors C4b-binding protein (C4BP) and factor H (FH) also interact with dying cells, most likely to decrease complement activation beyond the level of C3 in order to allow non-inflammatory clearance. Despite the fact that C4BP, FH and C1q share some ligands on dying cells, we showed that these three proteins did not compete with one another for binding to apoptotic cells. We additionally demonstrated that the way in which apoptosis is induced influenced both the degree of apoptosis and the binding of C1q. The knowledge, that annexin A2 and A5 act as ligands for C1q on apoptotic cells, sheds new light on the pathophysiology of autoimmune diseases.

AB - C1q is the initiator of the classical complement pathway and opsonizes apoptotic cells to facilitate phagocytosis. Deficiency of C1q is the strongest known risk factor for development of systemic lupus erythematosus (SLE)a, which appears to be related to ensuing impaired clearance of apoptotic material. The objective of the current study was to investigate new ligands for C1q on the surface of apoptotic cells. We revealed that the two phospholipid-binding proteins annexin A2 and A5 are, beside DNA, significant C1q ligands. We furthermore demonstrated that C1q binds directly to histones exposed on the surface of dying cells but we did not detect significant interaction with phosphatidylserine. The complement inhibitors C4b-binding protein (C4BP) and factor H (FH) also interact with dying cells, most likely to decrease complement activation beyond the level of C3 in order to allow non-inflammatory clearance. Despite the fact that C4BP, FH and C1q share some ligands on dying cells, we showed that these three proteins did not compete with one another for binding to apoptotic cells. We additionally demonstrated that the way in which apoptosis is induced influenced both the degree of apoptosis and the binding of C1q. The knowledge, that annexin A2 and A5 act as ligands for C1q on apoptotic cells, sheds new light on the pathophysiology of autoimmune diseases.

U2 - 10.1074/jbc.M112.341339

DO - 10.1074/jbc.M112.341339

M3 - Article

C2 - 22879587

VL - 287

SP - 33733

EP - 33744

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 1083-351X

IS - 40

ER -