Lectin pathway effector enzyme mannan-binding lectin-associated serine protease-2 can activate native complement C3 in absence of C4 and/or C2

TY - JOUR

T1 - Lectin pathway effector enzyme mannan-binding lectin-associated serine protease-2 can activate native complement C3 in absence of C4 and/or C2

AU - Yaseen, Sadam

AU - Demopulos, Gregory

AU - Dudler, Thomas

AU - Yabuki, Munehisa

AU - Wood, Christi L

AU - Cummings, W Jason

AU - Tjoelker, Larry W

AU - Fujita, Teizo

AU - Sacks, Steven

AU - Garred, Peter

AU - Andrew, Peter

AU - Sim, Robert B

AU - Lachmann, Peter J

AU - Wallis, Russell

AU - Lynch, Nicholas

AU - Schwaeble, Wilhelm J

N1 - © FASEB.

PY - 2017/5

Y1 - 2017/5

N2 - All 3 activation pathways of complement - the classic pathway (CP), the alternative pathway, and the lectin pathway (LP) - converge into a common central event: the cleavage and activation of the abundant third complement component, C3, via formation ofC3-activating enzymes (C3 convertases). The fourth complement component, C4, and the second component, C2, are indispensable constituents of the C3 convertase complex, C4bC2a,which is formed by both the CP and the LP. Whereas in the absence ofC4, CP can no longer activateC3, LP retains a residual but physiologically critical capacity to convert native C3 into its activation fragments, C3a and C3b. This residual C4 and/or C2 bypass route is dependent on LP-specific mannan-binding lectinassociated serine protease-2. By using various serum sources with defined complement deficiencies, we demonstrate that, under physiologic conditions LP-specific C4 and/or C2 bypass activation of C3 is mediated by direct cleavage of native C3 by mannan-binding lectin-associated serine protease-2 bound to LP-activation complexes captured on ligand-coated surfaces.

AB - All 3 activation pathways of complement - the classic pathway (CP), the alternative pathway, and the lectin pathway (LP) - converge into a common central event: the cleavage and activation of the abundant third complement component, C3, via formation ofC3-activating enzymes (C3 convertases). The fourth complement component, C4, and the second component, C2, are indispensable constituents of the C3 convertase complex, C4bC2a,which is formed by both the CP and the LP. Whereas in the absence ofC4, CP can no longer activateC3, LP retains a residual but physiologically critical capacity to convert native C3 into its activation fragments, C3a and C3b. This residual C4 and/or C2 bypass route is dependent on LP-specific mannan-binding lectinassociated serine protease-2. By using various serum sources with defined complement deficiencies, we demonstrate that, under physiologic conditions LP-specific C4 and/or C2 bypass activation of C3 is mediated by direct cleavage of native C3 by mannan-binding lectin-associated serine protease-2 bound to LP-activation complexes captured on ligand-coated surfaces.

KW - Complement Activation/physiology

KW - Complement C2/metabolism

KW - Complement C3/metabolism

KW - Complement C4/metabolism

KW - Humans

KW - Lectins/metabolism

KW - Mannose-Binding Protein-Associated Serine Proteases/metabolism

U2 - 10.1096/fj.201601306r

DO - 10.1096/fj.201601306r

M3 - Journal article

C2 - 28188176

SN - 0892-6638

VL - 31

SP - 2210

EP - 2219

JO - F A S E B Journal

JF - F A S E B Journal

IS - 5

ER -