The C5a receptor (C5aR) C5L2 is a modulator of C5aR-mediated signal transduction

Claire E Bamberg, Charles Mackay, Hyun Lee, David Zahra, Jenny Jackson, Yun Si Lim, Peter L Whitfeld, Stewart Craig, Erin Corsini, Bao Lu, Craig Gerard, Norman P Gerard

Research output: Contribution to journalArticleResearchpeer-review

154 Citations (Scopus)

Abstract

The complement anaphylatoxin C5a is a proinflammatory component of host defense that functions through two identified receptors, C5a receptor (C5aR) and C5L2. C5aR is a classical G protein-coupled receptor, whereas C5L2 is structurally homologous but deficient in G protein coupling. In human neutrophils, we show C5L2 is predominantly intracellular, whereas C5aR is expressed on the plasma membrane. Confocal analysis shows internalized C5aR following ligand binding is co-localized with both C5L2 and I?-arrestin. Antibody blockade of C5L2 results in a dramatic increase in C5a-mediated chemotaxis and ERK1/2 phosphorylation but does not alter C5a-mediated calcium mobilization, supporting its role in modulation of the beta -arrestin pathway. Association of C5L2 with beta -arrestin is confirmed by cellular co-immunoprecipitation assays. C5L2 blockade also has no effect on ligand uptake or C5aR endocytosis in human polymorphonuclear leukocytes, distinguishing its role from that of a rapid recycling or scavenging receptor in this cell type. This is thus the first example of a naturally occurring seven-transmembrane segment receptor that is both obligately uncoupled from G proteins and a negative modulator of signal transduction through the beta -arrestin pathway. Physiologically, these properties provide the possibility for additional fine-tuning of host defense.
Original languageEnglish
Pages (from-to)7633 - 7644
Number of pages12
JournalJournal of Biological Chemistry
Volume285
Issue number10
DOIs
Publication statusPublished - 2010
Externally publishedYes

Cite this

Bamberg, C. E., Mackay, C., Lee, H., Zahra, D., Jackson, J., Lim, Y. S., ... Gerard, N. P. (2010). The C5a receptor (C5aR) C5L2 is a modulator of C5aR-mediated signal transduction. Journal of Biological Chemistry, 285(10), 7633 - 7644. https://doi.org/10.1074/jbc.M109.092106
Bamberg, Claire E ; Mackay, Charles ; Lee, Hyun ; Zahra, David ; Jackson, Jenny ; Lim, Yun Si ; Whitfeld, Peter L ; Craig, Stewart ; Corsini, Erin ; Lu, Bao ; Gerard, Craig ; Gerard, Norman P. / The C5a receptor (C5aR) C5L2 is a modulator of C5aR-mediated signal transduction. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 10. pp. 7633 - 7644.
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Bamberg, CE, Mackay, C, Lee, H, Zahra, D, Jackson, J, Lim, YS, Whitfeld, PL, Craig, S, Corsini, E, Lu, B, Gerard, C & Gerard, NP 2010, 'The C5a receptor (C5aR) C5L2 is a modulator of C5aR-mediated signal transduction', Journal of Biological Chemistry, vol. 285, no. 10, pp. 7633 - 7644. https://doi.org/10.1074/jbc.M109.092106

The C5a receptor (C5aR) C5L2 is a modulator of C5aR-mediated signal transduction. / Bamberg, Claire E; Mackay, Charles; Lee, Hyun; Zahra, David; Jackson, Jenny; Lim, Yun Si; Whitfeld, Peter L; Craig, Stewart; Corsini, Erin; Lu, Bao; Gerard, Craig; Gerard, Norman P.

In: Journal of Biological Chemistry, Vol. 285, No. 10, 2010, p. 7633 - 7644.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - The C5a receptor (C5aR) C5L2 is a modulator of C5aR-mediated signal transduction

AU - Bamberg, Claire E

AU - Mackay, Charles

AU - Lee, Hyun

AU - Zahra, David

AU - Jackson, Jenny

AU - Lim, Yun Si

AU - Whitfeld, Peter L

AU - Craig, Stewart

AU - Corsini, Erin

AU - Lu, Bao

AU - Gerard, Craig

AU - Gerard, Norman P

PY - 2010

Y1 - 2010

N2 - The complement anaphylatoxin C5a is a proinflammatory component of host defense that functions through two identified receptors, C5a receptor (C5aR) and C5L2. C5aR is a classical G protein-coupled receptor, whereas C5L2 is structurally homologous but deficient in G protein coupling. In human neutrophils, we show C5L2 is predominantly intracellular, whereas C5aR is expressed on the plasma membrane. Confocal analysis shows internalized C5aR following ligand binding is co-localized with both C5L2 and I?-arrestin. Antibody blockade of C5L2 results in a dramatic increase in C5a-mediated chemotaxis and ERK1/2 phosphorylation but does not alter C5a-mediated calcium mobilization, supporting its role in modulation of the beta -arrestin pathway. Association of C5L2 with beta -arrestin is confirmed by cellular co-immunoprecipitation assays. C5L2 blockade also has no effect on ligand uptake or C5aR endocytosis in human polymorphonuclear leukocytes, distinguishing its role from that of a rapid recycling or scavenging receptor in this cell type. This is thus the first example of a naturally occurring seven-transmembrane segment receptor that is both obligately uncoupled from G proteins and a negative modulator of signal transduction through the beta -arrestin pathway. Physiologically, these properties provide the possibility for additional fine-tuning of host defense.

AB - The complement anaphylatoxin C5a is a proinflammatory component of host defense that functions through two identified receptors, C5a receptor (C5aR) and C5L2. C5aR is a classical G protein-coupled receptor, whereas C5L2 is structurally homologous but deficient in G protein coupling. In human neutrophils, we show C5L2 is predominantly intracellular, whereas C5aR is expressed on the plasma membrane. Confocal analysis shows internalized C5aR following ligand binding is co-localized with both C5L2 and I?-arrestin. Antibody blockade of C5L2 results in a dramatic increase in C5a-mediated chemotaxis and ERK1/2 phosphorylation but does not alter C5a-mediated calcium mobilization, supporting its role in modulation of the beta -arrestin pathway. Association of C5L2 with beta -arrestin is confirmed by cellular co-immunoprecipitation assays. C5L2 blockade also has no effect on ligand uptake or C5aR endocytosis in human polymorphonuclear leukocytes, distinguishing its role from that of a rapid recycling or scavenging receptor in this cell type. This is thus the first example of a naturally occurring seven-transmembrane segment receptor that is both obligately uncoupled from G proteins and a negative modulator of signal transduction through the beta -arrestin pathway. Physiologically, these properties provide the possibility for additional fine-tuning of host defense.

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U2 - 10.1074/jbc.M109.092106

DO - 10.1074/jbc.M109.092106

M3 - Article

VL - 285

SP - 7633

EP - 7644

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 1083-351X

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