The systemic lupus erythematosus–associated single nucleotide polymorphism rs1143678 in integrin αM cytoplasmic tail generates a 14-3-3ζ binding site that is proinflammatory

The leukocyte integrin αMβ2 (CR3 or Mac-1) has both proinflammatory and immune regulatory functions. Genome-wide association studies have identified several ITGAM (αM subunit) single nucleotide polymorphisms that are associated with systemic lupus erythematosus. The single nucleotide polymorphism rs...

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Main Authors: Ong, Li-Teng, Tan, Hui-Foon, Feng, Chen, Qu, Jing, Loh, Shuzk-Cheng, Bhattacharyya, Surajit, Tan, Suet-Mien
Other Authors: School of Biological Sciences
Format: Article
Language:English
Published: 2019
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Online Access:https://hdl.handle.net/10356/107073
http://hdl.handle.net/10220/49045
http://dx.doi.org/10.4049/jimmunol.1601447
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Institution: Nanyang Technological University
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spelling sg-ntu-dr.10356-1070732019-12-06T22:24:12Z The systemic lupus erythematosus–associated single nucleotide polymorphism rs1143678 in integrin αM cytoplasmic tail generates a 14-3-3ζ binding site that is proinflammatory Ong, Li-Teng Tan, Hui-Foon Feng, Chen Qu, Jing Loh, Shuzk-Cheng Bhattacharyya, Surajit Tan, Suet-Mien School of Biological Sciences Systemic Lupus Erythematosus Single Nucleotide Polymorphism Science::Biological sciences The leukocyte integrin αMβ2 (CR3 or Mac-1) has both proinflammatory and immune regulatory functions. Genome-wide association studies have identified several ITGAM (αM subunit) single nucleotide polymorphisms that are associated with systemic lupus erythematosus. The single nucleotide polymorphism rs1143678 substitutes Pro1146 for Ser in the integrin αM cytoplasmic tail. A detailed functional characterization of this substitution is lacking. Using transfected human cell lines, reconstituted mouse bone marrow neutrophils, and bone marrow–derived macrophages (BMDMs), we showed that P1146S (PS) substitution promoted integrin αMβ2–mediated adhesion, spreading, and migration of cells on iC3b and fibrinogen. In the presence of LPS together with iC3b or fibrinogen, the expression levels of IL-6 and TNF-α in integrin αM(PS)β2 BMDMs were significantly higher than those of integrin αM(wild-type)β2 BMDMs, and they showed faster kinetics of Erk1/2 activation through the src family kinase(s)–Syk signaling pathway. Integrin αM(PS)β2 BMDMs also exhibited higher levels of active RhoA and phagocytic activity. Mechanistically, P1146S substitution in the αM cytoplasmic tail generates a noncanonical 14-3-3ζ binding site that modulates integrin αM(PS)β2 outside-in signaling. MOE (Min. of Education, S’pore) 2019-07-01T05:18:58Z 2019-12-06T22:24:12Z 2019-07-01T05:18:58Z 2019-12-06T22:24:12Z 2016 Journal Article Ong, L.-T., Tan, H.-F., Feng, C., Qu, J., Loh, S.-C., Bhattacharyya, S., & Tan, S.-M. (2017). The systemic lupus erythematosus–associated single nucleotide polymorphism rs1143678 in integrin αM cytoplasmic tail generates a 14-3-3ζ binding site that is proinflammatory. The Journal of Immunology, 198(2), 883-894. doi:10.4049/jimmunol.1601447 0022-1767 https://hdl.handle.net/10356/107073 http://hdl.handle.net/10220/49045 http://dx.doi.org/10.4049/jimmunol.1601447 en The Journal of Immunology © 2017 The American Association of Immunologists, Inc. All rights reserved.
institution Nanyang Technological University
building NTU Library
country Singapore
collection DR-NTU
language English
topic Systemic Lupus Erythematosus
Single Nucleotide Polymorphism
Science::Biological sciences
spellingShingle Systemic Lupus Erythematosus
Single Nucleotide Polymorphism
Science::Biological sciences
Ong, Li-Teng
Tan, Hui-Foon
Feng, Chen
Qu, Jing
Loh, Shuzk-Cheng
Bhattacharyya, Surajit
Tan, Suet-Mien
The systemic lupus erythematosus–associated single nucleotide polymorphism rs1143678 in integrin αM cytoplasmic tail generates a 14-3-3ζ binding site that is proinflammatory
description The leukocyte integrin αMβ2 (CR3 or Mac-1) has both proinflammatory and immune regulatory functions. Genome-wide association studies have identified several ITGAM (αM subunit) single nucleotide polymorphisms that are associated with systemic lupus erythematosus. The single nucleotide polymorphism rs1143678 substitutes Pro1146 for Ser in the integrin αM cytoplasmic tail. A detailed functional characterization of this substitution is lacking. Using transfected human cell lines, reconstituted mouse bone marrow neutrophils, and bone marrow–derived macrophages (BMDMs), we showed that P1146S (PS) substitution promoted integrin αMβ2–mediated adhesion, spreading, and migration of cells on iC3b and fibrinogen. In the presence of LPS together with iC3b or fibrinogen, the expression levels of IL-6 and TNF-α in integrin αM(PS)β2 BMDMs were significantly higher than those of integrin αM(wild-type)β2 BMDMs, and they showed faster kinetics of Erk1/2 activation through the src family kinase(s)–Syk signaling pathway. Integrin αM(PS)β2 BMDMs also exhibited higher levels of active RhoA and phagocytic activity. Mechanistically, P1146S substitution in the αM cytoplasmic tail generates a noncanonical 14-3-3ζ binding site that modulates integrin αM(PS)β2 outside-in signaling.
author2 School of Biological Sciences
author_facet School of Biological Sciences
Ong, Li-Teng
Tan, Hui-Foon
Feng, Chen
Qu, Jing
Loh, Shuzk-Cheng
Bhattacharyya, Surajit
Tan, Suet-Mien
format Article
author Ong, Li-Teng
Tan, Hui-Foon
Feng, Chen
Qu, Jing
Loh, Shuzk-Cheng
Bhattacharyya, Surajit
Tan, Suet-Mien
author_sort Ong, Li-Teng
title The systemic lupus erythematosus–associated single nucleotide polymorphism rs1143678 in integrin αM cytoplasmic tail generates a 14-3-3ζ binding site that is proinflammatory
title_short The systemic lupus erythematosus–associated single nucleotide polymorphism rs1143678 in integrin αM cytoplasmic tail generates a 14-3-3ζ binding site that is proinflammatory
title_full The systemic lupus erythematosus–associated single nucleotide polymorphism rs1143678 in integrin αM cytoplasmic tail generates a 14-3-3ζ binding site that is proinflammatory
title_fullStr The systemic lupus erythematosus–associated single nucleotide polymorphism rs1143678 in integrin αM cytoplasmic tail generates a 14-3-3ζ binding site that is proinflammatory
title_full_unstemmed The systemic lupus erythematosus–associated single nucleotide polymorphism rs1143678 in integrin αM cytoplasmic tail generates a 14-3-3ζ binding site that is proinflammatory
title_sort systemic lupus erythematosus–associated single nucleotide polymorphism rs1143678 in integrin αm cytoplasmic tail generates a 14-3-3ζ binding site that is proinflammatory
publishDate 2019
url https://hdl.handle.net/10356/107073
http://hdl.handle.net/10220/49045
http://dx.doi.org/10.4049/jimmunol.1601447
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