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...
| Main Authors: | , , , , , , |
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| Format: | Journal Article |
| Language: | English |
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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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| author | Ong, Li-Teng Tan, Hui-Foon Feng, Chen Qu, Jing Loh, Shuzk-Cheng Bhattacharyya, Surajit Tan, Suet-Mien |
| 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 |
| author_sort | Ong, Li-Teng |
| collection | NTU |
| 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. |
| first_indexed | 2024-10-01T05:55:27Z |
| format | Journal Article |
| id | ntu-10356/107073 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T05:55:27Z |
| publishDate | 2019 |
| record_format | dspace |
| spelling | ntu-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. |
| 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 |
| 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_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_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_sort | systemic lupus erythematosus associated single nucleotide polymorphism rs1143678 in integrin αm cytoplasmic tail generates a 14 3 3ζ binding site that is proinflammatory |
| topic | Systemic Lupus Erythematosus Single Nucleotide Polymorphism Science::Biological sciences |
| 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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