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.
abstract: The leukocyte integrin αMβ2(CR3 or Mac-1) has both proinflammatory and immune regulatory functions. Genome-wide association studies have identified several ITGAM (αMsubunit) single nucleotide polymorphisms that are associated with systemic lupus erythematosus. The single nucleotide polymorphism rs1143678 substitutes Pro1146for Ser in the integrin αMcytoplasmic 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)β2BMDMs were significantly higher than those of integrin αM(wild-type)β2BMDMs, and they showed faster kinetics of Erk1/2 activation through the src family kinase(s)-Syk signaling pathway. Integrin αM(PS)β2BMDMs also exhibited higher levels of active RhoA and phagocytic activity. Mechanistically, P1146S substitution in the αMcytoplasmic tail generates a noncanonical 14-3-3ζ binding site that modulates integrin αM(PS)β2outside-in signaling.
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore.
authors.forename: Li-Teng
authors.identifier: 0000-0001-6741-6009
authors.initials: LT
authors.lastname: Ong
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore.
authors.forename: Hui-Foon
authors.initials: HF
authors.lastname: Tan
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore.
authors.forename: Chen
authors.initials: C
authors.lastname: Feng
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore.
authors.forename: Jing
authors.initials: J
authors.lastname: Qu
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore.
authors.forename: Shuzk-Cheng
authors.initials: SC
authors.lastname: Loh
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore.
authors.forename: Surajit
authors.initials: S
authors.lastname: Bhattacharyya
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore smtan@ntu.edu.sg.
authors.forename: Suet-Mien
authors.initials: SM
authors.lastname: Tan
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D005434:Flow Cytometry; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000378:metabolism; D016177:Macrophage-1 Antigen / Q000235:genetics*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide
chemical_list: D048948:14-3-3 Proteins; D016177:Macrophage-1 Antigen