An essential role for RGS protein/Gαi2 interactions in B lymphocyte-directed cell migration and trafficking

Il-Young Hwang; Chung Park; Kathleen Harrison; Cedric Boularan; Céline Galés; John H Kehrl

doi:10.4049/jimmunol.1401952

An essential role for RGS protein/Gαi2 interactions in B lymphocyte-directed cell migration and trafficking

J Immunol. 2015 Mar 1;194(5):2128-39. doi: 10.4049/jimmunol.1401952. Epub 2015 Jan 23.

Authors

Il-Young Hwang¹, Chung Park¹, Kathleen Harrison¹, Cedric Boularan², Céline Galés³, John H Kehrl⁴

Affiliations

¹ Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and.
² Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and INSERM U1048, Institut des Maladies Métaboliques et Cardiovasculaires, 31432 Toulouse Cedex 4, France.
³ INSERM U1048, Institut des Maladies Métaboliques et Cardiovasculaires, 31432 Toulouse Cedex 4, France.
⁴ Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and [email protected].

Abstract

Chemokines engage B lymphocyte surface receptors, triggering heterotrimeric G protein Gαi subunit guanine nucleotide exchange. RGS proteins limit the duration that Gαi subunits remain GTP bound, and the loss of an individual RGS protein typically enhances chemokine receptor signaling. In this study, we show that B cells carrying a Gαi2 (G184S/G184S) mutation that disables all RGS protein/Gαi2 interactions exhibit an unexpectedly severe reduction in chemokine receptor signaling. The Gαi2 (G184S/G184S) B cells have markedly elevated basal calcium levels, but poor chemokine-induced increases, enhanced nonspecific migration, but extremely poor chemotaxis. In striking contrast, the Gαi2 (G184S/G184S) B cells exhibited enhanced sensitivity to sphingosine 1-phosphate (S1P). S1P elicited heightened intracellular calcium responses and enhanced S1P-triggered cell migration. Mice with the Gαi2 (G184S/G184S) mutation displayed excessive numbers of germinal center-like structures; abnormal serum Ig profiles; and aberrant B lymphocyte trafficking. These findings establish an essential role for RGS proteins in B cell chemoattractant signaling and for the proper position of B lymphocytes in lymphoid organs.

Publication types

Research Support, N.I.H., Intramural

MeSH terms

Animals
B-Lymphocyte Subsets / cytology
B-Lymphocyte Subsets / drug effects
B-Lymphocyte Subsets / immunology
B-Lymphocyte Subsets / metabolism*
Binding Sites
Bone Marrow Cells / cytology
Bone Marrow Cells / drug effects
Bone Marrow Cells / immunology
Bone Marrow Cells / metabolism
Calcium / immunology
Calcium / metabolism
Chemokines / pharmacology
Chemotaxis, Leukocyte / drug effects*
Female
GTP-Binding Protein alpha Subunit, Gi2 / genetics
GTP-Binding Protein alpha Subunit, Gi2 / immunology
GTP-Binding Protein alpha Subunit, Gi2 / metabolism*
Gene Expression Regulation
Germinal Center / cytology
Germinal Center / drug effects
Germinal Center / immunology
Germinal Center / metabolism
Lysophospholipids / pharmacology
Mice
Mice, Inbred C57BL
Mice, Transgenic
Mutation
Primary Cell Culture
Protein Binding
RGS Proteins / genetics
RGS Proteins / immunology
RGS Proteins / metabolism*
Signal Transduction
Sphingosine / analogs & derivatives
Sphingosine / pharmacology
Spleen / cytology
Spleen / drug effects
Spleen / immunology
Spleen / metabolism*

Substances

Chemokines
Lysophospholipids
RGS Proteins
sphingosine 1-phosphate
GTP-Binding Protein alpha Subunit, Gi2
Gnai2 protein, mouse
Sphingosine
Calcium

Grants and funding

Z01 AI000738-13/Intramural NIH HHS/United States