B cell antigen receptor signal strength and peripheral B cell development are regulated by a 9-O-acetyl sialic acid esterase.
We show that the enzymatic acetylation and deacetylation of a cell surface carbohydrate controls B cell development, signaling, and immunological tolerance. Mice with a mutation in sialate:O-acetyl esterase, an enzyme that specifically removes acetyl moieties from the 9-OH position of alpha2-6-linked sialic acid, exhibit enhanced B cell receptor (BCR) activation, defects in peripheral B cell development, and spontaneously develop antichromatin autoantibodies and glomerular immune complex deposits. The 9-O-acetylation state of sialic acid regulates the function of CD22, a Siglec that functions in vivo as an inhibitor of BCR signaling. These results describe a novel catalytic regulator of B cell signaling and underscore the crucial role of inhibitory signaling in the maintenance of immunological tolerance in the B lineage.
Cariappa
Annaiah
A
Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA.
Takematsu
Hiromu
H
Liu
Haoyuan
H
Diaz
Sandra
S
Haider
Khaleda
K
Boboila
Cristian
C
Kalloo
Geetika
G
Connole
Michelle
M
Shi
Hai Ning
HN
Varki
Nissi
N
Varki
Ajit
A
Pillai
Shiv
S
D000107:Acetylation; D000115:Acetylesterase; D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood; D016175:B-Lymphocyte Subsets / Q000166:cytology; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000166:cytology; D002265:Carboxylic Ester Hydrolases / Q000235:genetics / Q000378:metabolism*; D002452:Cell Count; D002454:Cell Differentiation / Q000502:physiology*; D005921:Glomerulonephritis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008954:Models, Biological; D009154:Mutation; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000378:metabolism; D012794:Sialic Acids / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013154:Spleen / Q000166:cytology
D000974:Antibodies, Antinuclear; C497868:Cd22 protein, mouse; D011947:Receptors, Antigen, B-Cell; D051918:Sialic Acid Binding Ig-like Lectin 2; D012794:Sialic Acids; D002265:Carboxylic Ester Hydrolases; D000115:Acetylesterase; C046298:sialate O-acetylesterase; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C509248:Ptpn6 protein, mouse