Interaction of TAPP adapter proteins with phosphatidylinositol (3,4)-bisphosphate regulates B-cell activation and autoantibody production.
TAPP1 and TAPP2 (where TAPP is tandem PH domain containing protein) are dual PH domain adaptors that selectively bind PI(3,4)P2 (phosphatidylinositol (3,4)-bisphosphate). PI(3,4)P2 is a lipid messenger generated by phosphoinositide 3-kinase (PI3K) and SHIP, both of which are critical regulators of B-cell activation. To determine the functional role of TAPP-PI(3,4)P2 interactions, we utilized a double knock-in (KI) mouse bearing mutations within the PI-binding pocket of both TAPP1 and TAPP2. TAPP KI mice show evidence of altered B-cell development, but generate phenotypically normal mature B-cell populations. Total serum immunoglobulin IgM and IgG levels were found to be markedly elevated in TAPP KI mice. B cells purified from TAPP KI mice were hyper-responsive to antigen receptor cross-linking, showing increased proliferation, CD86 expression, and Akt phosphorylation on Ser473 and Thr308. Female TAPP KI mice developed elevated levels of anti-DNA and antinuclear antibodies with age, associated with IgG deposition in kidneys and significant glomerulonephritis pathology. Together our results indicate that interaction of TAPPs with PI(3,4)P2 mediates feedback inhibition impacting on BCR signaling, with functional significance for control of autoreactive B cells.
Department of Immunology, University of Manitoba, Winnipeg, Canada.
Ivan
I
Landego
Nipun
N
Jayachandran
Stephan
S
Wullschleger
Ting-ting
TT
Zhang
Ian W
IW
Gibson
Angela
A
Miller
Dario R
DR
Alessi
Aaron J
AJ
Marshall
D000818:Animals; D000936:Antigen-Antibody Complex / Q000378:metabolism; D001323:Autoantibodies / Q000378:metabolism*; D001402:B-Lymphocytes / Q000276:immunology*; D051940:B7-2 Antigen / Q000378:metabolism; D001665:Binding Sites / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D002478:Cells, Cultured; D025461:Feedback, Physiological; D005260:Female; D005921:Glomerulonephritis / Q000235:genetics / Q000276:immunology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000276:immunology*; D008213:Lymphocyte Activation / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics
D000936:Antigen-Antibody Complex; D001323:Autoantibodies; D051940:B7-2 Antigen; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D010716:Phosphatidylinositols; C461495:Plekha1 protein, mouse; C461496:Plekha2 protein, mouse; C118301:phosphoinositide-3,4-bisphosphate; D051058:Oncogene Protein v-akt