Platelet-associated IgAs and impaired GPVI responses in platelets lacking WIP.
The role of the Wiskott-Aldrich syndrome protein (WASp) in platelet function is unclear because platelets that lack WASp function normally. WASp constitutively associates with WASp-interacting protein (WIP) in resting and activated platelets. The role of WIP in platelet function was investigated using mice that lack WIP or WASp. WIP knockout (KO) platelets lack WASp and thus are double deficient. WIP KO mice have a thrombocytopenia, similar to WASp KO mice, resulting in part from enhanced platelet clearance. Most WIP KO, but not WASp KO, mice evolved platelet-associated immunoglobulins (Ig) of the IgA class, which normalize their platelet survival but diminish their glycoprotein VI (GPVI) responses. Protein tyrosine phosphorylation, including that of phospholipase C-gamma2, and calcium mobilization are impaired in IgA-presenting WIP KO platelets stimulated through GPVI, resulting in defects in alpha-granule secretion, integrin alphaIIbbeta3 activation, and actin assembly. The anti-GPVI antibody JAQ1 induces the irreversible loss of GPVI from circulating platelets in wild-type mice, but not in WIP KO mice that bear high levels of platelet-associated IgAs. Together, the data indicate that platelet-associated IgAs negatively modulate GPVI signaling and function in WIP KO mice.
Falet
Hervé
H
Division of Translational Medicine, Brigham and Women's Hospital, One Blackfan Cir, Karp 6, Boston, MA02115, USA. hfalet@rics.bwh.harvard.edu
Marchetti
Michael P
MP
Hoffmeister
Karin M
KM
Massaad
Michel J
MJ
Geha
Raif S
RS
Hartwig
John H
JH
D000818:Animals; D001792:Blood Platelets / Q000276:immunology / Q000378:metabolism*; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D003598:Cytoskeletal Proteins; D004591:Electrophoresis, Polyacrylamide Gel; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007070:Immunoglobulin A / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013921:Thrombocytopenia / Q000235:genetics / Q000378:metabolism; D051316:Wiskott-Aldrich Syndrome Protein / Q000235:genetics / Q000378:metabolism*
D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D007070:Immunoglobulin A; D010980:Platelet Membrane Glycoproteins; C491671:Waspip protein, mouse; D051316:Wiskott-Aldrich Syndrome Protein; C098341:platelet membrane glycoprotein VI
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