Phosphatidylinositol-3-kinase C2β and TRIM27 function to positively and negatively regulate IgE receptor activation of mast cells.
Cross-linking of the IgE receptor (FcεRI) on mast cells plays a critical role in IgE-dependent allergy, including allergic rhinitis, asthma, anaphylaxis, and immediate-type hypersensitivity reactions. Previous studies have demonstrated that the K(+) channel, KCa3.1, plays a critical role in IgE-stimulated Ca(2+) entry and degranulation in both human and mouse mast cells. We now have shown that the class II phosphatidylinositol-3-kinase C2β (PI3KC2β) is necessary for FcεRI-stimulated activation of KCa3.1, Ca(2+) influx, cytokine production, and degranulation of bone marrow-derived mast cells (BMMC). In addition, we found that the E3 ubiquitin ligase, tripartite motif containing protein 27 (TRIM27), negatively regulates FcεRI activation of KCa3.1 and downstream signaling by ubiquitinating and inhibiting PI3KC2β. TRIM27(-/-) mice are also more susceptible in vivo to acute anaphylaxis. These findings identify TRIM27 as an important negative regulator of mast cells in vivo and suggest that PI3KC2β is a potential new pharmacologic target to treat IgE-mediated disease.
Division of Nephrology, The Helen L and Martin S Kimmel Center for Biology and Medicine at the Skirball Institute for Biomolecular Medicine, New York University Langone Medical Center, New York, New York, USA.
Shekhar
S
Srivastava
Xinjiang
X
Cai
Zhai
Z
Li
Yi
Y
Sun
Edward Y
EY
Skolnik
D000707:Anaphylaxis / Q000235:genetics; D000818:Animals; D015550:Cell Degranulation; D058534:Class I Phosphatidylinositol 3-Kinases; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006967:Hypersensitivity / Q000276:immunology*; D007073:Immunoglobulin E / Q000276:immunology; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism; D008407:Mast Cells / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering; D017455:Receptors, IgE / Q000378:metabolism*; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases; D054875:Ubiquitination; D000070584:Tripartite Motif Proteins
D058534:Class I Phosphatidylinositol 3-Kinases; D004268:DNA-Binding Proteins; D007073:Immunoglobulin E; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D034741:RNA, Small Interfering; D017455:Receptors, IgE; D044767:Ubiquitin-Protein Ligases; C496925:Kcnn4 protein, mouse; C489296:Trim27 protein, mouse; D000070584:Tripartite Motif Proteins; C546640:Pik3cb protein, mouse