Department of Immunology, University of Manitoba, Winnipeg, Canada.
Eur J Immunol. 2012 Oct;42(10):2760-70. doi: 10.1002/eji.201242371. Epub 2012 Aug 8.
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.
TAPP1 和 TAPP2（其中 TAPP 是串联 PH 结构域蛋白）是双 PH 结构域衔接蛋白，可特异性结合 PI(3,4)P2（磷脂酰肌醇（3,4）-二磷酸）。PI(3,4)P2 是由磷酸肌醇 3-激酶 (PI3K) 和 SHIP 产生的脂质信使，两者都是 B 细胞激活的关键调节因子。为了确定 TAPP-PI(3,4)P2 相互作用的功能作用，我们利用了在 TAPP1 和 TAPP2 的 PI 结合口袋内均具有突变的双敲入 (KI) 小鼠。TAPP KI 小鼠表现出 B 细胞发育改变的证据，但产生表型正常的成熟 B 细胞群体。发现 TAPP KI 小鼠的总血清免疫球蛋白 IgM 和 IgG 水平明显升高。从 TAPP KI 小鼠中纯化的 B 细胞对抗原受体交联表现出过度反应，表现为增殖增加、CD86 表达增加以及 Akt 在 Ser473 和 Thr308 上的磷酸化。随着年龄的增长，雌性 TAPP KI 小鼠产生了升高的抗 DNA 和抗核抗体水平，与 IgG 在肾脏中的沉积和显著的肾小球肾炎病理有关。总之，我们的结果表明，TAPP 与 PI(3,4)P2 的相互作用介导了对 BCR 信号的反馈抑制，对自身反应性 B 细胞的控制具有功能意义。
