Department of Molecular Biology and Biochemistry, and Center Institute for Immunology, University of California, Irvine, Irvine, CA 92697-3900, USA.
Autoimmunity. 2009 Aug;42(5):447-58. doi: 10.1080/08916930902911746.
Phosphoinositide kinase (PI3K) is activated by various receptors on lymphocytes and regulates development, activation, and tolerance. Genetic ablation of PI3K function in T cells leads to the appearance of autoimmune disorders. In B cells, loss of the class IA regulatory subunit p85alpha causes a partial defect in B cell development and proliferation, whereas loss of p85beta alone causes no apparent changes in B cell function. Here we investigate further the consequences of p85beta deletion in B cells, in the presence or absence of p85alpha. We demonstrate that p85beta partially compensates for loss of p85alpha in B cell development and peripheral survival, with greater defects observed when both isoforms are absent. BCR-mediated AKT phosphorylation is partially reduced in p85alpha-deficient B cells and further diminished with concomitant loss of p85beta. Unexpectedly, loss of p85beta results in increased BCR-mediated proliferation and ERK phosphorylation. These results indicate that the p85beta regulatory isoform has partially overlapping functions with p85alpha in B cells as well as a unique role in opposing BCR responses.
磷酸肌醇激酶（PI3K）被淋巴细胞上的各种受体激活，并调节其发育、激活和耐受。T 细胞中 PI3K 功能的遗传缺失会导致自身免疫疾病的出现。在 B 细胞中，IA 类调节亚基 p85alpha 的缺失会导致 B 细胞发育和增殖的部分缺陷，而单独缺失 p85beta 则不会导致 B 细胞功能的明显变化。在这里，我们进一步研究了在存在或不存在 p85alpha 的情况下，p85beta 在 B 细胞中的缺失所带来的后果。我们证明，p85beta 在 B 细胞发育和外周存活方面部分补偿了 p85alpha 的缺失，当两种同工酶都缺失时，观察到的缺陷更大。在 p85alpha 缺陷型 B 细胞中，BCR 介导的 AKT 磷酸化部分减少，而伴随 p85beta 的缺失则进一步减少。出乎意料的是，p85beta 的缺失导致 BCR 介导的增殖和 ERK 磷酸化增加。这些结果表明，p85beta 调节同工酶在 B 细胞中与 p85alpha 具有部分重叠的功能，并且在拮抗 BCR 反应中具有独特的作用。
