Lewis J, Eiben L J, Nelson D L, Cohen J I, Nichols K E, Ochs H D, Notarangelo L D, Duckett C S
Metabolism Branch, National Cancer Institute, Bethesda, Maryland 20892-1578, USA.
Clin Immunol. 2001 Jul;100(1):15-23. doi: 10.1006/clim.2001.5035.
X-linked lymphoproliferative syndrome (XLP; Duncan's disease) is a primary immunodeficiency disease that manifests as an inability to regulate the immune response to Epstein-Barr virus (EBV) infection. Here we examine the ability of the product of the gene defective in XLP, SAP (DSHP/SH2D1A), to associate with the cytoplasmic domains of several members of the CD2 subfamily of cell surface receptors, including SLAM, 2B4, and CD84. While recruitment of SAP to SLAM occurred in a phosphorylation-independent manner, SAP was found to bind preferentially to tyrosine-phosphorylated cytoplasmic domains within 2B4 and CD84. Missense or nonsense mutations in the SAP open reading frame were identified in five of seven clinically diagnosed XLP patients from different kindreds. Four of these variants retained the ability to bind to the cytoplasmic tails of SLAM and CD84. While ectopic expression of wild-type SAP was observed to block the binding of SHP-2 to SLAM, mutant SAP derivatives that retained the ability to bind SLAM did not inhibit recruitment of SHP-2 to SLAM. In contrast, SAP binding to CD84 had no effect on the ability of CD84 to recruit SHP-2, but instead displaced SHP-1 from the cytoplasmic tail of CD84. These results suggest that mutations in the gene encoding the XLP protein SAP lead to functional defects in the protein that include receptor binding and SHP-1 and SHP-2 displacement and that SAP utilizes different mechanisms to regulate signaling through the CD2 family of receptors.
X连锁淋巴增殖综合征（XLP；邓肯氏病）是一种原发性免疫缺陷疾病，表现为无法调节对爱泼斯坦-巴尔病毒（EBV）感染的免疫反应。在此，我们研究了XLP中缺陷基因的产物SAP（DSHP/SH2D1A）与细胞表面受体CD2亚家族的几个成员（包括信号淋巴细胞激活分子（SLAM）、2B4和CD84）的胞质结构域结合的能力。虽然SAP募集到SLAM是以一种不依赖磷酸化的方式发生的，但发现SAP优先结合2B4和CD84内酪氨酸磷酸化的胞质结构域。在来自不同家族的7例临床诊断的XLP患者中的5例中，鉴定出了SAP开放阅读框中的错义或无义突变。这些变体中的4个保留了与SLAM和CD84的胞质尾部结合的能力。虽然观察到野生型SAP的异位表达可阻断SHP-2与SLAM的结合，但保留与SLAM结合能力的突变型SAP衍生物并未抑制SHP-2募集到SLAM。相反，SAP与CD84的结合对CD84募集SHP-2的能力没有影响，但反而将SHP-1从CD84的胞质尾部置换出来。这些结果表明，编码XLP蛋白SAP的基因突变导致该蛋白出现功能缺陷，包括受体结合以及SHP-1和SHP-2的置换，并且SAP利用不同机制来调节通过CD2受体家族的信号传导。
