Schnell Silke, Démollière Corinne, van den Berk Paul, Jacobs Heinz
Division of Immunology, The Netherlands Cancer Institute, Amsterdam.
Blood. 2006 Jul 15;108(2):591-9. doi: 10.1182/blood-2005-11-4616. Epub 2006 Mar 28.
Gimap4, a member of the newly identified GTPase of the immunity-associated protein family (Gimap), is strongly induced by the pre-T-cell receptor in precursor T lymphocytes, transiently shut off in double-positive thymocytes, and reappears after TCR-mediated positive selection. Here, we show that Gimap4 remains expressed constitutively in the cytosol of mature T cells. A C-terminal IQ domain binds calmodulin in the absence of calcium, and conserved PKC phosphorylation motifs are targets of concanavalin A (ConA)- or PMA/ionomycin-induced PKC activation. To address the role of Gimap4 in T-cell physiology, we completed the genomic organization of the gimap4 locus and generated a Gimap4-null mutant mouse. Studies in these mice revealed no critical role of Gimap4 in T-cell development but in the regulation of apoptosis. We have found that Gimap4 accelerates the execution of programmed cell death induced by intrinsic stimuli downstream of caspase-3 activation and phosphatidylserine exposure. Apoptosis directly correlates with the phosphorylation status of Gimap4.
Gimap4是新发现的免疫相关蛋白家族GTP酶（Gimap）的成员之一，在前体T淋巴细胞中由前T细胞受体强烈诱导表达，在双阳性胸腺细胞中短暂关闭，并在TCR介导的阳性选择后重新出现。在此，我们表明Gimap4在成熟T细胞的细胞质中持续表达。其C末端的IQ结构域在无钙情况下与钙调蛋白结合，保守的蛋白激酶C（PKC）磷酸化基序是伴刀豆球蛋白A（ConA）或佛波酯/离子霉素诱导的PKC激活的靶点。为了研究Gimap4在T细胞生理学中的作用，我们完成了gimap4基因座的基因组结构分析，并制备了Gimap4基因敲除突变小鼠。对这些小鼠的研究表明，Gimap4在T细胞发育中无关键作用，但在细胞凋亡调控中起作用。我们发现，Gimap4加速了由半胱天冬酶-3激活和磷脂酰丝氨酸暴露下游的内在刺激诱导的程序性细胞死亡的执行。细胞凋亡与Gimap4的磷酸化状态直接相关。
