Zhu D, Cardenas M E, Heitman J
Department of Genetics, Howard Hughes Medical Institute, Duke University Medical Center, Durham, North Carolina 27710, USA.
Mol Pharmacol. 1996 Sep;50(3):506-11.
The immunosuppressants cyclosporin A (CsA) and FK506 have been widely used to prevent and treat graft rejection after human organ and tissue transplantations. CsA and FK506 associate with intracellular binding proteins (i.e., CsA with cyclophilin A and FK506 with FKBP12) to form protein/drug complexes that suppress the immune system by preventing activation of T cells in response to antigen presentation. The common target of CsA and FK506 is calcineurin, a Ca2+/calmodulin-regulated, serine/threonine-specific protein phosphatase that regulates the nuclear import of a transcription factor, NF-AT, required for expression of T cell activation genes. In previous studies, we identified calcineurin mutations that block binding by the cyclophilin A/CsA or FKBP12/FK506 complexes and thereby render yeast cells resistant to the antifungal effects of CsA or FK506. In this report, we demonstrate that the corresponding mutations in murine calcineurin render the T cell receptor signal transduction cascade CsA resistant in human Jurkat T cells. Our findings support the recently determined calcineurin X-ray crystal structure, provide evidence that calcineurin is the only CsA-sensitive component limiting signaling from the T cell receptor to the nucleus, and suggest a means to render cells and tissues resistant to the toxic side effects of CsA and FK506.
免疫抑制剂环孢素A（CsA）和FK506已被广泛用于预防和治疗人体器官及组织移植后的移植物排斥反应。CsA和FK506与细胞内结合蛋白（即CsA与亲环蛋白A结合，FK506与FKBP12结合）形成蛋白/药物复合物，通过阻止T细胞在抗原呈递时的激活来抑制免疫系统。CsA和FK506的共同靶点是钙调神经磷酸酶，它是一种受Ca2+/钙调蛋白调节的丝氨酸/苏氨酸特异性蛋白磷酸酶，可调节T细胞激活基因表达所需的转录因子NF-AT的核转运。在先前的研究中，我们鉴定出了钙调神经磷酸酶的突变，这些突变可阻止亲环蛋白A/CsA或FKBP12/FK506复合物的结合，从而使酵母细胞对CsA或FK506的抗真菌作用产生抗性。在本报告中，我们证明小鼠钙调神经磷酸酶中的相应突变使人类Jurkat T细胞中的T细胞受体信号转导级联对CsA产生抗性。我们的研究结果支持了最近确定的钙调神经磷酸酶X射线晶体结构，提供了钙调神经磷酸酶是限制从T细胞受体到细胞核信号传导的唯一对CsA敏感成分的证据，并提出了一种使细胞和组织对CsA和FK506毒性副作用产生抗性的方法。
