GRANZYME-A RELEASED UPON STIMULATION OF CYTOTOXIC T-LYMPHOCYTES ACTIVATES THE THROMBIN RECEPTOR ON NEURONAL CELLS AND ASTROCYTES
GRANZYME-A RELEASED UPON STIMULATION OF CYTOTOXIC T-LYMPHOCYTES ACTIVATES THE THROMBIN RECEPTOR ON NEURONAL CELLS AND ASTROCYTES
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DOI：
10.1073/pnas.91.17.8112
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发表时间：
1994-08-16
影响因子：
11.1
通讯作者：
TSCHOPP, J
中科院分区：
文献类型：
--
作者：
SUIDAN, HS;BOUVIER, J;TSCHOPP, J
粒酶是丝氨酸蛋白酶家族，其存在于活化的T淋巴细胞的角质颗粒中，并在靶细胞相互作用时释放。当添加颗粒蛋白的总提取物时，小鼠神经元细胞系中诱导了立即且完全的神经突回缩。该活性被分离并鉴定为颗粒酶A。这种蛋白酶不仅在纳摩尔浓度下诱导神经突收缩，而且还逆转了星形胶质细胞的星座。这两种作用都依赖于颗粒酶A的酯酶活性。由于已知神经突收缩由凝血酶诱导，因此研究了凝血酶受体的可能裂解和活化。一个合成的肽跨越N-末端凝血酶受体激活序列被颗粒酶A在真实的凝血酶裂解位点Leu-Asp-Pro-Arg-Ser裂解。凝血酶受体的抗体抑制凝血酶和颗粒酶A介导的神经突起收缩。因此，T细胞释放的颗粒酶A通过激活凝血酶受体诱导细胞应答。由于脑内浸润的CD 4（+）淋巴细胞是实验性变态反应性脑脊髓炎的效应细胞，脑内释放的颗粒酶A可能参与神经系统自身免疫性疾病的病因。
Granzymes are a family of serine proteases that are harbored in cutoplasmic granules of activated T lymphocytes and are released upon target cell interaction. Immediate and complete neurite retraction was induced in a mouse neuronal cell line when total extracts of granule proteins were added. This activity was isolated and identified as granzyme A. This protease not only induced neurite retraction at nanomolar concentrations but also reversed the stellation of astrocytes. Both effects were critically dependent on the esterolytic activity of granzyme A. As neurite retraction is known to be induced by thrombin, possible cleavage and activation of the thrombin receptor were investigated. A synthetic peptide span ning the N-terminal thrombin receptor activation sequence was cleaved by granzyme A at the authentic thrombin cleavage site Leu-Asp-Pro-Arg-Ser. Antibodies to the thrombin receptor inhibited both thrombin and granzyme A-mediated neurite retraction. Thus, T-cell-released granzyme A induces cellular responses by activation of the thrombin receptor. As brain-infiltrating CD4(+) lymphocytes are the effector cells in experimental allergic encephalomyelitis, granzyme A released in the brain may contribute to the etiology of autoimmune disorders in the nervous system.