Role of the inflammatory protein serine protease inhibitor Kazal in preventing cytolytic granule granzyme A-mediated apoptosis
Role of the inflammatory protein serine protease inhibitor Kazal in preventing cytolytic granule granzyme A-mediated apoptosis
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DOI：
10.1111/j.1365-2567.2011.03498.x
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发表时间：
2011-12-01
期刊：
影响因子：
6.4
通讯作者：
Lu, Xuanyong
中科院分区：
文献类型：
--
作者：
Lu, Felix;Lamontagne, Jason;Lu, Xuanyong
丝氨酸蛋白酶抑制剂卡扎尔（SPIK）是一种炎症蛋白，其水平在许多癌症中升高。然而，这种蛋白在癌症发展中的作用尚不清楚。我们最近发现SPIK抑制丝氨酸蛋白酶依赖的细胞凋亡。在这里，我们报道了抗SPIK抗体可以共同免疫沉淀丝氨酸蛋白酶颗粒酶A (GzmA)，这是一种在免疫监视过程中由细胞毒性T淋巴细胞和自然杀伤细胞分泌的细胞溶解颗粒，并且SPIK抑制GzmA诱导的细胞凋亡。缺失研究表明，SPIK的C3-C4区域对这种抑制至关重要。这些研究表明，SPIK的过表达可能会阻止gzma介导的免疫杀伤，从而建立癌细胞对人体免疫监视系统的耐受性。抑制过表达的SPIK可以恢复这些细胞对GzmA引发的凋亡死亡的易感性。这一发现表明，通过抑制SPIK的过度表达，有可能克服癌细胞对机体免疫监视系统的耐受，恢复gzma介导的免疫杀伤。
Serine protease inhibitor Kazal (SPIK) is an inflammatory protein whose levels are elevated in numerous cancers. However, the role of this protein in cancer development is unknown. We have recently found that SPIK suppresses serine protease-dependent cell apoptosis. Here, we report that anti-SPIK antibodies can co-immmunoprecipitate serine protease granzyme A (GzmA), a cytolytic granule secreted by cytotoxic T lymphocytes and natural killer cells during immune surveillance, and that SPIK suppresses GzmA-induced cell apoptosis. Deletion studies show that the C3-C4 region of SPIK is critical for this suppression. These studies suggest that over-expression of SPIK may prevent GzmA-mediated immune-killing, thereby establishing the tolerance of cancer cells to the body's immune surveillance system. Suppression of over-expressed SPIK can restore the susceptibility of these cells to apoptotic death triggered by GzmA. This finding implies that it is possible to overcome tolerance of cancer cells to the body's immune surveillance system and restore the GzmA-mediated immune-killing by suppressing the over-expression of SPIK.