Perforin activates clathrin- and dynamin-dependent endocytosis, which is required for plasma membrane repair and delivery of granzyme B for granzyme-mediated apoptosis.
Perforin activates clathrin- and dynamin-dependent endocytosis, which is required for plasma membrane repair and delivery of granzyme B for granzyme-mediated apoptosis.
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DOI：
10.1182/blood-2009-10-246116
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发表时间：
2010-02
期刊：
影响因子：
20.3
通讯作者：
J. Thiery;Dennis Keefe;Saviz Saffarian;D. Martinvalet;M. Walch;Emmanuel Boucrot;T. Kirchhausen;J. Lieberman
中科院分区：
文献类型：
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作者：
J. Thiery;Dennis Keefe;Saviz Saffarian;D. Martinvalet;M. Walch;Emmanuel Boucrot;T. Kirchhausen;J. Lieberman
细胞毒性 T 淋巴细胞和自然杀伤细胞通过裂解效应蛋白、穿孔素和颗粒酶的极化胞吐作用进入免疫突触，从而破坏靶细胞。这些分子如何进入靶细胞尚不完全清楚。关于颗粒酶是否通过质膜上形成的穿孔素孔进入，或者穿孔素和颗粒酶是否首先被内吞，然后颗粒酶从内体释放到细胞质中，存在争议。我们之前表明，穿孔素对质膜的破坏会诱导短暂的 Ca(2+) 流入靶细胞，从而触发受伤的膜修复反应，其中溶酶体和内涵体捐赠其膜来重新密封受损的膜。在这里，我们发现穿孔素激活网格蛋白和动力依赖性内吞作用，从而将穿孔素和颗粒酶从质膜去除到早期内体，从而保持外膜的完整性。抑制网格蛋白或动力依赖性内吞作用可将穿孔素和颗粒酶 B 导致的死亡从细胞凋亡转变为坏死。因此，通过激活内吞作用以保持膜的完整性，穿孔素促进颗粒酶的摄取并避免膜受损细胞的促炎性坏死性死亡。
Cytotoxic T lymphocytes and natural killer cells destroy target cells via the polarized exocytosis of lytic effector proteins, perforin and granzymes, into the immunologic synapse. How these molecules enter target cells is not fully understood. It is debated whether granzymes enter via perforin pores formed at the plasma membrane or whether perforin and granzymes are first endocytosed and granzymes are then released from endosomes into the cytoplasm. We previously showed that perforin disruption of the plasma membrane induces a transient Ca(2+) flux into the target cell that triggers a wounded membrane repair response in which lysosomes and endosomes donate their membranes to reseal the damaged membrane. Here we show that perforin activates clathrin- and dynamin-dependent endocytosis, which removes perforin and granzymes from the plasma membrane to early endosomes, preserving outer membrane integrity. Inhibiting clathrin- or dynamin-dependent endocytosis shifts death by perforin and granzyme B from apoptosis to necrosis. Thus by activating endocytosis to preserve membrane integrity, perforin facilitates granzyme uptake and avoids the proinflammatory necrotic death of a membrane-damaged cell.