Genentech, Inc., South San Francisco, CA 94080, USA.
Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA.
Science. 2022 Apr 22;376(6591):377-382. doi: 10.1126/science.abl3855. Epub 2022 Apr 21.
Cytotoxic T lymphocytes (CTLs) and natural killer cells kill virus-infected and tumor cells through the polarized release of perforin and granzymes. Perforin is a pore-forming toxin that creates a lesion in the plasma membrane of the target cell through which granzymes enter the cytosol and initiate apoptosis. Endosomal sorting complexes required for transport (ESCRT) proteins are involved in the repair of small membrane wounds. We found that ESCRT proteins were precisely recruited in target cells to sites of CTL engagement immediately after perforin release. Inhibition of ESCRT machinery in cancer-derived cells enhanced their susceptibility to CTL-mediated killing. Thus, repair of perforin pores by ESCRT machinery limits granzyme entry into the cytosol, potentially enabling target cells to resist cytolytic attack.
细胞毒性 T 淋巴细胞 (CTL) 和自然杀伤细胞通过极化释放穿孔素和颗粒酶来杀死病毒感染和肿瘤细胞。穿孔素是一种形成孔的毒素，它在靶细胞膜上形成一个损伤，颗粒酶通过这个损伤进入细胞质并引发细胞凋亡。内体分选复合物所需的运输 (ESCRT) 蛋白参与小膜损伤的修复。我们发现，ESCRT 蛋白在穿孔素释放后立即被精确招募到 CTL 作用的靶细胞部位。在癌细胞中抑制 ESCRT 机制增强了它们对 CTL 介导的杀伤的敏感性。因此，ESCRT 机制修复穿孔素孔限制了颗粒酶进入细胞质，可能使靶细胞能够抵抗细胞溶解攻击。
