小柯机器人

美国杜克大学医学院Edward A. Miao团队近期取得重要工作进展，他们研究发现了Caspase-7激活ASM修复焦孔素和穿孔素的孔。相关论文2022年6月15日在线发表于《自然》杂志上。

在这里，研究人员发现在类器官和小鼠中都显示Caspase-7缺陷型IEC不能完全挤出。从机制上讲，Caspase-7通过切割和激活酸性鞘磷脂酶（ASM）来抵消焦孔素D的孔并保持细胞完整性，从而产生大量神经酰胺以增强膜修复。这为完成IEC挤压过程提供了时间。同时，他们还发现，在自然杀伤细胞或细胞毒性T淋巴细胞通过穿孔素介导攻击紫杆菌和单核增生李斯特菌后，通常会导致感染的肝细胞凋亡，而Caspase-7和ASM裂解是清除紫杆菌和单核增生李斯特菌所必需的。因此，Caspase-7不是传统的刽子手，而是一种死亡促进剂，可以延迟孔驱动的裂解，以便在细胞死亡之前完成更专业的过程，例如挤出或细胞凋亡。细胞必须在死前安排好自己的事务。

据了解，在导致调节性细胞死亡的Caspase中，Caspase-7的独特功能仍然难以捉摸。Caspase-3执行细胞凋亡，而Caspase-7通常被认为是低效的备份。Caspase-1激活焦孔素D的孔裂解细胞。然而，Caspase-1也会以未知的原因激活Caspase-7。Caspases也可以触发细胞类型特异性死亡反应，例如，Caspase-1使肠道上皮细胞（IECs）在感染沙门氏菌亚种(S. Typhimurium)时被挤出。

附：英文原文

Title: Caspase-7 activates ASM to repair gasdermin and perforin pores

Author: Nozaki, Kengo, Maltez, Vivien I., Rayamajhi, Manira, Tubbs, Alan L., Mitchell, Joseph E., Lacey, Carolyn A., Harvest, Carissa K., Li, Lupeng, Nash, William T., Larson, Heather N., McGlaughon, Benjamin D., Moorman, Nathaniel J., Brown, Michael G., Whitmire, Jason K., Miao, Edward A.

Issue&Volume: 2022-06-15

Abstract: Among the caspases that cause regulated cell death, a unique function for caspase-7 has remained elusive. Caspase-3 performs apoptosis, whereas caspase-7 is typically considered an inefficient back-up. Caspase-1 activates gasdermin D pores to lyse the cell; however, caspase-1 also activates caspase-7 for unknown reasons1. Caspases can also trigger cell-type-specific death responses; for example, caspase-1 causes the extrusion of intestinal epithelial cell (IECs) in response to infection with Salmonella enterica subsp. enterica serovar Typhimurium (S. Typhimurium)2,3. Here we show in both organoids and mice that caspase-7-deficient IECs do not complete extrusion. Mechanistically, caspase-7 counteracts gasdermin D pores and preserves cell integrity by cleaving and activating acid sphingomyelinase (ASM), which thereby generates copious amounts of ceramide to enable enhanced membrane repair. This provides time to complete the process of IEC extrusion. In parallel, we also show that caspase-7 and ASM cleavage are required to clear Chromobacterium violaceum and Listeria monocytogenes after perforin-pore-mediated attack by natural killer cells or cytotoxic T lymphocytes, which normally causes apoptosis in infected hepatocytes. Therefore, caspase-7 is not a conventional executioner but instead is a death facilitator that delays pore-driven lysis so that more-specialized processes, such as extrusion or apoptosis, can be completed before cell death. Cells must put their affairs in order before they die.

DOI: 10.1038/s41586-022-04825-8

Source: https://www.nature.com/articles/s41586-022-04825-8

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html