英国弗朗西斯·克里克研究所Maximiliano G. Gutierrez、Claudio Bussi研究小组近日取得一项新成果。他们发现应激颗粒堵塞并稳定受损的内溶酶体膜。这一研究成果发表在2023年11月15日出版的国际学术期刊《自然》上。

通过将体外和细胞内研究与计算建模相结合，研究人员发现了应激颗粒的生物功能，即这些生物分子凝聚体在内膜损伤部位迅速形成，并充当稳定破裂膜的塞子。在功能上，研究证明了应力颗粒的形成和膜稳定，能够通过ESCRT（运输所需的内膜分选复合物）依赖和非依赖的机制有效修复受损的内溶酶体。研究还证明，阻断人类巨噬细胞中应力颗粒的形成会为结核分枝杆菌创造有利的生存环境，结核分枝杆菌是一种利用内膜损伤在宿主体内生存的人类病原体。

据了解，内膜损伤是一种对真核细胞有害的应激形式。为了应对这种威胁，细胞进化出修复损伤和恢复细胞平衡的机制。内膜损伤也会导致细胞器的不稳定，而细胞稳定受损内膜以实现膜修复的机制仍然未知。

附：英文原文

Title: Stress granules plug and stabilize damaged endolysosomal membranes

Author: Bussi, Claudio, Mangiarotti, Agustn, Vanhille-Campos, Christian, Aylan, Beren, Pellegrino, Enrica, Athanasiadi, Natalia, Fearns, Antony, Rodgers, Angela, Franzmann, Titus M., ari, Anela, Dimova, Rumiana, Gutierrez, Maximiliano G.

Issue&Volume: 2023-11-15

Abstract: Endomembrane damage represents a form of stress that is detrimental for eukaryotic cells1,2. To cope with this threat, cells possess mechanisms that repair the damage and restore cellular homeostasis3,4,5,6,7. Endomembrane damage also results in organelle instability and the mechanisms by which cells stabilize damaged endomembranes to enable membrane repair remains unknown. Here, by combining in vitro and in cellulo studies with computational modelling we uncover a biological function for stress granules whereby these biomolecular condensates form rapidly at endomembrane damage sites and act as a plug that stabilizes the ruptured membrane. Functionally, we demonstrate that stress granule formation and membrane stabilization enable efficient repair of damaged endolysosomes, through both ESCRT (endosomal sorting complex required for transport)-dependent and independent mechanisms. We also show that blocking stress granule formation in human macrophages creates a permissive environment for Mycobacterium tuberculosis, a human pathogen that exploits endomembrane damage to survive within the host.

DOI: 10.1038/s41586-023-06726-w

Source: https://www.nature.com/articles/s41586-023-06726-w