加拿大病童医院Spencer A. Freeman研究组发现，溶酶体的压力感应可控制巨噬细胞中的TFEB反应。2024年7月12日，国际知名学术期刊《自然—细胞生物学》在线发表了这一成果。

研究人员表示，聚合物通过内吞作用被吞噬并由溶酶体酶水解生成可运输的溶质。虽然各种有机溶质跨越细胞膜的运输已被广泛研究，但它们从内吞液进入细胞质的持续流出相比之下鲜为人知。使用专门类型的内吞作用（即吞噬作用和大吞噬作用）的髓样细胞高度依赖这种运输途径，以防止因静水压力积聚而影响溶酶体动力学，包括囊泡化、管状化和裂解。

在不发生破裂的情况下，研究人员发现，由于溶质流出缺陷而承受这种压力的溶酶体无法保持腔内Na⁺，从而导致其与细胞质的梯度崩溃。这种阳离子“泄漏”由溶酶体上的压力敏感通道介导，并导致mTORC1的抑制，而mTORC1通常由Na⁺梯度驱动的Na⁺耦合氨基酸转运蛋白激活。因此，在溶酶体膨胀的巨噬细胞中，转录因子TFEB/TFE3被激活。除了在溶酶体生成中的作用外，TFEB/TFE3的激活还导致MCP-1/CCL2的释放。在代谢压力组织中，内吞途径溶质流出缺陷导致单核细胞招募增加。研究人员提出，巨噬细胞通过溶酶体上的压力感应途径响应，以协调溶酶体生成以及髓样细胞的招募。

附：英文原文

Title: Pressure sensing of lysosomes enables control of TFEB responses in macrophages

Author: Cai, Ruiqi, Scott, Ori, Ye, Gang, Le, Trieu, Saran, Ekambir, Kwon, Whijin, Inpanathan, Subothan, Sayed, Blayne A., Botelho, Roberto J., Saric, Amra, Uderhardt, Stefan, Freeman, Spencer A.

Issue&Volume: 2024-07-12

Abstract: Polymers are endocytosed and hydrolysed by lysosomal enzymes to generate transportable solutes. While the transport of diverse organic solutes across the plasma membrane is well studied, their necessary ongoing efflux from the endocytic fluid into the cytosol is poorly appreciated by comparison. Myeloid cells that employ specialized types of endocytosis, that is, phagocytosis and macropinocytosis, are highly dependent on such transport pathways to prevent the build-up of hydrostatic pressure that otherwise offsets lysosomal dynamics including vesiculation, tubulation and fission. Without undergoing rupture, we found that lysosomes incurring this pressure owing to defects in solute efflux, are unable to retain luminal Na+, which collapses its gradient with the cytosol. This cation ‘leak’ is mediated by pressure-sensitive channels resident to lysosomes and leads to the inhibition of mTORC1, which is normally activated by Na+-coupled amino acid transporters driven by the Na+ gradient. As a consequence, the transcription factors TFEB/TFE3 are made active in macrophages with distended lysosomes. In addition to their role in lysosomal biogenesis, TFEB/TFE3 activation causes the release of MCP-1/CCL2. In catabolically stressed tissues, defects in efflux of solutes from the endocytic pathway leads to increased monocyte recruitment. Here we propose that macrophages respond to a pressure-sensing pathway on lysosomes to orchestrate lysosomal biogenesis as well as myeloid cell recruitment.

DOI: 10.1038/s41556-024-01459-y

Source: https://www.nature.com/articles/s41556-024-01459-y