Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada.
Front Immunol. 2022 Jul 14;13:944142. doi: 10.3389/fimmu.2022.944142. eCollection 2022.
Phagocytes, such as macrophages and dendritic cells, possess the ability to ingest large quantities of exogenous material into membrane-bound endocytic organelles such as macropinosomes and phagosomes. Typically, the ingested material, which consists of diverse macromolecules such as proteins and nucleic acids, is delivered to lysosomes where it is digested into smaller molecules like amino acids and nucleosides. These smaller molecules can then be exported out of the lysosomes by transmembrane transporters for incorporation into the cell's metabolic pathways or for export from the cell. There are, however, exceptional instances when undigested macromolecules escape degradation and are instead delivered across the membrane of endocytic organelles into the cytosol of the phagocyte. For example, double stranded DNA, a damage associated molecular pattern shed by necrotic tumor cells, is endocytosed by phagocytes in the tumor microenvironment and delivered to the cytosol for detection by the cytosolic "danger" sensor cGAS. Other macromolecular "danger" signals including lipopolysaccharide, intact proteins, and peptidoglycans can also be actively transferred from within endocytic organelles to the cytosol. Despite the obvious biological importance of these processes, we know relatively little of how macromolecular "danger" signals are transferred across endocytic organelle membranes for detection by cytosolic sensors. Here we review the emerging evidence for the active cytosolic transfer of diverse macromolecular "danger" signals across endocytic organelle membranes. We will highlight developing trends and discuss the potential molecular mechanisms driving this emerging phenomenon.
吞噬细胞，如巨噬细胞和树突状细胞，具有将大量外源性物质摄入到膜结合的内吞细胞器中的能力，如巨胞饮体和吞噬体。通常，被摄入的物质由各种大分子组成，如蛋白质和核酸，被递送到溶酶体中，在那里被消化成更小的分子，如氨基酸和核苷。这些小分子可以通过跨膜转运体从溶酶体中输出，用于纳入细胞的代谢途径或从细胞中输出。然而，也有例外情况，即未消化的大分子逃避降解，反而被递送到内吞细胞器的膜内，进入吞噬细胞的细胞质中。例如，双链 DNA，是坏死肿瘤细胞释放的一种损伤相关分子模式，被肿瘤微环境中的吞噬细胞内吞，并递送到细胞质中，由细胞质“危险”传感器 cGAS 检测。其他大分子“危险”信号，包括脂多糖、完整蛋白质和肽聚糖，也可以从内吞细胞器主动转移到细胞质中。尽管这些过程具有明显的生物学重要性，但我们对大分子“危险”信号如何穿过内吞细胞器膜被细胞质传感器检测知之甚少。在这里，我们回顾了关于各种大分子“危险”信号穿过内吞细胞器膜被细胞质传感器主动转移的新证据。我们将强调发展趋势，并讨论推动这一新兴现象的潜在分子机制。
