CEDOC, NOVA Medical School|Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, 1169-056, Lisboa, Portugal.
CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Largo Marquês de Pombal, 3004-517, Coimbra, Portugal.
Sci Rep. 2017 Jul 19;7(1):5812. doi: 10.1038/s41598-017-05687-1.
Erythrophagocytosis, the phagocytic removal of damaged red blood cells (RBC), and subsequent phagolysosome biogenesis are important processes in iron/heme metabolism and homeostasis. Phagolysosome biogenesis implies the interaction of nascent phagosomes with endocytic compartments and also autophagy effectors. Here, we report that besides recruitment of microtubule-associated protein-1-light chain 3 (LC3), additional autophagy machinery such as sequestosome 1 (p62) is also acquired by single-membrane phagosomes at very early stages of the phagocytic process and that its acquisition is very important to the outcome of the process. In bone marrow-derived macrophages (BMDM) silenced for p62, RBC degradation is inhibited. P62, is also required for nuclear translocation and activation of the transcription factor Nuclear factor E2-related Factor 2 (NRF2) during erythrophagocytosis. Deletion of the Nrf2 allele reduces p62 expression and compromises RBC degradation. In conclusion, we reveal that erythrophagocytosis relies on an interplay between p62 and NRF2, potentially acting as protective mechanism to maintain reactive oxygen species at basal levels and preserve macrophage homeostasis.
红细胞吞噬作用，即吞噬清除受损的红细胞 (RBC)，以及随后的吞噬溶酶体的生物发生，是铁/血红素代谢和体内平衡的重要过程。吞噬溶酶体的生物发生意味着新生的吞噬体与内吞隔室的相互作用，也涉及自噬效应蛋白。在这里，我们报告说，除了微管相关蛋白 1 轻链 3 (LC3)的募集外，在吞噬过程的非常早期阶段，单一膜吞噬体还获得了其他自噬机制，如自噬相关蛋白 1 (p62)，其获得对于吞噬过程的结果非常重要。在 p62 沉默的骨髓来源的巨噬细胞 (BMDM)中，RBC 的降解受到抑制。在红细胞吞噬过程中，p62 还需要核易位和转录因子核因子 E2 相关因子 2 (NRF2)的激活。NRF2 等位基因的缺失会降低 p62 的表达并损害 RBC 的降解。总之，我们揭示了红细胞吞噬作用依赖于 p62 和 NRF2 之间的相互作用，这可能是一种保护机制，可以将活性氧维持在基础水平并维持巨噬细胞的体内平衡。
