期刊
PLOS PATHOGENS
卷 10, 期 1, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.ppat.1003879
关键词
-
资金
- long term EMBO Fellowship
- Optimus Foundation
- Canton of Basel
- Swiss National Science Foundation
Following an infectious challenge, macrophages have to be activated in order to allow efficient clearance of infectious pathogens, but how macrophage activation is coupled to increased clearance remains largely unknown. We here describe that inflammatory stimuli induced the reprogramming of the macrophage endocytic machinery from receptor-mediated phagocytosis to macropinocytosis, allowing the rapid transfer of internalized cargo to lysosomes in a receptor-independent manner. Reprogramming occurred through protein kinase C-mediated phosphorylation of the macrophage protein coronin 1, thereby activating phosphoinositol (PI)-3-kinase activity necessary for macropinocytic uptake. Expression of a phosphomimetic form of coronin 1 was sufficient to induce PI3-kinase activation and macropinocytosis even in the absence of inflammatory stimuli. Together these results suggest a hitherto unknown mechanism to regulate the internalization and degradation of infectious material during inflammation. Author Summary The main cells that are involved in cleaning up microbial pathogens are macrophages. Upon an infection, macrophages are being recruited to the site of infection by a number of different stimuli. In addition, during an infection, macrophages are also activated by cytokines such as interferon- and tumor necrosis factor- that is released from other immune cells. Such macrophage activation is important to achieve a rapid and efficient clearance of microbial pathogens. In this study, we found that macrophage activation induces uptake through macropinocytosis rather than receptor-mediate phagocytosis. As a consequence, microbial material as well as particles can be internalized far more efficiently; In addition, the internalized cargo is rapidly destroyed within lysosomes. We also provide the mechanisms for the switch from phagocytosis to macropinocytosis, which turned out to be the cytokine-induced phosphorylation of the host protein coronin 1. Phosphorylated coronin 1 activated the lipid kinase phosphoinositide 3-kinase, which is known to be responsible for the entry of cargo through macropinocytosis. Together these results provide evidence for a hitherto unrecognized mechanisms to regulate the internalization and degradation of infectious material during an infection.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据