Sphingomyelin Biosynthesis Is Essential for Phagocytic Signaling during Mycobacterium tuberculosis Host Cell Entry
| Autor: | Hans C. Leier, Fabian Pott, Caroline Barisch, Patrick Niekamp, Fikadu G. Tafesse, Ali Rashidfarrokhi, Veronica Richina, Gaelen Guzman, Joost C. M. Holthuis |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Phagocytic cup
THP-1 Cells Phagocytosis chemical and pharmacologic phenomena GTPase Biology Endocytosis Microbiology Host-Microbe Biology sphingomyelin 03 medical and health sciences Mice 0302 clinical medicine Virology Macrophages Alveolar Animals Humans cell signaling Phagocytic Cell Cells Cultured 030304 developmental biology Phagosome 0303 health sciences sphingolipids phagocytosis Mycobacterium tuberculosis respiratory system bacterial infections and mycoses Sphingolipid QR1-502 Cell biology Biosynthetic Pathways Sphingomyelins RAW 264.7 Cells 030220 oncology & carcinogenesis Host-Pathogen Interactions lipids (amino acids peptides and proteins) Sphingomyelin Signal Transduction Research Article |
| Zdroj: | mBio mBio, Vol 12, Iss 1 (2021) |
| ISSN: | 2150-7511 |
| Popis: | Mycobacterium tuberculosis (Mtb) invades alveolar macrophages through phagocytosis to establish infection and cause disease. The molecular mechanisms underlying Mtb entry are still poorly understood. Phagocytosis by alveolar macrophages is the obligate first step in Mycobacterium tuberculosis (Mtb) infection, yet the mechanism underlying this process is incompletely understood. Here, we show that Mtb invasion relies on an intact sphingolipid biosynthetic pathway. Inhibition or knockout of early sphingolipid biosynthetic enzymes greatly reduces Mtb uptake across multiple phagocytic cell types without affecting other forms of endocytosis. While the phagocytic receptor dectin-1 undergoes normal clustering at the pathogen contact sites, sphingolipid biosynthetic mutant cells fail to segregate the regulatory phosphatase CD45 from the clustered receptors. Blocking sphingolipid production also impairs downstream activation of Rho GTPases, actin dynamics, and phosphoinositide turnover at the nascent phagocytic cup. Moreover, we found that production of sphingomyelin, not glycosphingolipids, is essential for Mtb uptake. Collectively, our data support a critical role of sphingomyelin biosynthesis in an early stage of Mtb infection and provide novel insights into the mechanism underlying phagocytic entry of this pathogen. |
| Databáze: | OpenAIRE |
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