Journal
CELL HOST & MICROBE
Volume 26, Issue 4, Pages 551-+Publisher
CELL PRESS
DOI: 10.1016/j.chom.2019.08.017
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Funding
- NIH [1DP2HD084069-01, 2T32CA009302]
- RO1 grant from NIH [AI118974]
- Pew Charitable Trust [A129837]
- HPMI: Host Pathogen Mapping Initiative grant [U19AI135990]
- Hubert Shaw and Sandra Lui Stanford Graduate Fellowship
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During infection, Legionella pneumophila translocates over 300 effector proteins into the host cytosol, allowing the pathogen to establish an endoplasmic reticulum (ER)-like Legionella-containing vacuole (LCV) that supports bacterial replication. Here, we perform a genome-wide CRISPR-Cas9 screen and secondary targeted screens in U937 human monocyte/macrophage-like cells to systematically identify host factors that regulate killing by L. pneumophila. The screens reveal known host factors hijacked by L. pneumophila, as well as genes spanning diverse trafficking and signaling pathways previously not linked to L. pneumophila pathogenesis. We further characterize C1orf43 and KIAA1109 as regulators of phagocytosis and show that RAB10 and its chaperone RABIF are required for optimal L. pneumophila replication and ER recruitment to the LCV. Finally, we show that Rab10 protein is recruited to the LCV and ubiquitinated by the effectors SidC/SdcA. Collectively, our results provide a wealth of previously undescribed insights into L. pneumophila pathogenesis and mammalian cell function.
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