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A genome-wide genetic screen identifies CYRI-B as a negative regulator of CEACAM3-mediated phagocytosis

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2023

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Deutsche Forschungsgemeinschaft (DFG): Ha 2856/10-1
Deutsche Forschungsgemeinschaft (DFG): Ha 2856/11-1

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Journal of Cell Science. The Company of Biologists. 2023, 136(11), jcs260771. ISSN 0021-9533. eISSN 1477-9137. Available under: doi: 10.1242/jcs.260771

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Opsonin-independent phagocytosis mediated by human carcinoembryonic antigen-related cell adhesion molecule 3 (CEACAM3) has evolved to control a subset of human-restricted bacterial pathogens. CEACAM3 engagement triggers rapid GTP-loading of the small GTPase Rac as a master regulator of cytoskeletal rearrangements and lamellipodia-driven internalization. To identify components of the CEACAM3-initiated signaling cascade, we performed a genome-wide CRISPR/Cas9-based screen in human myeloid cells. Following infection with fluorescently labeled bacteria, cells exhibiting elevated phagocytosis (gain-of-function) as well as cells showing reduced phagocytosis (loss-of-function) were sorted and enrichment of individual single-guide RNAs (sgRNAs) was determined by next generation sequencing. Concentrating on genes whose targeting by three distinct sgRNAs consistently resulted in a gain-of-function phenotype, we identified the Rac-GTP-sequestering protein CYRI-B as a negative regulator of CEACAM3-mediated phagocytosis. Clonal HL-60 cell lines with CYRI-B knockout showed enhanced CEACAM3-downstream signaling, such as Rac GTP loading and phosphorylation of PAK kinases, leading to increased phagocytosis of bacteria. Complementation of the CYRI-B knockout cells reverted the knockout phenotype. Our results unravel components of CEACAM3-initiated opsonin-independent phagocytosis on a genome-wide level and highlight CYRI-B as a negative regulator of CEACAM3-initiated signaling in myeloid cells.

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570 Biowissenschaften, Biologie

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CEACAM, GTPase, Rac, Phagocytosis, Pathogenic bacteria

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ISO 690KUIPER, Johannes W. P., Julia KRAUSE, Leon POTGETER, Jonas ADRIAN, Christof R. HAUCK, 2023. A genome-wide genetic screen identifies CYRI-B as a negative regulator of CEACAM3-mediated phagocytosis. In: Journal of Cell Science. The Company of Biologists. 2023, 136(11), jcs260771. ISSN 0021-9533. eISSN 1477-9137. Available under: doi: 10.1242/jcs.260771
BibTex
@article{Kuiper2023genom-68573,
  year={2023},
  doi={10.1242/jcs.260771},
  title={A genome-wide genetic screen identifies CYRI-B as a negative regulator of CEACAM3-mediated phagocytosis},
  number={11},
  volume={136},
  issn={0021-9533},
  journal={Journal of Cell Science},
  author={Kuiper, Johannes W. P. and Krause, Julia and Potgeter, Leon and Adrian, Jonas and Hauck, Christof R.},
  note={Article Number: jcs260771}
}
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