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Cell surface receptors TREM2, CD14 and integrin αMβ2 drive sinking engulfment in phosphatidylserine-mediated phagocytosis

View ORCID ProfileDaan Vorselen, View ORCID ProfileRoarke A. Kamber, View ORCID ProfileRamon Lorenzo D. Labitigan, View ORCID ProfileAaron P. van Loon, View ORCID ProfileEric Peterman, View ORCID ProfileMelissa K. Delgado, Sijie Lin, View ORCID ProfileJeffrey P. Rasmussen, View ORCID ProfileMichael C. Bassik, View ORCID ProfileJulie A. Theriot
doi: https://doi.org/10.1101/2022.07.30.502145
Daan Vorselen
1Department of Biology, University of Washington, Seattle, WA, 98105, USA
2Howard Hughes Medical Institute, University of Washington, Seattle, WA, 98105, USA
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Roarke A. Kamber
3Department of Genetics, Stanford University School of Medicine, Stanford, CA, 94305, USA
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Ramon Lorenzo D. Labitigan
1Department of Biology, University of Washington, Seattle, WA, 98105, USA
2Howard Hughes Medical Institute, University of Washington, Seattle, WA, 98105, USA
4Department of Biochemistry, Stanford University School of Medicine, Stanford, CA, 94305, USA
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Aaron P. van Loon
1Department of Biology, University of Washington, Seattle, WA, 98105, USA
2Howard Hughes Medical Institute, University of Washington, Seattle, WA, 98105, USA
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Eric Peterman
1Department of Biology, University of Washington, Seattle, WA, 98105, USA
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Melissa K. Delgado
1Department of Biology, University of Washington, Seattle, WA, 98105, USA
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Sijie Lin
3Department of Genetics, Stanford University School of Medicine, Stanford, CA, 94305, USA
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Jeffrey P. Rasmussen
1Department of Biology, University of Washington, Seattle, WA, 98105, USA
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Michael C. Bassik
3Department of Genetics, Stanford University School of Medicine, Stanford, CA, 94305, USA
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  • For correspondence: bassik@stanford.edu jtheriot@uw.edu
Julie A. Theriot
1Department of Biology, University of Washington, Seattle, WA, 98105, USA
2Howard Hughes Medical Institute, University of Washington, Seattle, WA, 98105, USA
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  • For correspondence: bassik@stanford.edu jtheriot@uw.edu
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Summary

Macrophages phagocytose and thereby eliminate a wide array of extracellular threats, ranging from antibody-coated bacteria to apoptotic cells. Precision modulation of phagocytosis has emerged as a therapeutic strategy across a range of diseases, but is limited by our incomplete understanding of how macrophages recognize, engulf, and respond to different phagocytic targets. Here, we undertook a systematic investigation of the morphological, biophysical and regulatory differences between two major types of phagocytosis: an immunostimulatory form of phagocytosis triggered by antibody-coated targets and an immunosuppressive form triggered by phosphatidylserine (PS)-coated targets. We confirmed classic observations that antibody-mediated phagocytosis involves the extension of thin actin-rich protrusions around the target, but find that PS-mediated phagocytosis involves an unexpected combination of filopodial probing, piecemeal phagocytosis and a distinct ‘sinking’ mechanism of uptake. Using a genome-wide screening approach, we identified genes specifically required for each form of phagocytosis, including actin regulators, cell surface receptors and intracellular signaling molecules. Three cell surface receptors - TREM2, CD14 and integrin αMβ2 - were revealed as essential for PS-mediated uptake. Strikingly, each receptor exhibited a distinct pattern of localization at the plasma membrane and contributed uniquely to the organization of the PS-dependent phagocytic cup. Overall, this work reveals divergent genetic requirements for the morphologically and mechanically distinct forms of PS-mediated and antibody-mediated phagocytosis, thereby informing therapeutic strategies for substrate-specific phagocytosis modulation.

Competing Interest Statement

M.C.B. and R.A.K. have outside interest in DEM Biopharma.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted July 31, 2022.
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Cell surface receptors TREM2, CD14 and integrin αMβ2 drive sinking engulfment in phosphatidylserine-mediated phagocytosis
Daan Vorselen, Roarke A. Kamber, Ramon Lorenzo D. Labitigan, Aaron P. van Loon, Eric Peterman, Melissa K. Delgado, Sijie Lin, Jeffrey P. Rasmussen, Michael C. Bassik, Julie A. Theriot
bioRxiv 2022.07.30.502145; doi: https://doi.org/10.1101/2022.07.30.502145
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Cell surface receptors TREM2, CD14 and integrin αMβ2 drive sinking engulfment in phosphatidylserine-mediated phagocytosis
Daan Vorselen, Roarke A. Kamber, Ramon Lorenzo D. Labitigan, Aaron P. van Loon, Eric Peterman, Melissa K. Delgado, Sijie Lin, Jeffrey P. Rasmussen, Michael C. Bassik, Julie A. Theriot
bioRxiv 2022.07.30.502145; doi: https://doi.org/10.1101/2022.07.30.502145

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