Profiling phagosome proteins identifies PD-L1 as a fungal-binding receptor

Kai Li (), Avradip Chatterjee, Chen Qian, Katherine Lagree, Yang Wang, Courtney A. Becker, Michael R. Freeman, Ramachandran Murali, Wei Yang and David M. Underhill ()
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Kai Li: Cedars-Sinai Medical Center
Avradip Chatterjee: Cedars-Sinai Medical Center
Chen Qian: Cedars-Sinai Medical Center
Katherine Lagree: Cedars-Sinai Medical Center
Yang Wang: Cedars-Sinai Medical Center
Courtney A. Becker: Cedars-Sinai Medical Center
Michael R. Freeman: Cedars-Sinai Medical Center
Ramachandran Murali: Cedars-Sinai Medical Center
Wei Yang: Cedars-Sinai Medical Center
David M. Underhill: Cedars-Sinai Medical Center

Nature, 2024, vol. 630, issue 8017, 736-743

Abstract: Abstract Phagocytosis is the process by which myeloid phagocytes bind to and internalize potentially dangerous microorganisms1. During phagocytosis, innate immune receptors and associated signalling proteins are localized to the maturing phagosome compartment, forming an immune information processing hub brimming with microorganism-sensing features2–8. Here we developed proximity labelling of phagosomal contents (PhagoPL) to identify proteins localizing to phagosomes containing model yeast and bacteria. By comparing the protein composition of phagosomes containing evolutionarily and biochemically distinct microorganisms, we unexpectedly identified programmed death-ligand 1 (PD-L1) as a protein that specifically enriches in phagosomes containing yeast. We found that PD-L1 directly binds to yeast upon processing in phagosomes. By surface display library screening, we identified the ribosomal protein Rpl20b as a fungal protein ligand for PD-L1. Using an auxin-inducible depletion system, we found that detection of Rpl20b by macrophages cross-regulates production of distinct cytokines including interleukin-10 (IL-10) induced by the activation of other innate immune receptors. Thus, this study establishes PhagoPL as a useful approach to quantifying the collection of proteins enriched in phagosomes during host–microorganism interactions, exemplified by identifying PD-L1 as a receptor that binds to fungi.

Date: 2024
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DOI: 10.1038/s41586-024-07499-6

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