Phenotypic screens for SIRPA expression reveal RAB21 as a general regulator of macrophage surface identity
Summary: Factors influencing the macrophage surfaceome define macrophage identity and behavior. Here, we use genome-wide phenotypic screens to identify genes affecting the accessibility and surface expression of macrophage signal regulatory protein alpha (SIRPA). Our data are consistent with previou...
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Elsevier
2025-07-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124725006928 |
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| author | Adrian Granda Farias Brian Feng Shahbaz Khan Wayne Ngo Jamie L.Y. Wu Magali Aguilera-Uribe Shan Grewal Patricia Mero Sheila K. Singh Thomas Kislinger Warren C.W. Chan Jason Moffat |
| author_facet | Adrian Granda Farias Brian Feng Shahbaz Khan Wayne Ngo Jamie L.Y. Wu Magali Aguilera-Uribe Shan Grewal Patricia Mero Sheila K. Singh Thomas Kislinger Warren C.W. Chan Jason Moffat |
| author_sort | Adrian Granda Farias |
| collection | DOAJ |
| description | Summary: Factors influencing the macrophage surfaceome define macrophage identity and behavior. Here, we use genome-wide phenotypic screens to identify genes affecting the accessibility and surface expression of macrophage signal regulatory protein alpha (SIRPA). Our data are consistent with previous evidence but also implicate glutaminyl-peptide cyclotransferase-like (QPCTL) in cis CD47-SIRPA interactions. We also identify endolysosomal factors encoded by Ras-associated binding protein 21 (RAB21) and members of the CCC (COMMD/CCDC22/CCDC93) and Wiskott-Aldrich syndrome protein and SCAR homolog (WASH) complexes as modulators of SIRPA expression. Surface immunophenotyping and surfaceome profiling show that inactivation of either Sirpa or Rab21 remodels cell surface protein expression. In contrast to Sirpa, Rab21 appears to be a general regulator of established macrophage cell surface markers. Perturbation of RAB21/Rab21 reduced Fc gamma receptor (FcγR) expression, leading to decreased uptake of antibody-nanoparticle conjugates and impaired phagocytosis of opsonized cells. To summarize, our study describes circuitry controlling SIRPA expression on macrophages and reveals a conserved RAB21-dependent trafficking pathway that has a role in modeling the cell surface of macrophages. |
| format | Article |
| id | doaj-art-c35bfaf37e1a4cf19e52c8de599bdec6 |
| institution | Kabale University |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-c35bfaf37e1a4cf19e52c8de599bdec62025-08-20T03:32:50ZengElsevierCell Reports2211-12472025-07-0144711592110.1016/j.celrep.2025.115921Phenotypic screens for SIRPA expression reveal RAB21 as a general regulator of macrophage surface identityAdrian Granda Farias0Brian Feng1Shahbaz Khan2Wayne Ngo3Jamie L.Y. Wu4Magali Aguilera-Uribe5Shan Grewal6Patricia Mero7Sheila K. Singh8Thomas Kislinger9Warren C.W. Chan10Jason Moffat11Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, CanadaGenetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, CanadaPrincess Margaret Cancer Centre, University Health Network, Toronto, ON, CanadaInstitute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada; Gladstone Institutes, San Francisco, CA, USA; California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA, USA; Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USAInstitute of Biomedical Engineering, University of Toronto, Toronto, ON, CanadaGenetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, CanadaDepartment of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada; Centre for Discovery in Cancer Research (CDCR), McMaster University, Hamilton, ON, CanadaGenetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, CanadaDepartment of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada; Centre for Discovery in Cancer Research (CDCR), McMaster University, Hamilton, ON, Canada; Department of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, ON, CanadaPrincess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, CanadaInstitute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada; Department of Chemistry, University of Toronto, Toronto, ON, CanadaGenetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada; Corresponding authorSummary: Factors influencing the macrophage surfaceome define macrophage identity and behavior. Here, we use genome-wide phenotypic screens to identify genes affecting the accessibility and surface expression of macrophage signal regulatory protein alpha (SIRPA). Our data are consistent with previous evidence but also implicate glutaminyl-peptide cyclotransferase-like (QPCTL) in cis CD47-SIRPA interactions. We also identify endolysosomal factors encoded by Ras-associated binding protein 21 (RAB21) and members of the CCC (COMMD/CCDC22/CCDC93) and Wiskott-Aldrich syndrome protein and SCAR homolog (WASH) complexes as modulators of SIRPA expression. Surface immunophenotyping and surfaceome profiling show that inactivation of either Sirpa or Rab21 remodels cell surface protein expression. In contrast to Sirpa, Rab21 appears to be a general regulator of established macrophage cell surface markers. Perturbation of RAB21/Rab21 reduced Fc gamma receptor (FcγR) expression, leading to decreased uptake of antibody-nanoparticle conjugates and impaired phagocytosis of opsonized cells. To summarize, our study describes circuitry controlling SIRPA expression on macrophages and reveals a conserved RAB21-dependent trafficking pathway that has a role in modeling the cell surface of macrophages.http://www.sciencedirect.com/science/article/pii/S2211124725006928CP: Immunology |
| spellingShingle | Adrian Granda Farias Brian Feng Shahbaz Khan Wayne Ngo Jamie L.Y. Wu Magali Aguilera-Uribe Shan Grewal Patricia Mero Sheila K. Singh Thomas Kislinger Warren C.W. Chan Jason Moffat Phenotypic screens for SIRPA expression reveal RAB21 as a general regulator of macrophage surface identity Cell Reports CP: Immunology |
| title | Phenotypic screens for SIRPA expression reveal RAB21 as a general regulator of macrophage surface identity |
| title_full | Phenotypic screens for SIRPA expression reveal RAB21 as a general regulator of macrophage surface identity |
| title_fullStr | Phenotypic screens for SIRPA expression reveal RAB21 as a general regulator of macrophage surface identity |
| title_full_unstemmed | Phenotypic screens for SIRPA expression reveal RAB21 as a general regulator of macrophage surface identity |
| title_short | Phenotypic screens for SIRPA expression reveal RAB21 as a general regulator of macrophage surface identity |
| title_sort | phenotypic screens for sirpa expression reveal rab21 as a general regulator of macrophage surface identity |
| topic | CP: Immunology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124725006928 |
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