Phenotypic screens for SIRPA expression reveal RAB21 as a general regulator of macrophage surface identity
Bibliographic record
Abstract
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.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".