{"doi":"10.1101/2022.07.30.502145","title":"Cell surface receptors TREM2, CD14 and integrin α <sub>M</sub> β <sub>2</sub> drive sinking engulfment in phosphatidylserine-mediated phagocytosis","abstract":"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 α M β 2 - 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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":297066,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":13,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9526,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":830263,"name":"Roarke A. Kamber","orcid":"0000-0001-8462-4782","position":1,"is_corresponding":false},{"id":312516,"name":"Ramon Lorenzo D. Labitigan","orcid":"0000-0002-8676-9931","position":2,"is_corresponding":false},{"id":355157,"name":"Aaron P. van Loon","orcid":"0000-0002-8597-1572","position":3,"is_corresponding":false},{"id":202119,"name":"Eric Peterman","orcid":"0000-0002-7635-6658","position":4,"is_corresponding":false},{"id":488884,"name":"Melissa K. Delgado","orcid":"0000-0001-7480-9206","position":5,"is_corresponding":false},{"id":294441,"name":"Sijie Lin","orcid":"0000-0002-6970-8221","position":6,"is_corresponding":false},{"id":747996,"name":"Jeffrey P. Rasmussen","orcid":"0000-0001-6997-3773","position":7,"is_corresponding":false},{"id":62612,"name":"Michael C. Bassik","orcid":"0000-0001-5185-8427","position":8,"is_corresponding":false},{"id":256098,"name":"Julie A. Theriot","orcid":"0000-0002-2334-2535","position":9,"is_corresponding":false},{"id":256091,"name":"Daan Vorselen","orcid":"0000-0002-7800-4023","position":0,"is_corresponding":true}],"reference_count":69,"raw_metadata":null,"created_at":"2026-07-19T00:31:21.257700Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}