{"doi":"10.1074/jbc.m115.645986","title":"DAP12 Stabilizes the C-terminal Fragment of the Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) and Protects against LPS-induced Pro-inflammatory Response","abstract":null,"journal":"Journal of Biological Chemistry","year":2015,"id":594588,"datarank":0.7335523692332632,"base_score":4.890349128221754,"endowment":4.890349128221754,"self_citation_contribution":0.7335523692332632,"citation_network_contribution":0.0,"self_endowment_contribution":0.7335523692332632,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":132,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1522166,"name":"Xiao-Fen Chen","orcid":null,"position":1,"is_corresponding":false},{"id":1522167,"name":"Zhen-Lian Zhang","orcid":null,"position":2,"is_corresponding":false},{"id":471199,"name":"Zhe Wang","orcid":"0000-0002-3939-4452","position":3,"is_corresponding":false},{"id":1522169,"name":"Xin-Zhen Shi","orcid":null,"position":4,"is_corresponding":false},{"id":1017730,"name":"Kai Xu","orcid":"0000-0002-5648-605X","position":5,"is_corresponding":false},{"id":1522171,"name":"Yun-Wu Zhang","orcid":null,"position":6,"is_corresponding":false},{"id":241297,"name":"Huaxi Xu","orcid":"0000-0001-7031-7853","position":7,"is_corresponding":false},{"id":230893,"name":"Guojun Bu","orcid":"0000-0003-3491-1016","position":8,"is_corresponding":false},{"id":266518,"name":"Li Zhong","orcid":"0000-0003-3094-4806","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"DAP12 Stabilizes the C-terminal Fragment of the Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) and Protects against LPS-induced Pro-inflammatory Response","abstract":"Triggering receptor expressed on myeloid cells 2 (TREM2) is a DAP12-associated receptor expressed in microglia, macrophages, and other myeloid-derived cells. Previous studies have suggested that TREM2/DAP12 signaling pathway reduces inflammatory responses and promotes phagocytosis of apoptotic neurons. Recently, TREM2 has been identified as a risk gene for Alzheimer disease (AD). Here, we show that DAP12 stabilizes the C-terminal fragment of TREM2 (TREM2-CTF), a substrate for γ-secretase. Co-expression of DAP12 with TREM2 selectively increased the level of TREM2-CTF with little effects on that of full-length TREM2. The interaction between DAP12 and TREM2 is essential for TREM2-CTF stabilization as a mutant form of DAP12 with disrupted interaction with TREM2 failed to exhibit such an effect. Silencing of either Trem2 or Dap12 gene significantly exacerbated pro-inflammatory responses induced by lipopolysaccharides (LPS). Importantly, overexpression of either full-length TREM2 or TREM2-CTF reduced LPS-induced inflammatory responses. Taken together, our results support a role of DAP12 in stabilizing TREM2-CTF, thereby protecting against excessive pro-inflammatory responses. Background: TREM2 is a DAP12-coupled receptor associated with neurodegenerative diseases. Results: Co-expression of DAP12 increased the level of TREM2 C-terminal fragment (TREM2-CTF) which suppressed the release of pro-inflammatory cytokines. Conclusion: A major function of DAP12 is to stabilize TREM2-CTF, which regulates inflammatory responses in microglia. Significance: Our studies unraveled a novel function of DAP12 and provided new link between TREM2/DAP12 complexes and neuroinflammation.","is_dataset_classified":null,"base_score":4.890349128221754,"endowment":4.890349128221754,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"25957402","pmcid":"PMC4505493","openalex_id":"https://openalex.org/W1519122400","authors":[],"funders":[{"funder_name":"National Institutes of Health","grant_id":"R01AG027924","title":null},{"funder_name":"National Institutes of Health","grant_id":"R01AG035355","title":null},{"funder_name":"National Institutes of Health","grant_id":"R01AG046205","title":null},{"funder_name":"National Institutes of Health","grant_id":"81370459","title":null},{"funder_name":"National Institutes of Health","grant_id":"31400914","title":null},{"funder_name":"NIA NIH HHS","grant_id":"RF1 AG046205","title":null},{"funder_name":"NIA NIH HHS","grant_id":"P01 AG030128","title":null},{"funder_name":"NINDS NIH HHS","grant_id":"P01 NS074969","title":null},{"funder_name":"NIA NIH HHS","grant_id":"P50 AG016574","title":null}],"total_grants":9,"fwci":6.842,"citation_percentile":0.97079197,"influential_citations":0,"citation_trend":[{"year":2015,"count":6},{"year":2016,"count":6},{"year":2017,"count":13},{"year":2018,"count":14},{"year":2019,"count":12},{"year":2020,"count":16},{"year":2021,"count":16},{"year":2022,"count":14},{"year":2023,"count":14},{"year":2024,"count":9},{"year":2025,"count":8},{"year":2026,"count":4}],"oa_status":"hybrid","license":"cc-by","oa_locations":[{"url":"http://www.jbc.org/article/S0021925820350791/pdf","host_type":"journal"},{"url":"http://www.jbc.org/article/S0021925820350791/pdf","host_type":"publisher"},{"url":"https://api.elsevier.com/content/article/PII:S0021925820350791?httpAccept=text/xml","host_type":"publisher"},{"url":"https://api.elsevier.com/content/article/PII:S0021925820350791?httpAccept=text/plain","host_type":"publisher"},{"url":"https://syndication.highwire.org/content/doi/10.1074/jbc.M115.645986","host_type":"publisher"},{"url":"https://doi.org/10.1074/jbc.m115.645986","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/25957402","host_type":"repository"},{"url":"https://repository.hkust.edu.hk/ir/Record/1783.1-130595","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/4505493","host_type":"repository"}],"fields_of_study":["Neuroinflammation and Neurodegeneration Mechanisms","Inflammation biomarkers and pathways","Neurological Disease Mechanisms and Treatments","Adaptor Proteins, Signal Transducing","Amyloid Precursor Protein Secretases","Animals","HEK293 Cells","Humans","Inflammation","Lipopolysaccharides","Membrane Glycoproteins","Membrane Proteins","Mice","Mutation","Protein Stability","Protein Structure, Tertiary","Receptors, Immunologic"],"mesh_terms":["Animals","Humans","Inflammation","Lipopolysaccharides","Membrane Glycoproteins","Membrane Proteins","Mutation","Receptors, Immunologic","Protein Structure, Tertiary","Adaptor Proteins, Signal Transducing","Mice","Amyloid Precursor Protein Secretases","Protein Stability","HEK293 Cells"],"keywords":["TREM2","Terminal (telecommunication)","Myeloid cells","Receptor","Myeloid","Cell biology","Chemistry","Inflammatory response","Inflammation","Molecular biology","Biology","Immunology","Biochemistry","Cytokine","Alzheimer disease","Microglia","Lipopolysaccharide (LPS)","Γ-secretase","Dap12","Trem-ctf"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-07-27T14:58:16.341110Z","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":[]}