{"doi":"10.1101/2020.08.29.273516","title":"TLR4 signaling and macrophage inflammatory responses are dampened by GIV/Girdin","abstract":"Abstract Sensing of pathogens by Toll-like receptor 4 (TLR4) induces an inflammatory response; controlled responses confer immunity but uncontrolled responses cause harm. Here we define how a multi-modular scaffold, GIV (a.k.a Girdin) titrates such inflammatory response in macrophages. Upon challenge with either live microbes or microbe-derived lipopolysaccharides (LPS, a ligand for TLR4), macrophages with GIV mount a more tolerant (hypo-reactive) transcriptional response and suppress pro-inflammatory cytokines and signaling pathways (i.e., NFkB and CREB) downstream of TLR4 compared to their GIV-depleted counterparts. Myeloid-specific gene depletion studies confirmed that the presence of GIV ameliorates DSS-induced colitis and sepsis-induced death. The anti-inflammatory actions of GIV are mediated via its C-terminally located TIR-like BB-loop (TILL)-motif which binds the cytoplasmic TIR-modules of TLR4 in a manner that precludes receptor dimerization; the latter is a pre-requisite for pro-inflammatory signaling. Binding of GIV’s TILL motif to other TIR modules inhibits pro-inflammatory signaling via other TLRs, suggesting a convergent paradigm for fine-tuning macrophage inflammatory responses. Significance To ensure immunity, and yet limit pathology, inflammatory responses must be confined within the proverbial ‘ Goldilocks zone’. TLR4 is the prototypical sensor that orchestrates inflammatory responses through a series of well characterized downstream cascades. How TLR4 signals are confined remain incompletely understood. Using trans-scale approaches ranging from disease modeling in live animals, through cell-based interventional studies, to structure-guided biochemical studies that offer an atomic-level resolution, this study unravels the existence of a ‘brake’ within the TLR4 signaling cascade, i.e., GIV; the latter is a prototypical member of an emerging class of scaffold proteins. By showing that GIV uses conserved mechanisms to impact multi-TLR signaling, this work unravels a multi-scale point of convergence of immune signaling of broader impact beyond TLR4.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":122281,"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":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.957,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":552315,"name":"Gajanan D. Katkar","orcid":"0000-0002-9982-8582","position":1,"is_corresponding":false},{"id":563992,"name":"Julian S. Tam","orcid":null,"position":2,"is_corresponding":false},{"id":563927,"name":"Rama F. Pranadinata","orcid":null,"position":3,"is_corresponding":false},{"id":563993,"name":"Yogitha Chareddy","orcid":null,"position":4,"is_corresponding":false},{"id":563994,"name":"Jane Coates","orcid":null,"position":5,"is_corresponding":false},{"id":563995,"name":"Mahitha Shree Amandachar","orcid":null,"position":6,"is_corresponding":false},{"id":552316,"name":"Vanessa Castillo","orcid":"0000-0002-4182-8846","position":7,"is_corresponding":false},{"id":270145,"name":"Joshua Olson","orcid":"0000-0002-1733-0431","position":8,"is_corresponding":false},{"id":225262,"name":"Victor Nizet","orcid":"0000-0003-3847-0422","position":9,"is_corresponding":false},{"id":354098,"name":"Irina Kufareva","orcid":"0000-0001-9083-7039","position":10,"is_corresponding":false},{"id":348404,"name":"Soumita Das","orcid":"0000-0003-3895-3643","position":11,"is_corresponding":false},{"id":294967,"name":"Pradipta Ghosh","orcid":"0000-0002-8917-3201","position":12,"is_corresponding":false},{"id":467348,"name":"Lee Swanson","orcid":"0000-0002-1201-1298","position":0,"is_corresponding":true}],"reference_count":59,"raw_metadata":null,"created_at":"2026-07-18T23:14:51.076430Z","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":[]}