{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTIFA is a central adaptor protein in innate immune signaling that senses bacterial-derived metabolites, notably the lipopolysaccharide (LPS) biosynthetic intermediate heptose-1,7-bisphosphate (HBP). Upon recognition of such pathogen-associated molecular patterns, TIFA undergoes threonine phosphorylation (at Thr9) that triggers its oligomerization via phospho–forkhead-associated (FHA) domain interactions. This oligomerization, in turn, mediates the activation of the IκB kinase (IKK) complex through direct interactions with TRAF6, thereby initiating robust nuclear factor κB (NF-κB) signaling and promoting both innate and adaptive immune responses."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role as a cytosolic signal transducer, TIFA functions in multiple cellular contexts to orchestrate inflammatory responses to pathogenic insults. In gastric epithelial cells infected by Helicobacter pylori, HBP is delivered via the cag type IV secretion system and triggers TIFA-dependent NF-κB activation that precedes other pathogen recognition pathways, while associated signaling also induces DNA damage in replicating cells. In Shigella infections, cytosolic TIFA assembles into higher-order complexes that serve as a rheostat to gauge bacterial replication dynamics. Moreover, in vascular endothelial cells, TIFA is upregulated in response to oxidative and inflammatory stresses where it primes and amplifies NLRP3 inflammasome activation, thereby linking pathogen recognition with cytokine production."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nDysregulation of TIFA-driven signaling has significant implications in disease. In acute myeloid leukemia, for example, Aurora A kinase–mediated phosphorylation of TIFA enhances NF-κB–dependent survival pathways and chemoresistance. Nuclear translocation of TIFA following genotoxic stress further promotes cytokine secretion via TRAF2-mediated ubiquitination of key NF-κB regulators, underlining a link between DNA damage responses and inflammation. Elevated TIFA expression has also been associated with enhanced tumor cell proliferation and migration in lung adenocarcinoma and colorectal cancer, with its effects dependent on intact oligomerization and TRAF6 binding. In nonmalignant diseases, upregulated TIFA contributes to sepsis-induced acute kidney injury via mitochondrial damage and pyroptosis, and increased TIFA levels in circulating immune cells correlate with inflammatory cytokine secretion and hemodynamic impairment in pulmonary arterial hypertension. Structural studies provide further evidence by demonstrating direct, salt-bridge–mediated binding between TIFA and TRAF6, reinforcing its central role as a modulator of TRAF-dependent innate immune responses."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "18"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Chee-Kwee Ea, Lijun Sun, Jun-Ichiro Inoue, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Intermolecular binding between TIFA-FHA and TIFA-pT mediates tumor necrosis factor alpha stimulation and NF-κB activation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.00438-12"}], "href": "https://doi.org/10.1128/MCB.00438-12"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22566686"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22566686"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Ryan G Gaudet, Anna Sintsova, Carolyn M Buckwalter, et al. "}, {"type": "b", "children": [{"type": "t", "text": "INNATE IMMUNITY. Cytosolic detection of the bacterial metabolite HBP activates TIFA-dependent innate immunity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Science (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/science.aaa4921"}], "href": "https://doi.org/10.1126/science.aaa4921"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26068852"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26068852"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Jui-Hung Weng, Yin-Cheng Hsieh, Chia-Chi Flora Huang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Uncovering the Mechanism of Forkhead-Associated Domain-Mediated TIFA Oligomerization That Plays a Central Role in Immune Responses."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochemistry (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1021/acs.biochem.5b00500"}], "href": "https://doi.org/10.1021/acs.biochem.5b00500"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26389808"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26389808"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Ting-Yang Lin, Tong-You Wade Wei, Shuai Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TIFA as a crucial mediator for NLRP3 inflammasome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1618773114"}], "href": "https://doi.org/10.1073/pnas.1618773114"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27965388"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27965388"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Ryan G Gaudet, Cynthia X Guo, Raphael Molinaro, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Innate Recognition of Intracellular Bacterial Growth Is Driven by the TIFA-Dependent Cytosolic Surveillance Pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Rep (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.celrep.2017.04.063"}], "href": "https://doi.org/10.1016/j.celrep.2017.04.063"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28514661"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28514661"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Alevtina Gall, Ryan G Gaudet, Scott D Gray-Owen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TIFA Signaling in Gastric Epithelial Cells Initiates the "}, {"type": "a", "children": [{"type": "t", "text": "i"}], "href": "i"}, {"type": "t", "text": "cag"}, {"type": "a", "children": [{"type": "t", "text": "/i"}], "href": "/i"}, {"type": "t", "text": " Type 4 Secretion System-Dependent Innate Immune Response to "}, {"type": "a", "children": [{"type": "t", "text": "i"}], "href": "i"}, {"type": "t", "text": "Helicobacter pylori"}, {"type": "a", "children": [{"type": "t", "text": "/i"}], "href": "/i"}, {"type": "t", "text": " Infection."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "mBio (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/mBio.01168-17"}], "href": "https://doi.org/10.1128/mBio.01168-17"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28811347"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28811347"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Le Ying, Richard L Ferrero "}, {"type": "b", "children": [{"type": "t", "text": "Role of NOD1 and ALPK1/TIFA Signalling in Innate Immunity Against Helicobacter pylori Infection."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Curr Top Microbiol Immunol (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/978-3-030-15138-6_7"}], "href": "https://doi.org/10.1007/978-3-030-15138-6_7"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31123889"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31123889"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Michael Bauer, Zuzana Nascakova, Anca-Irina Mihai, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The ALPK1/TIFA/NF-κB axis links a bacterial carcinogen to R-loop-induced replication stress."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41467-020-18857-z"}], "href": "https://doi.org/10.1038/s41467-020-18857-z"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33037203"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33037203"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Gunter Maubach, Michelle C C Lim, Olga Sokolova, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TIFA has dual functions in Helicobacter pylori-induced classical and alternative NF-κB pathways."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO Rep (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.15252/embr.202152878"}], "href": "https://doi.org/10.15252/embr.202152878"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34328245"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34328245"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Tong-You Wade Wei, Pei-Yu Wu, Ting-Jung Wu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Aurora A and NF-κB Survival Pathway Drive Chemoresistance in Acute Myeloid Leukemia via the TRAF-Interacting Protein TIFA."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-16-1004"}], "href": "https://doi.org/10.1158/0008-5472.CAN-16-1004"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28069801"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28069801"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Jingxuan Fu, Daoyuan Huang, Fuwen Yuan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TRAF-interacting protein with forkhead-associated domain (TIFA) transduces DNA damage-induced activation of NF-κB."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.RA117.001684"}], "href": "https://doi.org/10.1074/jbc.RA117.001684"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29581234"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29581234"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Wanfu Men, Wenya Li, Jungang Zhao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TIFA Promotes Cell Survival and Migration in Lung Adenocarcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Physiol Biochem (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1159/000491478"}], "href": "https://doi.org/10.1159/000491478"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29975933"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29975933"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Wei-Cheng Huang, Jiahn-Haur Liao, Tzu-Chun Hsiao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Binding and Enhanced Binding between Key Immunity Proteins TRAF6 and TIFA."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Chembiochem (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/cbic.201800436"}], "href": "https://doi.org/10.1002/cbic.201800436"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30378729"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30378729"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Madeline Niederkorn, Puneet Agarwal, Daniel T Starczynowski "}, {"type": "b", "children": [{"type": "t", "text": "TIFA and TIFAB: FHA-domain proteins involved in inflammation, hematopoiesis, and disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Exp Hematol (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.exphem.2020.08.010"}], "href": "https://doi.org/10.1016/j.exphem.2020.08.010"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32910997"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32910997"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Hao-Chih Chang, Tong-You Wade Wei, Pei-Yu Wu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TIFA protein expression is associated with pulmonary arterial hypertension."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41598-021-93582-1"}], "href": "https://doi.org/10.1038/s41598-021-93582-1"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34238983"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34238983"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Wenzhi Shen, Wenfei Du, Yanping Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TIFA promotes colorectal cancer cell proliferation in an RSK- and PRAS40-dependent manner."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Sci (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/cas.15432"}], "href": "https://doi.org/10.1111/cas.15432"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35635239"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35635239"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Yiming Li, Jing Zhang, Pan Zhai, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The potential biomarker TIFA regulates pyroptosis in sepsis-induced acute kidney injury."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int Immunopharmacol (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.intimp.2022.109580"}], "href": "https://doi.org/10.1016/j.intimp.2022.109580"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36586274"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36586274"}]}]}]}