{"gene":"LITAF","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2006,"finding":"LITAF functions as a transcription factor mediating LPS-induced cytokine (TNF-α, IL-6, sTNF-RII, CXCL16) expression in macrophages. p38α kinase was identified as the specific kinase that phosphorylates LITAF and mediates its nuclear translocation; inhibition of p38α with SB203580 blocked LITAF nuclear translocation and reduced LPS-induced TNF-α. The LITAF pathway is downstream of TLR-2 and TLR-4 (both requiring MyD88) and is distinct from the NF-κB pathway. Macrophage-specific LITAF-knockout mice showed reduced cytokine levels and increased resistance to LPS-induced lethality.","method":"Macrophage-specific knockout mouse, kinase array, p38α inhibitor (SB203580), TLR2/4/9 knockout macrophages, LITAF cDNA rescue transfection, in vivo LPS challenge","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (KO mouse, kinase array, pharmacological inhibition, genetic rescue) in a single study, with clear mechanistic pathway placement","pmids":["16954198"],"is_preprint":false},{"year":2001,"finding":"LITAF/PIG7 and the newly identified SIMPLE protein are small integral membrane proteins of the lysosome/late endosome. Experimental evidence (including detailed analysis of domain structure) showed the protein is neither a RING family member nor a nuclear protein, despite possessing a RING domain signature. The protein is unglycosylated and its expression in monocytes is induced by BCG, LPS, and TNF-α.","method":"Differential display cloning, full-length cDNA cloning, expressed sequence tag search, genome sequence analysis, cell fractionation/localization experiments","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — molecular cloning with functional characterization, localization evidence, but single lab and limited orthogonal functional validation","pmids":["11274176"],"is_preprint":false},{"year":2003,"finding":"Missense mutations G112S, T115N, and W116G in LITAF/SIMPLE cause CMT type 1C (autosomal dominant demyelinating neuropathy). The mutations cluster within a small domain of the LITAF protein, defining a region critical for peripheral nerve function. Western blot showed T115N and W116G mutations do not alter LITAF protein levels.","method":"Positional cloning, candidate gene approach, Western blot, Northern blot, mutation screening in CMT1C pedigrees","journal":"Neurology","confidence":"High","confidence_rationale":"Tier 2 / Strong — replicated across multiple independent CMT1C pedigrees, positional cloning with functional domain implication, confirmed by multiple subsequent studies","pmids":["12525712"],"is_preprint":false},{"year":2011,"finding":"LITAF interacts with the WW-domain-containing ubiquitin ligase Itch via two PPXY motifs in the N-terminus of LITAF. Co-expression of LITAF with Itch relocates Itch from the trans-Golgi network to lysosomes. LITAF itself localizes to the late endosome/lysosomal compartment. Disruption of the PPXY motifs abrogates Itch re-localization.","method":"Co-immunoprecipitation, immunofluorescence, subcellular localization in multiple cell lines, PPXY motif mutagenesis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction demonstrated with mutagenesis validation, single lab but multiple orthogonal methods","pmids":["21326863"],"is_preprint":false},{"year":2011,"finding":"LITAF is a downstream transcriptional target of AMPK. AMPK activation upregulates LITAF transcription, and LITAF binds to a specific sequence in the promoter region of TNFSF15 to regulate its transcription. Silencing LITAF by shRNA enhances proliferation and anchorage-independent growth of prostate cancer cells, suggesting a tumor suppressor function. This establishes an AMPK–LITAF–TNFSF15 regulatory axis.","method":"shRNA knockdown, dominant-negative AMPK mutant, AMPK activator (AICAR), promoter binding assay, xenograft tumor model, in vitro proliferation/anchorage-independent growth assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (shRNA, DN mutant, promoter assay, in vivo xenograft), single lab","pmids":["21217782"],"is_preprint":false},{"year":2013,"finding":"BCL6 directly represses LITAF transcription in B cells. LITAF does not induce LPS-mediated TNF secretion in B cells (negative result in this cellular context). Instead, LITAF regulates autophagy in B-cell lymphomas: ectopic LITAF expression enhances autophagy in response to starvation, while LITAF silencing impairs it. LITAF co-localizes with autophagosomes in B cells.","method":"Chromatin immunoprecipitation (ChIP), luciferase reporter assay, BCL6 silencing, gain- and loss-of-function in B-cell lymphoma lines, gene expression microarrays, immunofluorescence co-localization","journal":"British journal of haematology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assay for direct transcriptional repression, multiple cell-line experiments for autophagy phenotype, single lab","pmids":["23795761"],"is_preprint":false},{"year":2014,"finding":"CMT1C-associated LITAF mutations (A111G, G112S, W116G, T115N) cause mislocalization of LITAF from the late endosome/lysosome to the mitochondria. Mutations T49M, L122V, and P135T show partial mislocalization. CMT1C mutants act in a dominant manner: co-transfection of wild-type LITAF with G112S or T49M mutants relocates wild-type LITAF to the mitochondria. Wild-type LITAF traffics to the late endosome/lysosome via the secretory pathway (blocked by Brefeldin A), whereas LITAF mutants transit to mitochondria independently of the secretory pathway. The C-terminus of LITAF is necessary and sufficient for late endosome/lysosome targeting.","method":"Subcellular localization by immunofluorescence in transfected cells, Brefeldin A treatment, C-terminal truncation constructs, co-transfection of WT and mutant LITAF","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic localization of multiple mutants, dominant behavior demonstrated, secretory pathway dependence tested pharmacologically, single lab","pmids":["25058650"],"is_preprint":false},{"year":2016,"finding":"LITAF is a zinc-binding monotopic membrane protein. In vitro translation shows LITAF integrates poorly into ER-derived microsomes compared with the bona fide tail-anchored protein Sec61β. N-linked glycosylation reporters confirm that neither the N-terminal nor C-terminal domains of LITAF translocate into the ER lumen. Both N- and C-termini face the cytoplasm (immunofluorescence latency assay). Recombinant LITAF contains 1 mol/mol zinc; mutation of predicted zinc-binding residues disrupts LITAF membrane association. The related protein CDIP1 displays identical membrane topology.","method":"In vitro translation/microsome integration assay, glycosylation reporter constructs, immunofluorescence latency assay, zinc content measurement by ICP-MS, zinc-binding residue mutagenesis","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal biochemical methods (in vitro reconstitution, glycosylation reporters, latency assay, metal content measurement, mutagenesis) all converge on same conclusion in one rigorous study","pmids":["27582497"],"is_preprint":false},{"year":2015,"finding":"ERK2 is the kinase upstream of LITAF that controls LPS-induced TNF-α expression. Kavain reduces LPS-induced TNF-α by dephosphorylating ERK2, which in turn prevents LITAF nuclear translocation. LITAF nuclear translocation depends on ERK2 Serine 206 residue. This effect was abrogated in both LITAF-/- and ERK2-/- macrophages.","method":"LITAF-knockout and ERK2-knockout primary macrophages, ERK2 gene re-introduction (rescue), site-directed analysis of ERK2 S206, in vivo CAIA arthritis model","journal":"Toxicology research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO validation with rescue, specific residue identified, in vivo confirmation; single lab","pmids":["26918116"],"is_preprint":false},{"year":2011,"finding":"LITAF mediates increased TNF-α secretion from lamina propria macrophages during colonic inflammation. Macrophage-specific LITAF knockout mice show reduced MPO activity and reduced colonic TNF-α mRNA following TNBS-induced colitis, and LITAF-deficient LPM secrete significantly less TNF-α in response to LPS.","method":"TNBS colitis mouse model, macrophage-specific LITAF knockout mice, LPM isolation, ex vivo TNF-α secretion assay, MPO activity assay, LITAF mRNA/protein measurement","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — specific genetic KO model with defined in vivo and ex vivo phenotype, single lab","pmids":["21984950"],"is_preprint":false},{"year":2020,"finding":"LITAF functions as a host cell-surface or membrane receptor for the Bacillus cereus pore-forming toxin hemolysin BL (HBL). LITAF-deficient cells identified by genome-wide CRISPR-Cas9 knockout screen are resistant to HBL. A second CRISPR screen in LITAF-deficient cells identified CDIP1 as an alternative HBL receptor. LITAF-deficient mice exhibit marked resistance to lethal HBL challenges in vivo.","method":"Genome-wide CRISPR-Cas9 knockout screen (two sequential screens), LITAF-deficient cell lines, LITAF-deficient mouse generation, in vivo HBL lethality challenge","journal":"Cell host & microbe","confidence":"High","confidence_rationale":"Tier 2 / Strong — unbiased genome-wide screen validated with KO cells and KO mice in vivo, iterative screens provide strong convergent evidence","pmids":["32544461"],"is_preprint":false},{"year":2018,"finding":"LITAF is a direct target of miR-106a (validated by 3'UTR luciferase assay and western blotting). LITAF knockdown phenocopies miR-106a overexpression in conferring radioresistance. LITAF mediates upregulation of ATM expression, providing a novel mechanistic link between LITAF and the DNA damage response in prostate cancer cells.","method":"3'UTR luciferase reporter assay, western blotting, miR-106a overexpression and knockdown of LITAF, radiation resistance assays, transcriptomic analysis","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter confirms direct miRNA targeting, phenocopy experiment places LITAF in ATM regulation, single lab with multiple methods","pmids":["29845714"],"is_preprint":false},{"year":2014,"finding":"The LITAF I92V sequence variant partially mislocalizes to the mitochondria (compared to wild-type LITAF which localizes to late endosome/lysosomes) and is associated with a tendency for PMP22 to accumulate in cells. This variant predisposes CMT1A/HNPP patients to an earlier age of disease onset.","method":"Cell transfection with LITAF I92V construct, immunofluorescence-based subcellular localization, PMP22 accumulation assay, clinical cohort analysis","journal":"Neurogenetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — localization demonstrated experimentally with functional consequence (PMP22 accumulation), clinical cohort supports relevance; single lab","pmids":["25342198"],"is_preprint":false},{"year":2004,"finding":"LITAF/SIMPLE mutations (G112S, W116G, and others) are found exclusively in CMT1 (demyelinating) patients. SIMPLE protein is expressed in Schwann cells, the affected cell type in CMT1C. Clustering of mutations G112S, T115N, W116G within five amino acids identifies a critical domain for peripheral nerve myelination.","method":"Mutation screening of 152 neuropathy probands, haplotype analysis, electrophysiological studies, immunohistochemistry of sciatic nerve sections","journal":"Annals of neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — large cohort mutation analysis with Schwann cell expression demonstrated by direct immunostaining; replicates Street et al. 2003 findings","pmids":["15122712"],"is_preprint":false},{"year":2019,"finding":"LITAF enhances radiosensitivity of glioma cells via the FoxO1 pathway and its downstream targets BIM, TRAIL, and FASLG. Knockdown or overexpression of LITAF did not affect proliferation or apoptosis under basal conditions, but modulated radiation response through FoxO1.","method":"LITAF knockdown and overexpression in glioma cell lines, radiation assays, FoxO1 pathway analysis, apoptosis assays","journal":"Cellular and molecular neurobiology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single cell-line system, pathway placement is functional but without direct biochemical interaction evidence between LITAF and FoxO1","pmids":["31098771"],"is_preprint":false}],"current_model":"LITAF (also known as SIMPLE/PIG7) is a zinc-binding monotopic integral membrane protein that localizes to the late endosome/lysosome via its C-terminal LITAF domain; it functions as a transcription factor downstream of TLR/MyD88/p38α (and ERK2) signaling to drive TNF-α and other inflammatory cytokine expression in macrophages, interacts with the ubiquitin ligase Itch via PPXY motifs to regulate its endolysosomal trafficking, participates in multivesicular body sorting and autophagy, acts downstream of AMPK to regulate TNFSF15 transcription and suppress tumor growth, and serves as a plasma membrane receptor for the bacterial pore-forming toxin hemolysin BL; CMT1C-causing mutations in its conserved C-terminal domain mislocalize the protein from lysosomes to mitochondria, disrupting Schwann cell function and causing demyelinating neuropathy."},"narrative":{"mechanistic_narrative":"LITAF (also SIMPLE/PIG7) is a zinc-binding monotopic membrane protein that integrates innate-immune and trafficking functions at the endolysosomal system [PMID:27582497]. Biochemically, it associates with membranes through a single hydrophobic region without translocating either terminus into the ER lumen, both N- and C-termini facing the cytoplasm, and binds one mole of zinc whose coordinating residues are required for membrane association [PMID:27582497]. Its conserved C-terminal LITAF domain is necessary and sufficient to target the protein to the late endosome/lysosome via the secretory pathway [PMID:25058650]. In macrophages, LITAF acts as an inflammatory effector downstream of TLR2/TLR4–MyD88 signaling, where it is phosphorylated by p38α (and controlled by ERK2) to drive nuclear translocation and expression of TNF-α and other cytokines, distinct from the NF-κB pathway; loss of LITAF reduces cytokine output and protects against LPS lethality and TNBS colitis [PMID:16954198, PMID:26918116, PMID:21984950]. LITAF also operates as a transcriptional node in other contexts, acting downstream of AMPK to bind the TNFSF15 promoter and restrain tumor growth, and being repressed by BCL6 in B cells where it instead supports starvation-induced autophagy [PMID:21217782, PMID:23795761]. Through two N-terminal PPXY motifs it binds the ubiquitin ligase Itch and redirects it from the trans-Golgi network to lysosomes, linking LITAF to endolysosomal ubiquitin-dependent trafficking [PMID:21326863]. Independently, LITAF serves as a host cell-surface receptor for the Bacillus cereus pore-forming toxin hemolysin BL, with CDIP1 acting as an alternative receptor [PMID:32544461]. Missense mutations clustered in a five-residue stretch of the C-terminal domain (e.g. G112S, T115N, W116G) cause autosomal-dominant demyelinating Charcot-Marie-Tooth disease type 1C by mislocalizing the protein from lysosomes to mitochondria, dominantly redirecting wild-type LITAF and disrupting Schwann-cell function [PMID:12525712, PMID:25058650, PMID:15122712].","teleology":[{"year":2001,"claim":"Established the basic identity of LITAF/SIMPLE as a small, unglycosylated integral membrane protein of the late endosome/lysosome rather than a RING-type or nuclear protein, correcting the initial sequence-based assumption.","evidence":"cDNA cloning, genome analysis, and cell-fractionation/localization experiments in monocytes","pmids":["11274176"],"confidence":"Medium","gaps":["Membrane topology and metal-binding not resolved","No defined molecular activity assigned"]},{"year":2003,"claim":"Demonstrated that LITAF mutations cause human disease by mapping CMT1C to a tight cluster of missense mutations in the C-terminal domain, defining a region critical for peripheral nerve function.","evidence":"Positional/candidate cloning and mutation screening in CMT1C pedigrees with Western/Northern blots","pmids":["12525712"],"confidence":"High","gaps":["Cellular mechanism by which mutations impair myelination unknown","No demonstration of where mutant protein mislocalizes"]},{"year":2004,"claim":"Tied the genetic disease to the affected cell type by showing SIMPLE/LITAF is expressed in Schwann cells and that demyelinating mutations cluster in a five-residue domain.","evidence":"Large-cohort mutation screening, haplotype/electrophysiology, sciatic nerve immunohistochemistry","pmids":["15122712"],"confidence":"Medium","gaps":["Molecular consequence of mutations still undefined","Schwann-cell function of wild-type LITAF unknown"]},{"year":2006,"claim":"Placed LITAF in a specific innate-immune signaling pathway, showing it acts as a transcription factor downstream of TLR/MyD88 and is phosphorylated by p38α to translocate to the nucleus and drive cytokine expression, separate from NF-κB.","evidence":"Macrophage-specific knockout mice, kinase array, p38α inhibition, TLR-knockout macrophages, cDNA rescue, in vivo LPS challenge","pmids":["16954198"],"confidence":"High","gaps":["How a membrane-anchored protein reaches the nucleus mechanistically unresolved","Direct DNA target sites in cytokine genes not defined here"]},{"year":2011,"claim":"Connected LITAF to ubiquitin-dependent trafficking by identifying a PPXY-mediated interaction with the ligase Itch and showing LITAF recruits Itch from the TGN to lysosomes.","evidence":"Reciprocal co-immunoprecipitation, immunofluorescence, and PPXY motif mutagenesis in multiple cell lines","pmids":["21326863"],"confidence":"Medium","gaps":["Functional consequence of Itch relocalization (substrates) not defined","Single lab, no in vivo validation"]},{"year":2011,"claim":"Defined an AMPK–LITAF–TNFSF15 transcriptional axis and a tumor-suppressor role, showing LITAF is induced by AMPK and binds the TNFSF15 promoter to limit cancer-cell growth.","evidence":"shRNA knockdown, dominant-negative AMPK, AICAR, promoter binding assay, prostate xenograft and growth assays","pmids":["21217782"],"confidence":"Medium","gaps":["How a lysosomal membrane protein engages a promoter not reconciled","Single lab"]},{"year":2011,"claim":"Extended the macrophage TNF-α role to intestinal disease, showing LITAF drives lamina propria macrophage TNF-α secretion during colitis.","evidence":"TNBS colitis model with macrophage-specific LITAF knockout mice, ex vivo LPM TNF-α secretion and MPO assays","pmids":["21984950"],"confidence":"Medium","gaps":["Upstream sensing in this tissue not dissected","Single lab"]},{"year":2013,"claim":"Revealed context-dependent regulation and a distinct cellular function, showing BCL6 represses LITAF in B cells where LITAF promotes autophagy rather than TNF secretion.","evidence":"ChIP, luciferase reporter, BCL6 silencing, gain/loss-of-function in B-cell lymphoma lines, autophagosome co-localization","pmids":["23795761"],"confidence":"Medium","gaps":["Molecular basis of autophagy regulation by LITAF unknown","Why TNF induction is absent in B cells unexplained"]},{"year":2014,"claim":"Provided the cell-biological mechanism of CMT1C by showing disease mutations mislocalize LITAF from lysosomes to mitochondria, that the C-terminus is necessary and sufficient for lysosomal targeting, and that mutants dominantly redirect wild-type protein.","evidence":"Immunofluorescence localization of multiple mutants, Brefeldin A secretory-pathway block, C-terminal truncations, WT/mutant co-transfection","pmids":["25058650"],"confidence":"Medium","gaps":["How mitochondrial mislocalization damages Schwann cells unresolved","Single lab, transfected-cell system"]},{"year":2014,"claim":"Linked a LITAF variant to a trafficking phenotype relevant to peripheral neuropathy, showing I92V partially mislocalizes to mitochondria and promotes PMP22 accumulation.","evidence":"Transfection/immunofluorescence of I92V, PMP22 accumulation assay, clinical cohort analysis","pmids":["25342198"],"confidence":"Medium","gaps":["Mechanism linking LITAF mislocalization to PMP22 handling unclear","Single lab"]},{"year":2015,"claim":"Refined the macrophage signaling module by identifying ERK2 (via Ser206) as an upstream kinase controlling LITAF nuclear translocation and LPS-induced TNF-α.","evidence":"LITAF-/- and ERK2-/- macrophages with ERK2 rescue, ERK2 S206 analysis, in vivo CAIA arthritis model","pmids":["26918116"],"confidence":"Medium","gaps":["Relationship between ERK2 and p38α inputs not integrated","Direct phosphosite on LITAF not mapped"]},{"year":2016,"claim":"Resolved the long-standing topology and metal-binding questions, establishing LITAF as a zinc-binding monotopic membrane protein with both termini cytoplasmic, sharing topology with CDIP1.","evidence":"In vitro translation/microsome integration, glycosylation reporters, immunofluorescence latency assay, ICP-MS zinc measurement, zinc-residue mutagenesis","pmids":["27582497"],"confidence":"High","gaps":["Functional role of zinc binding beyond membrane association unknown","How cytoplasmic-facing topology permits nuclear/transcriptional roles unexplained"]},{"year":2018,"claim":"Placed LITAF in DNA-damage signaling, showing it is a direct miR-106a target and mediates ATM upregulation and radiosensitivity in prostate cancer cells.","evidence":"3'UTR luciferase assay, western blotting, miR-106a/LITAF perturbation, radiation resistance and transcriptomic analysis","pmids":["29845714"],"confidence":"Medium","gaps":["Mechanistic link between LITAF and ATM not biochemically defined","Single lab"]},{"year":2019,"claim":"Proposed an additional radiosensitization function in glioma via the FoxO1 pathway and apoptotic effectors.","evidence":"LITAF knockdown/overexpression in glioma lines, radiation and apoptosis assays, FoxO1 pathway analysis","pmids":["31098771"],"confidence":"Low","gaps":["No direct biochemical interaction between LITAF and FoxO1 shown","Single cell-line system, single lab"]},{"year":2020,"claim":"Identified a wholly distinct function as a toxin receptor, showing LITAF (and alternatively CDIP1) is the host membrane receptor for Bacillus cereus hemolysin BL, with LITAF-deficient cells and mice resistant to the toxin.","evidence":"Two sequential genome-wide CRISPR-Cas9 knockout screens, LITAF-deficient cells and mice, in vivo HBL lethality challenge","pmids":["32544461"],"confidence":"High","gaps":["Direct toxin-LITAF binding interface not defined","Relationship between receptor role and endolysosomal/transcriptional functions unknown"]},{"year":null,"claim":"It remains unresolved how a zinc-binding, cytoplasmic-facing monotopic endolysosomal membrane protein executes its reported nuclear transcription-factor activities, and how its trafficking, immune, autophagy, and toxin-receptor roles are mechanistically unified.","evidence":"No timeline study reconciles the membrane topology with the nuclear/transcriptional and receptor functions","pmids":[],"confidence":"Low","gaps":["No structure of LITAF or its complexes","No mechanism for membrane-to-nucleus relocation","No unified model linking the functional contexts"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,4]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[4]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[10]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[7]}],"localization":[{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[1,3,6]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[1,3,6]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[6,12]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[10]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,8]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,8,9]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,4,5]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[5]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,6,10]}],"complexes":[],"partners":["ITCH","CDIP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q99732","full_name":"Lipopolysaccharide-induced tumor necrosis factor-alpha factor","aliases":["Small integral membrane protein of lysosome/late endosome","p53-induced gene 7 protein"],"length_aa":161,"mass_kda":17.1,"function":"Plays a role in endosomal protein trafficking and in targeting proteins for lysosomal degradation (PubMed:23166352). Plays a role in targeting endocytosed EGFR and ERGG3 for lysosomal degradation, and thereby helps down-regulate downstream signaling cascades (PubMed:23166352). Helps recruit the ESCRT complex components TSG101, HGS and STAM to cytoplasmic membranes (PubMed:23166352). Probably plays a role in regulating protein degradation via its interaction with NEDD4 (PubMed:15776429). May also contribute to the regulation of gene expression in the nucleus (PubMed:10200294, PubMed:15793005). Binds DNA (in vitro) and may play a synergistic role with STAT6 in the nucleus in regulating the expression of various cytokines (PubMed:15793005). May regulate the expression of numerous cytokines, such as TNF, CCL2, CCL5, CXCL1, IL1A and IL10 (PubMed:10200294, PubMed:15793005)","subcellular_location":"Cytoplasm; Nucleus; Lysosome membrane; Early endosome membrane; Late endosome membrane; Endosome membrane; Cell membrane; Golgi apparatus membrane","url":"https://www.uniprot.org/uniprotkb/Q99732/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LITAF","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/LITAF","total_profiled":1310},"omim":[{"mim_id":"607678","title":"CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, TYPE 1D; CMT1D","url":"https://www.omim.org/entry/607678"},{"mim_id":"603795","title":"LIPOPOLYSACCHARIDE-INDUCED TUMOR NECROSIS FACTOR; LITAF","url":"https://www.omim.org/entry/603795"},{"mim_id":"601098","title":"CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, TYPE 1C; CMT1C","url":"https://www.omim.org/entry/601098"},{"mim_id":"601097","title":"PERIPHERAL MYELIN PROTEIN 22; PMP22","url":"https://www.omim.org/entry/601097"},{"mim_id":"129010","title":"EARLY GROWTH RESPONSE 2; EGR2","url":"https://www.omim.org/entry/129010"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nuclear speckles","reliability":"Additional"},{"location":"Golgi apparatus","reliability":"Additional"},{"location":"Vesicles","reliability":"Additional"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/LITAF"},"hgnc":{"alias_symbol":["PIG7","SIMPLE","FLJ38636","TP53I7"],"prev_symbol":[]},"alphafold":{"accession":"Q99732","domains":[{"cath_id":"-","chopping":"110-150_157-161","consensus_level":"medium","plddt":84.2322,"start":110,"end":161}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99732","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q99732-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q99732-F1-predicted_aligned_error_v6.png","plddt_mean":69.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LITAF","jax_strain_url":"https://www.jax.org/strain/search?query=LITAF"},"sequence":{"accession":"Q99732","fasta_url":"https://rest.uniprot.org/uniprotkb/Q99732.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q99732/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99732"}},"corpus_meta":[{"pmid":"1691208","id":"PMC_1691208","title":"Rapid and simple method for purification of nucleic acids.","date":"1990","source":"Journal of clinical microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/1691208","citation_count":3873,"is_preprint":false},{"pmid":"16921404","id":"PMC_16921404","title":"Notch signalling: a simple pathway becomes complex.","date":"2006","source":"Nature reviews. 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a family with a demyelinating form of Charcot-Marie-Tooth disease.","date":"2014","source":"Journal of the neurological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/24880540","citation_count":17,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":38476,"output_tokens":4287,"usd":0.089867,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12290,"output_tokens":4964,"usd":0.092775,"stage2_stop_reason":"end_turn"},"total_usd":0.182642,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"LITAF functions as a transcription factor mediating LPS-induced cytokine (TNF-α, IL-6, sTNF-RII, CXCL16) expression in macrophages. p38α kinase was identified as the specific kinase that phosphorylates LITAF and mediates its nuclear translocation; inhibition of p38α with SB203580 blocked LITAF nuclear translocation and reduced LPS-induced TNF-α. The LITAF pathway is downstream of TLR-2 and TLR-4 (both requiring MyD88) and is distinct from the NF-κB pathway. Macrophage-specific LITAF-knockout mice showed reduced cytokine levels and increased resistance to LPS-induced lethality.\",\n      \"method\": \"Macrophage-specific knockout mouse, kinase array, p38α inhibitor (SB203580), TLR2/4/9 knockout macrophages, LITAF cDNA rescue transfection, in vivo LPS challenge\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (KO mouse, kinase array, pharmacological inhibition, genetic rescue) in a single study, with clear mechanistic pathway placement\",\n      \"pmids\": [\"16954198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"LITAF/PIG7 and the newly identified SIMPLE protein are small integral membrane proteins of the lysosome/late endosome. Experimental evidence (including detailed analysis of domain structure) showed the protein is neither a RING family member nor a nuclear protein, despite possessing a RING domain signature. The protein is unglycosylated and its expression in monocytes is induced by BCG, LPS, and TNF-α.\",\n      \"method\": \"Differential display cloning, full-length cDNA cloning, expressed sequence tag search, genome sequence analysis, cell fractionation/localization experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — molecular cloning with functional characterization, localization evidence, but single lab and limited orthogonal functional validation\",\n      \"pmids\": [\"11274176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Missense mutations G112S, T115N, and W116G in LITAF/SIMPLE cause CMT type 1C (autosomal dominant demyelinating neuropathy). The mutations cluster within a small domain of the LITAF protein, defining a region critical for peripheral nerve function. Western blot showed T115N and W116G mutations do not alter LITAF protein levels.\",\n      \"method\": \"Positional cloning, candidate gene approach, Western blot, Northern blot, mutation screening in CMT1C pedigrees\",\n      \"journal\": \"Neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — replicated across multiple independent CMT1C pedigrees, positional cloning with functional domain implication, confirmed by multiple subsequent studies\",\n      \"pmids\": [\"12525712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"LITAF interacts with the WW-domain-containing ubiquitin ligase Itch via two PPXY motifs in the N-terminus of LITAF. Co-expression of LITAF with Itch relocates Itch from the trans-Golgi network to lysosomes. LITAF itself localizes to the late endosome/lysosomal compartment. Disruption of the PPXY motifs abrogates Itch re-localization.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, subcellular localization in multiple cell lines, PPXY motif mutagenesis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction demonstrated with mutagenesis validation, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"21326863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"LITAF is a downstream transcriptional target of AMPK. AMPK activation upregulates LITAF transcription, and LITAF binds to a specific sequence in the promoter region of TNFSF15 to regulate its transcription. Silencing LITAF by shRNA enhances proliferation and anchorage-independent growth of prostate cancer cells, suggesting a tumor suppressor function. This establishes an AMPK–LITAF–TNFSF15 regulatory axis.\",\n      \"method\": \"shRNA knockdown, dominant-negative AMPK mutant, AMPK activator (AICAR), promoter binding assay, xenograft tumor model, in vitro proliferation/anchorage-independent growth assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (shRNA, DN mutant, promoter assay, in vivo xenograft), single lab\",\n      \"pmids\": [\"21217782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"BCL6 directly represses LITAF transcription in B cells. LITAF does not induce LPS-mediated TNF secretion in B cells (negative result in this cellular context). Instead, LITAF regulates autophagy in B-cell lymphomas: ectopic LITAF expression enhances autophagy in response to starvation, while LITAF silencing impairs it. LITAF co-localizes with autophagosomes in B cells.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), luciferase reporter assay, BCL6 silencing, gain- and loss-of-function in B-cell lymphoma lines, gene expression microarrays, immunofluorescence co-localization\",\n      \"journal\": \"British journal of haematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assay for direct transcriptional repression, multiple cell-line experiments for autophagy phenotype, single lab\",\n      \"pmids\": [\"23795761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CMT1C-associated LITAF mutations (A111G, G112S, W116G, T115N) cause mislocalization of LITAF from the late endosome/lysosome to the mitochondria. Mutations T49M, L122V, and P135T show partial mislocalization. CMT1C mutants act in a dominant manner: co-transfection of wild-type LITAF with G112S or T49M mutants relocates wild-type LITAF to the mitochondria. Wild-type LITAF traffics to the late endosome/lysosome via the secretory pathway (blocked by Brefeldin A), whereas LITAF mutants transit to mitochondria independently of the secretory pathway. The C-terminus of LITAF is necessary and sufficient for late endosome/lysosome targeting.\",\n      \"method\": \"Subcellular localization by immunofluorescence in transfected cells, Brefeldin A treatment, C-terminal truncation constructs, co-transfection of WT and mutant LITAF\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic localization of multiple mutants, dominant behavior demonstrated, secretory pathway dependence tested pharmacologically, single lab\",\n      \"pmids\": [\"25058650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"LITAF is a zinc-binding monotopic membrane protein. In vitro translation shows LITAF integrates poorly into ER-derived microsomes compared with the bona fide tail-anchored protein Sec61β. N-linked glycosylation reporters confirm that neither the N-terminal nor C-terminal domains of LITAF translocate into the ER lumen. Both N- and C-termini face the cytoplasm (immunofluorescence latency assay). Recombinant LITAF contains 1 mol/mol zinc; mutation of predicted zinc-binding residues disrupts LITAF membrane association. The related protein CDIP1 displays identical membrane topology.\",\n      \"method\": \"In vitro translation/microsome integration assay, glycosylation reporter constructs, immunofluorescence latency assay, zinc content measurement by ICP-MS, zinc-binding residue mutagenesis\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal biochemical methods (in vitro reconstitution, glycosylation reporters, latency assay, metal content measurement, mutagenesis) all converge on same conclusion in one rigorous study\",\n      \"pmids\": [\"27582497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ERK2 is the kinase upstream of LITAF that controls LPS-induced TNF-α expression. Kavain reduces LPS-induced TNF-α by dephosphorylating ERK2, which in turn prevents LITAF nuclear translocation. LITAF nuclear translocation depends on ERK2 Serine 206 residue. This effect was abrogated in both LITAF-/- and ERK2-/- macrophages.\",\n      \"method\": \"LITAF-knockout and ERK2-knockout primary macrophages, ERK2 gene re-introduction (rescue), site-directed analysis of ERK2 S206, in vivo CAIA arthritis model\",\n      \"journal\": \"Toxicology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO validation with rescue, specific residue identified, in vivo confirmation; single lab\",\n      \"pmids\": [\"26918116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"LITAF mediates increased TNF-α secretion from lamina propria macrophages during colonic inflammation. Macrophage-specific LITAF knockout mice show reduced MPO activity and reduced colonic TNF-α mRNA following TNBS-induced colitis, and LITAF-deficient LPM secrete significantly less TNF-α in response to LPS.\",\n      \"method\": \"TNBS colitis mouse model, macrophage-specific LITAF knockout mice, LPM isolation, ex vivo TNF-α secretion assay, MPO activity assay, LITAF mRNA/protein measurement\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — specific genetic KO model with defined in vivo and ex vivo phenotype, single lab\",\n      \"pmids\": [\"21984950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LITAF functions as a host cell-surface or membrane receptor for the Bacillus cereus pore-forming toxin hemolysin BL (HBL). LITAF-deficient cells identified by genome-wide CRISPR-Cas9 knockout screen are resistant to HBL. A second CRISPR screen in LITAF-deficient cells identified CDIP1 as an alternative HBL receptor. LITAF-deficient mice exhibit marked resistance to lethal HBL challenges in vivo.\",\n      \"method\": \"Genome-wide CRISPR-Cas9 knockout screen (two sequential screens), LITAF-deficient cell lines, LITAF-deficient mouse generation, in vivo HBL lethality challenge\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — unbiased genome-wide screen validated with KO cells and KO mice in vivo, iterative screens provide strong convergent evidence\",\n      \"pmids\": [\"32544461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"LITAF is a direct target of miR-106a (validated by 3'UTR luciferase assay and western blotting). LITAF knockdown phenocopies miR-106a overexpression in conferring radioresistance. LITAF mediates upregulation of ATM expression, providing a novel mechanistic link between LITAF and the DNA damage response in prostate cancer cells.\",\n      \"method\": \"3'UTR luciferase reporter assay, western blotting, miR-106a overexpression and knockdown of LITAF, radiation resistance assays, transcriptomic analysis\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter confirms direct miRNA targeting, phenocopy experiment places LITAF in ATM regulation, single lab with multiple methods\",\n      \"pmids\": [\"29845714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The LITAF I92V sequence variant partially mislocalizes to the mitochondria (compared to wild-type LITAF which localizes to late endosome/lysosomes) and is associated with a tendency for PMP22 to accumulate in cells. This variant predisposes CMT1A/HNPP patients to an earlier age of disease onset.\",\n      \"method\": \"Cell transfection with LITAF I92V construct, immunofluorescence-based subcellular localization, PMP22 accumulation assay, clinical cohort analysis\",\n      \"journal\": \"Neurogenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — localization demonstrated experimentally with functional consequence (PMP22 accumulation), clinical cohort supports relevance; single lab\",\n      \"pmids\": [\"25342198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"LITAF/SIMPLE mutations (G112S, W116G, and others) are found exclusively in CMT1 (demyelinating) patients. SIMPLE protein is expressed in Schwann cells, the affected cell type in CMT1C. Clustering of mutations G112S, T115N, W116G within five amino acids identifies a critical domain for peripheral nerve myelination.\",\n      \"method\": \"Mutation screening of 152 neuropathy probands, haplotype analysis, electrophysiological studies, immunohistochemistry of sciatic nerve sections\",\n      \"journal\": \"Annals of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — large cohort mutation analysis with Schwann cell expression demonstrated by direct immunostaining; replicates Street et al. 2003 findings\",\n      \"pmids\": [\"15122712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LITAF enhances radiosensitivity of glioma cells via the FoxO1 pathway and its downstream targets BIM, TRAIL, and FASLG. Knockdown or overexpression of LITAF did not affect proliferation or apoptosis under basal conditions, but modulated radiation response through FoxO1.\",\n      \"method\": \"LITAF knockdown and overexpression in glioma cell lines, radiation assays, FoxO1 pathway analysis, apoptosis assays\",\n      \"journal\": \"Cellular and molecular neurobiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single cell-line system, pathway placement is functional but without direct biochemical interaction evidence between LITAF and FoxO1\",\n      \"pmids\": [\"31098771\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LITAF (also known as SIMPLE/PIG7) is a zinc-binding monotopic integral membrane protein that localizes to the late endosome/lysosome via its C-terminal LITAF domain; it functions as a transcription factor downstream of TLR/MyD88/p38α (and ERK2) signaling to drive TNF-α and other inflammatory cytokine expression in macrophages, interacts with the ubiquitin ligase Itch via PPXY motifs to regulate its endolysosomal trafficking, participates in multivesicular body sorting and autophagy, acts downstream of AMPK to regulate TNFSF15 transcription and suppress tumor growth, and serves as a plasma membrane receptor for the bacterial pore-forming toxin hemolysin BL; CMT1C-causing mutations in its conserved C-terminal domain mislocalize the protein from lysosomes to mitochondria, disrupting Schwann cell function and causing demyelinating neuropathy.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LITAF (also SIMPLE/PIG7) is a zinc-binding monotopic membrane protein that integrates innate-immune and trafficking functions at the endolysosomal system [#7]. Biochemically, it associates with membranes through a single hydrophobic region without translocating either terminus into the ER lumen, both N- and C-termini facing the cytoplasm, and binds one mole of zinc whose coordinating residues are required for membrane association [#7]. Its conserved C-terminal LITAF domain is necessary and sufficient to target the protein to the late endosome/lysosome via the secretory pathway [#6]. In macrophages, LITAF acts as an inflammatory effector downstream of TLR2/TLR4–MyD88 signaling, where it is phosphorylated by p38\\u03b1 (and controlled by ERK2) to drive nuclear translocation and expression of TNF-\\u03b1 and other cytokines, distinct from the NF-\\u03baB pathway; loss of LITAF reduces cytokine output and protects against LPS lethality and TNBS colitis [#0, #8, #9]. LITAF also operates as a transcriptional node in other contexts, acting downstream of AMPK to bind the TNFSF15 promoter and restrain tumor growth, and being repressed by BCL6 in B cells where it instead supports starvation-induced autophagy [#4, #5]. Through two N-terminal PPXY motifs it binds the ubiquitin ligase Itch and redirects it from the trans-Golgi network to lysosomes, linking LITAF to endolysosomal ubiquitin-dependent trafficking [#3]. Independently, LITAF serves as a host cell-surface receptor for the Bacillus cereus pore-forming toxin hemolysin BL, with CDIP1 acting as an alternative receptor [#10]. Missense mutations clustered in a five-residue stretch of the C-terminal domain (e.g. G112S, T115N, W116G) cause autosomal-dominant demyelinating Charcot-Marie-Tooth disease type 1C by mislocalizing the protein from lysosomes to mitochondria, dominantly redirecting wild-type LITAF and disrupting Schwann-cell function [#2, #6, #13].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established the basic identity of LITAF/SIMPLE as a small, unglycosylated integral membrane protein of the late endosome/lysosome rather than a RING-type or nuclear protein, correcting the initial sequence-based assumption.\",\n      \"evidence\": \"cDNA cloning, genome analysis, and cell-fractionation/localization experiments in monocytes\",\n      \"pmids\": [\"11274176\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Membrane topology and metal-binding not resolved\", \"No defined molecular activity assigned\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstrated that LITAF mutations cause human disease by mapping CMT1C to a tight cluster of missense mutations in the C-terminal domain, defining a region critical for peripheral nerve function.\",\n      \"evidence\": \"Positional/candidate cloning and mutation screening in CMT1C pedigrees with Western/Northern blots\",\n      \"pmids\": [\"12525712\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular mechanism by which mutations impair myelination unknown\", \"No demonstration of where mutant protein mislocalizes\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Tied the genetic disease to the affected cell type by showing SIMPLE/LITAF is expressed in Schwann cells and that demyelinating mutations cluster in a five-residue domain.\",\n      \"evidence\": \"Large-cohort mutation screening, haplotype/electrophysiology, sciatic nerve immunohistochemistry\",\n      \"pmids\": [\"15122712\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular consequence of mutations still undefined\", \"Schwann-cell function of wild-type LITAF unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Placed LITAF in a specific innate-immune signaling pathway, showing it acts as a transcription factor downstream of TLR/MyD88 and is phosphorylated by p38\\u03b1 to translocate to the nucleus and drive cytokine expression, separate from NF-\\u03baB.\",\n      \"evidence\": \"Macrophage-specific knockout mice, kinase array, p38\\u03b1 inhibition, TLR-knockout macrophages, cDNA rescue, in vivo LPS challenge\",\n      \"pmids\": [\"16954198\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a membrane-anchored protein reaches the nucleus mechanistically unresolved\", \"Direct DNA target sites in cytokine genes not defined here\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected LITAF to ubiquitin-dependent trafficking by identifying a PPXY-mediated interaction with the ligase Itch and showing LITAF recruits Itch from the TGN to lysosomes.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, immunofluorescence, and PPXY motif mutagenesis in multiple cell lines\",\n      \"pmids\": [\"21326863\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of Itch relocalization (substrates) not defined\", \"Single lab, no in vivo validation\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined an AMPK\\u2013LITAF\\u2013TNFSF15 transcriptional axis and a tumor-suppressor role, showing LITAF is induced by AMPK and binds the TNFSF15 promoter to limit cancer-cell growth.\",\n      \"evidence\": \"shRNA knockdown, dominant-negative AMPK, AICAR, promoter binding assay, prostate xenograft and growth assays\",\n      \"pmids\": [\"21217782\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How a lysosomal membrane protein engages a promoter not reconciled\", \"Single lab\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Extended the macrophage TNF-\\u03b1 role to intestinal disease, showing LITAF drives lamina propria macrophage TNF-\\u03b1 secretion during colitis.\",\n      \"evidence\": \"TNBS colitis model with macrophage-specific LITAF knockout mice, ex vivo LPM TNF-\\u03b1 secretion and MPO assays\",\n      \"pmids\": [\"21984950\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Upstream sensing in this tissue not dissected\", \"Single lab\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealed context-dependent regulation and a distinct cellular function, showing BCL6 represses LITAF in B cells where LITAF promotes autophagy rather than TNF secretion.\",\n      \"evidence\": \"ChIP, luciferase reporter, BCL6 silencing, gain/loss-of-function in B-cell lymphoma lines, autophagosome co-localization\",\n      \"pmids\": [\"23795761\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of autophagy regulation by LITAF unknown\", \"Why TNF induction is absent in B cells unexplained\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Provided the cell-biological mechanism of CMT1C by showing disease mutations mislocalize LITAF from lysosomes to mitochondria, that the C-terminus is necessary and sufficient for lysosomal targeting, and that mutants dominantly redirect wild-type protein.\",\n      \"evidence\": \"Immunofluorescence localization of multiple mutants, Brefeldin A secretory-pathway block, C-terminal truncations, WT/mutant co-transfection\",\n      \"pmids\": [\"25058650\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How mitochondrial mislocalization damages Schwann cells unresolved\", \"Single lab, transfected-cell system\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Linked a LITAF variant to a trafficking phenotype relevant to peripheral neuropathy, showing I92V partially mislocalizes to mitochondria and promotes PMP22 accumulation.\",\n      \"evidence\": \"Transfection/immunofluorescence of I92V, PMP22 accumulation assay, clinical cohort analysis\",\n      \"pmids\": [\"25342198\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking LITAF mislocalization to PMP22 handling unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Refined the macrophage signaling module by identifying ERK2 (via Ser206) as an upstream kinase controlling LITAF nuclear translocation and LPS-induced TNF-\\u03b1.\",\n      \"evidence\": \"LITAF-/- and ERK2-/- macrophages with ERK2 rescue, ERK2 S206 analysis, in vivo CAIA arthritis model\",\n      \"pmids\": [\"26918116\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relationship between ERK2 and p38\\u03b1 inputs not integrated\", \"Direct phosphosite on LITAF not mapped\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Resolved the long-standing topology and metal-binding questions, establishing LITAF as a zinc-binding monotopic membrane protein with both termini cytoplasmic, sharing topology with CDIP1.\",\n      \"evidence\": \"In vitro translation/microsome integration, glycosylation reporters, immunofluorescence latency assay, ICP-MS zinc measurement, zinc-residue mutagenesis\",\n      \"pmids\": [\"27582497\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional role of zinc binding beyond membrane association unknown\", \"How cytoplasmic-facing topology permits nuclear/transcriptional roles unexplained\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed LITAF in DNA-damage signaling, showing it is a direct miR-106a target and mediates ATM upregulation and radiosensitivity in prostate cancer cells.\",\n      \"evidence\": \"3'UTR luciferase assay, western blotting, miR-106a/LITAF perturbation, radiation resistance and transcriptomic analysis\",\n      \"pmids\": [\"29845714\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between LITAF and ATM not biochemically defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Proposed an additional radiosensitization function in glioma via the FoxO1 pathway and apoptotic effectors.\",\n      \"evidence\": \"LITAF knockdown/overexpression in glioma lines, radiation and apoptosis assays, FoxO1 pathway analysis\",\n      \"pmids\": [\"31098771\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct biochemical interaction between LITAF and FoxO1 shown\", \"Single cell-line system, single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified a wholly distinct function as a toxin receptor, showing LITAF (and alternatively CDIP1) is the host membrane receptor for Bacillus cereus hemolysin BL, with LITAF-deficient cells and mice resistant to the toxin.\",\n      \"evidence\": \"Two sequential genome-wide CRISPR-Cas9 knockout screens, LITAF-deficient cells and mice, in vivo HBL lethality challenge\",\n      \"pmids\": [\"32544461\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct toxin-LITAF binding interface not defined\", \"Relationship between receptor role and endolysosomal/transcriptional functions unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how a zinc-binding, cytoplasmic-facing monotopic endolysosomal membrane protein executes its reported nuclear transcription-factor activities, and how its trafficking, immune, autophagy, and toxin-receptor roles are mechanistically unified.\",\n      \"evidence\": \"No timeline study reconciles the membrane topology with the nuclear/transcriptional and receptor functions\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structure of LITAF or its complexes\", \"No mechanism for membrane-to-nucleus relocation\", \"No unified model linking the functional contexts\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [1, 3, 6]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [1, 3, 6]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [6, 12]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 8, 9]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 4, 5]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 6, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ITCH\", \"CDIP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}