{"gene":"TAX1BP1","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2007,"finding":"TAX1BP1 is essential for termination of TNF-α-, IL-1-, and LPS-mediated NF-κB and JNK signaling. In TAX1BP1-deficient mouse fibroblasts, IKK and JNK activation is elevated and persistent due to enhanced ubiquitination of RIP1 and TRAF6. In the absence of TAX1BP1, A20 is impaired in RIP1 binding and TRAF6 deubiquitination, establishing TAX1BP1 as an essential regulator of A20 function.","method":"TAX1BP1-deficient mouse fibroblasts (KO), co-immunoprecipitation, ubiquitination assays, NF-κB/JNK activation assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined cellular phenotype, co-IP showing A20/RIP1/TRAF6 interactions, replicated across multiple stimuli","pmids":["17703191"],"is_preprint":false},{"year":2008,"finding":"TAX1BP1 acts as a negative regulator of TNF-α- and IL-1β-induced NF-κB activation. Ubiquitin binding via its C-terminal zinc finger domain is required for TRAF6 association and NF-κB inhibition. TAX1BP1-KO mice develop age-dependent inflammatory cardiac valvulitis, and TAX1BP1 functions as an essential adaptor between A20 and its ubiquitinated targets.","method":"TAX1BP1-KO mice, ubiquitin-binding zinc finger domain mutagenesis, NF-κB activation assays, co-immunoprecipitation","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse model with defined phenotype, domain mutagenesis establishing ubiquitin-binding requirement, replicated across multiple stimuli","pmids":["18239685"],"is_preprint":false},{"year":2010,"finding":"TAX1BP1 and A20 inhibit antiviral signaling by targeting TBK1 and IKKi kinases. TAX1BP1-deficient MEFs show increased IFN-β production upon viral challenge. TAX1BP1 and A20 block antiviral signaling by disrupting K63-linked polyubiquitination of TBK1/IKKi independently of A20's deubiquitination domain. TRAF3 promotes TBK1-IKKi ubiquitination upstream. A20 requires TAX1BP1 to target and inactivate TBK1 and IKKi.","method":"Tax1bp1−/− MEFs, viral challenge assays, ubiquitination assays, co-immunoprecipitation, IRF3 activation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO MEFs, multiple orthogonal assays (IP, ubiquitination, reporter), identification of TBK1/IKKi as novel substrates","pmids":["20304918"],"is_preprint":false},{"year":2011,"finding":"IKKα (but not IKKβ) phosphorylates TAX1BP1 on Ser593 and Ser624 in response to TNF or IL-1 stimulation. This phosphorylation is required for cytokine-dependent assembly of the A20 ubiquitin-editing complex (TAX1BP1, A20, Itch, RNF11) and subsequent downregulation of NF-κB canonical signaling.","method":"In vitro kinase assay, phospho-specific antibodies, IKKα KO/knockdown, co-immunoprecipitation, NF-κB reporter assays, site-directed mutagenesis (Ser593/Ser624)","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay with direct phosphorylation, mutagenesis of phosphosites, co-IP showing complex assembly, multiple orthogonal methods","pmids":["21765415"],"is_preprint":false},{"year":2011,"finding":"ABIN1 interacts with TAX1BP1 and is essential for recruitment of TAX1BP1 and A20 to TBK1 and IKKi in response to poly(I:C). ABIN1 and TAX1BP1 together disrupt TRAF3-TBK1/IKKi interactions to attenuate K63-linked polyubiquitination of TBK1/IKKi. ABIN1's intact ubiquitin binding domain is required for interaction with TBK1/IKKi and IFN-β inhibition.","method":"Co-immunoprecipitation, siRNA knockdown, ABIN1 ubiquitin-binding domain mutagenesis, IFN-β reporter assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, domain mutagenesis, functional reporter assays, single lab","pmids":["21885437"],"is_preprint":false},{"year":2012,"finding":"TAX1BP1 (as a paralogue of NDP52) functions as a bona fide cargo receptor for selective autophagy. Basal autophagy in K-Ras-dependent NSCLC is characterized by sequestration of TAX1BP1 (and NDP52), and this process promotes non-canonical NF-κB signaling in a TBK1-dependent manner.","method":"Autophagic flux assays, siRNA knockdown, non-canonical NF-κB reporter assays, TBK1 inhibition","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional KD with defined phenotype and pathway placement, single lab","pmids":["23209807"],"is_preprint":false},{"year":2013,"finding":"Crystal and NMR solution structures of the tandem UBZ1+2 (ubiquitin-binding zinc finger) domains of TAX1BP1 were determined, revealing conformational flexibility between the two domains that may influence recognition of interacting partners including ubiquitinated signaling proteins.","method":"X-ray crystallography, NMR spectroscopy, NMR relaxation analysis","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal and NMR structures with relaxation data, single lab but two orthogonal structural methods","pmids":["24239949"],"is_preprint":false},{"year":2015,"finding":"TAX1BP1 and myosin VI are recruited to ubiquitylated Salmonella and are required for xenophagic clearance. The ubiquitin-binding site of TAX1BP1 overlaps with the myosin VI binding site (in the zinc finger domains), such that ubiquitin and myosin VI bind TAX1BP1 in a mutually exclusive manner. Point mutations in the zinc finger domains that abrogate ubiquitin binding also ablate myosin VI binding. TAX1BP1 also associates with LC3 on the outer autophagosomal membrane.","method":"Structural analysis, point mutagenesis, co-immunoprecipitation, live-cell imaging, TAX1BP1 KD, Salmonella infection assays","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 1 / Strong — structural analysis plus mutagenesis plus functional xenophagy assays; mutually exclusive binding demonstrated biochemically","pmids":["26451915"],"is_preprint":false},{"year":2016,"finding":"TAX1BP1 restrains virus-induced apoptosis by recruiting the E3 ligase Itch to MAVS on mitochondria, triggering MAVS ubiquitination and degradation. Virus infection promotes mitochondrial localization of TAX1BP1 and interaction with MAVS. Loss of TAX1BP1 or Itch results in increased MAVS protein levels and hypersensitivity to apoptosis. TAX1BP1 also undergoes degradation during RNA virus infection.","method":"TAX1BP1-KO and Itch-KO cells, co-immunoprecipitation, subcellular fractionation, apoptosis assays, ubiquitination assays, viral infection (VSV, Sendai virus)","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO cells with defined apoptosis phenotype, co-IP, fractionation showing mitochondrial localization, ubiquitination assays, two orthogonal methods","pmids":["27736772"],"is_preprint":false},{"year":2017,"finding":"TRIM32 interacts with TRIF and mediates its selective autophagic degradation via TAX1BP1. TRIM32 links TRIF and TAX1BP1 through distinct domains, and poly(I:C)/LPS-induced TRIF degradation is inhibited by TAX1BP1 deficiency. This mechanism negatively regulates TLR3/4-mediated innate immune responses.","method":"Co-immunoprecipitation, TAX1BP1-deficient cells, domain mapping, autophagic flux assays, Trim32-KO mice, cytokine measurement","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse and KO cells, co-IP showing ternary complex, domain mapping, functional immune readout","pmids":["28898289"],"is_preprint":false},{"year":2017,"finding":"TAX1BP1 drives a specialized form of autophagy required for the metabolic transition of activated T cells. TAX1BP1 binding to LC3/GABARAP via its LIR motif (but not its ubiquitin-binding domain) supports T cell proliferation and mTOR complex formation. TAX1BP1-deficient T cells stall in S phase due to bioenergetic and biosynthetic defects from defective autophagy induction and insufficient mTOR activation.","method":"TAX1BP1-KO T cells, LIR/UBD domain mutants, mTOR complex assays, metabolic assays, L-cysteine supplementation rescue","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined phenotype, domain-specific mutants separating UBD from LIR function, metabolic rescue experiment","pmids":["28314591"],"is_preprint":false},{"year":2018,"finding":"Crystal structures of the SKICH domains of NDP52 and TAX1BP1 in complex with NAP1 were determined, revealing the mechanistic basis of NAP1-SKICH interaction and a general SKICH domain binding mode. TBK1-mediated phosphorylation sites in the SKICH domains of both receptors were evaluated with respect to their NAP1 interactions.","method":"X-ray crystallography, biochemical binding assays, phosphomimetic mutant analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — atomic-resolution crystal structures with biochemical validation, single lab","pmids":["30459273"],"is_preprint":false},{"year":2018,"finding":"Biochemical, NMR, and structural analyses defined the binding mechanism of TAX1BP1's tandem zinc fingers with ubiquitin, and showed that both tandem zinc fingers and the conformational rigidity between them are required for myosin VI binding. Ubiquitin and myosin VI bind TAX1BP1 in a mutually exclusive manner.","method":"NMR spectroscopy, biochemical assays, structural analysis, mutagenesis","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR and structural analysis with mutagenesis and biochemical validation of mutually exclusive binding","pmids":["29940186"],"is_preprint":false},{"year":2019,"finding":"LAMTOR2/LAMTOR1 complex is required for TAX1BP1-mediated xenophagy. LAMTOR1 localizes to bacterium-containing endosomes, and LAMTOR2 is recruited to damaged endosomes in a LAMTOR1-dependent manner. LAMTOR2 interacts with TAX1BP1 (and NBR1, p62) and is necessary for TAX1BP1 recruitment to pathogen-containing autophagosomes. TAX1BP1 KO reduces autolysosome formation and subsequent bacterial degradation.","method":"LAMTOR1/2 KO cells, TAX1BP1 KO cells, co-immunoprecipitation, live imaging, GAS/Salmonella infection assays, autolysosome formation assays","journal":"Cellular microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO cells with defined xenophagy phenotype, co-IP showing interactions, single lab","pmids":["30428163"],"is_preprint":false},{"year":2020,"finding":"Endogenous TAX1BP1 is recruited to and required for clearance of stress-induced protein aggregates via autophagy. TAX1BP1 depletion sensitizes cells to aggregate-induced proteotoxicity. Loss of TAX1BP1 in mice results in accumulation of high molecular weight ubiquitin conjugates and premature lipofuscin accumulation in brains, establishing TAX1BP1 as the primary autophagy receptor for aggregate clearance in the brain.","method":"TAX1BP1 KO mice, siRNA knockdown, autophagy receptor comparison (OPTN, NBR1, p62, NDP52, TAX1BP1), iPSC-derived neurons, viability assays, brain histology","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse model, iPSC-derived neurons, comparison across multiple receptors with defined phenotypic readouts","pmids":["33207181"],"is_preprint":false},{"year":2021,"finding":"In vitro reconstitution defined that p62 is the major driver of ubiquitin condensate formation; NBR1 promotes condensation and recruits TAX1BP1 to condensates; TAX1BP1 is the main driver of FIP200 recruitment to the condensates, thereby initiating autophagic degradation. All three receptors interact with FIP200, but TAX1BP1 is the primary mediator of autophagy machinery recruitment.","method":"In vitro reconstitution with purified proteins, cell biology assays, co-IP, ubiquitin condensate formation assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified components, cell biology validation, multiple orthogonal approaches","pmids":["34471133"],"is_preprint":false},{"year":2021,"finding":"Galectin-8 senses damaged Mtb-containing phagosomes and directly interacts with TAX1BP1. This galectin-8/TAX1BP1 interaction is necessary for efficient targeting of Mtb to selective autophagy in macrophages. Galectin-8 KO (but not galectin-3 or -9 KO alone) impairs TAX1BP1-mediated selective autophagy of Mtb.","method":"CRISPR/Cas9 KO macrophages (galectin-8-/-, galectin-3/8/9-/-), co-immunoprecipitation, confocal microscopy, Mtb replication assays","journal":"mBio","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with defined functional phenotype, co-IP identifying novel interaction, single lab","pmids":["34225486"],"is_preprint":false},{"year":2021,"finding":"RNF34 is recruited to interact with TAX1BP1 and facilitates autophagic degradation of MAVS through K27-linked polyubiquitination. TAX1BP1 overexpression suppresses NLRP3 mitochondrial localization by inhibiting NLRP3 interaction with MAVS. Knockdown of RNF34 nullifies TAX1BP1-mediated protection against MAVS accumulation and NLRP3 inflammasome activation.","method":"Co-immunoprecipitation, siRNA knockdown, TAX1BP1 overexpression (adenovirus), mitochondrial fractionation, ubiquitination assays, NLRP3 activation assays","journal":"Science bulletin","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with domain-specific interactions, KD rescue experiments, ubiquitination assays, single lab","pmids":["36654301"],"is_preprint":false},{"year":2023,"finding":"TNIP1 negatively regulates mitophagy rate through an evolutionarily conserved LIR motif (binding LC3/GABARAP) and an AHD3 domain that binds TAX1BP1. TNIP1 competes with autophagy receptors for FIP200 binding in a phosphorylation-dependent manner, providing a molecular basis for its inhibitory function during mitophagy.","method":"TNIP1 KO HeLa cells, ectopic expression, LIR/AHD3 domain mutants, co-immunoprecipitation, mitophagy rate assays, ULK1 complex interaction assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO and overexpression, domain mutagenesis establishing binding requirements, mechanistic competition assay for FIP200, single lab with multiple orthogonal methods","pmids":["36898370"],"is_preprint":false},{"year":2024,"finding":"Crystal structure of the TAX1BP1 SKICH domain in complex with the RB1CC1 (FIP200) coiled-coil region was determined. Two distinct binding sites between TAX1BP1 and RB1CC1 were identified: the SKICH/coiled-coil interaction and a CC1-domain/Claw interaction. RB1CC1 and NAP1 compete for SKICH binding, but NAP1's FIR motif can stabilize a ternary TAX1BP1/NAP1/RB1CC1 complex. The structure of GABARAP in complex with the non-canonical LIR motif of TAX1BP1 was also determined, revealing a unique binding mode.","method":"X-ray crystallography, biochemical binding assays, mutagenesis, ternary complex formation assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple crystal structures with biochemical validation and mutagenesis, two orthogonal binding studies in one report","pmids":["38437556"],"is_preprint":false},{"year":2024,"finding":"TBK1 and IKBKE/IKKi redundantly phosphorylate TAX1BP1 and regulate its autophagic turnover through canonical macroautophagy. TAX1BP1 phosphorylation promotes its localization to lysosomes resulting in degradation. TAX1BP1 plays a critical role in clearance of MAVS aggregates (aggrephagy), and its phosphorylation by TBK1/IKKi controls this MAVS aggrephagy function. During VSV infection, TAX1BP1 is targeted to lysosomes in an ATG8-family protein-independent manner.","method":"KO and KI MEFs, phospho-site mutagenesis, kinase assays, lysosomal localization assays, MAVS aggregate clearance assays (semi-denaturing AGE), VSV infection","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO/KI cells, phosphosite mutagenesis, multiple assays including semi-denaturing gel for aggregate clearance, lysosomal localization imaging","pmids":["39193925"],"is_preprint":false},{"year":2024,"finding":"TAX1BP1 recruitment to ubiquitin-containing protein aggregates correlates with induction of autophagosome biogenesis and is not a constitutive component of condensates. TAX1BP1 is sufficient to recruit TBK1 kinase via the SINTBAD adaptor. The NBR1-TAX1BP1 binding site was defined and is adjacent to the GABARAP/LC3 interaction site. Increased ubiquitin load on condensates enhances TAX1BP1 recruitment, suggesting a cargo-sensing switch from condensation to sequestration.","method":"In vitro reconstitution, domain mutagenesis, SINTBAD interaction assays, NBR1-binding site mapping, ubiquitin condensate assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with domain mutagenesis, binding-site mapping, TBK1 recruitment assays","pmids":["39448883"],"is_preprint":false},{"year":2024,"finding":"Tau fibrils from Alzheimer's disease brains are recognized by p62 but fail to recruit TAX1BP1 due to masking of ubiquitin moieties by excessive p62 coating. Monomeric Tau recruits both p62 and TAX1BP1. This irreversible, nonproductive p62-fibril interaction (due to fibril resistance to deubiquitylation) explains autophagy evasion by Tau aggregates.","method":"In vitro reconstitution with purified proteins and patient-derived Tau fibrils, ubiquitination assays, deubiquitylation resistance assays","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstitution with physiological and pathological substrates, mechanistic explanation of TAX1BP1 exclusion, single lab","pmids":["38865459"],"is_preprint":false},{"year":2025,"finding":"TAX1BP1 acts as an autophagic receptor for STING1 degradation through its coiled-coil domain interacting with the cyclic dinucleotide binding domain of STING1. K63-ubiquitination of STING1 at K224 is required for TAX1BP1-dependent STING1 autophagic degradation. TAX1BP1 thus negatively regulates cGAS-STING-dependent antitumor immunity.","method":"Proteomic lysosomal analysis, co-immunoprecipitation, systematic K-to-R STING1 mutagenesis, ubiquitination assays, TAX1BP1 KO cells","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP domain mapping, systematic mutagenesis, proteomics, KO cells; single lab","pmids":["40000606"],"is_preprint":false},{"year":2026,"finding":"TAX1BP1 negatively regulates cGAS-STING signaling by promoting STING degradation through microautophagy via facilitating STING interaction with the ESCRT-0 protein HGS. TAX1BP1 also mediates autophagic degradation of fragmented Golgi (Golgiphagy) upon STING activation. TAX1BP1-deficient macrophages accumulate higher-order STING aggregates at the trans-Golgi network and show heightened type I IFN and proinflammatory cytokine production.","method":"TAX1BP1-KO macrophages, co-immunoprecipitation (STING-HGS interaction), ESCRT-pathway assays, Golgi morphology imaging, cytokine measurement, cGAS/STING agonist treatment","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO macrophages, co-IP identifying HGS interaction, Golgiphagy assays, single lab with multiple orthogonal methods","pmids":["41673009"],"is_preprint":false},{"year":2025,"finding":"Parkin-dependent K63-ubiquitination of TAX1BP1 at K549 within its third coiled-coil domain (CC3) regulates TAX1BP1's mitophagy function. This modification is not required for proteasomal degradation of TAX1BP1 but is a regulatory modification; ubiquitination-deficient TAX1BP1 (lacking CC3) reroutes mitochondria degradation to a less efficient endolysosomal pathway engaging VPS35.","method":"Mass spectrometry-based phosphoproteomics/ubiquitinomics, parkin WT vs catalytically inactive mutant, lysosomal inhibitor (bafilomycin A), TAX1BP1 ubiquitination-deficient mutant, mitophagy flux assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS identification of ubiquitination site, functional mutant analysis, mitophagy flux assays; preprint, single lab","pmids":["40475537"],"is_preprint":true},{"year":2008,"finding":"Tax1BP1 functions as a transcriptional coactivator for nuclear receptors (glucocorticoid receptor). It forms a complex with p300 and synergistically enhances E2-dependent viral transcription. Tax1BP1 prevents proteasomal degradation of HPV E2 protein, regulating E2 steady-state levels. The C-terminal region of Tax1BP1 interacts with the N-terminal transactivation domain of BPV1 E2.","method":"Yeast two-hybrid, co-immunoprecipitation, chromatin immunoprecipitation, transcriptional reporter assays, proteasome inhibitor experiments","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, ChIP, reporter assays, proteasome inhibition; single lab with multiple methods","pmids":["19109394"],"is_preprint":false},{"year":2007,"finding":"TAX1BP1 is a nuclear receptor coactivator that forms a complex with the glucocorticoid receptor. HTLV-1 Tax protein binds TAX1BP1 directly, induces dissociation of TAX1BP1 from the glucocorticoid receptor complex, and represses TAX1BP1's coactivator function. Genetic knockout of Tax1bp1 in mice abrogates Tax's influence on nuclear receptor activation.","method":"Co-immunoprecipitation, immunofluorescence colocalization, TAX1BP1 KO mice, nuclear receptor transcriptional assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse, co-IP, immunofluorescence, reporter assays; single lab","pmids":["17283140"],"is_preprint":false},{"year":2009,"finding":"NRP/Optineurin interacts with TAX1BP1 in a cooperative manner to modulate Tax1 ubiquitination and NF-κB activation. NRP requires Tax1's ubiquitination sites and its own ubiquitin-binding activity for interaction with Tax1. NRP, TAX1BP1, and Tax1 colocalize in Golgi-associated structures.","method":"Co-immunoprecipitation, immunofluorescence, ubiquitin-binding domain mutagenesis, NF-κB reporter assays","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, immunofluorescence localization, domain mutagenesis, reporter assays; single lab","pmids":["19609363"],"is_preprint":false},{"year":2024,"finding":"TAX1BP1 and FIP200 mediate non-canonical autophagic degradation of p62 aggregates in neural stem cells (NSCs). Conditional deletion of Tax1bp1 in fip200 cKI mice (which have blocked canonical autophagy) leads to NSC deficiency and p62 aggregate accumulation phenocopying fip200 cKO mice. A TAX1BP1 mutant unable to bind FIP200 or NBR1/p62 fails to restore NSC maintenance.","method":"Conditional KO mouse models, TAX1BP1 domain mutants (FIP200-binding and NBR1/p62-binding deficient), NSC maintenance assays, p62 aggregate quantification","journal":"Zoological research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO genetic epistasis in vivo, domain mutant rescue experiments, single lab","pmids":["39021082"],"is_preprint":false},{"year":2025,"finding":"ASFV p22 promotes the association of TAX1BP1 with IFNAR1 via p22's transmembrane region, facilitating autophagic degradation of IFNAR1 and impairing JAK-STAT signaling. TAX1BP1 acts as the autophagy receptor mediating IFNAR1 degradation in this context.","method":"Co-immunoprecipitation, p22 domain mutagenesis (transmembrane region), IFNAR1 degradation assays, JAK-STAT signaling assays, TAX1BP1 interaction assays","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, domain mutagenesis, functional signaling assays; single lab","pmids":["40668839"],"is_preprint":false},{"year":2025,"finding":"The TBK1-SCFFBXO3-TMEM192-TAX1BP1 regulatory axis orchestrates lysophagic flux. TBK1-dependent phosphorylation of FBXO3 facilitates FBXO3 interaction with TMEM192, promoting its ubiquitination, which is then recognized by TAX1BP1. Disruption of this pathway reduces lysophagic flux and causes accumulation of damaged lysosomes.","method":"TBK1 inhibition/KO, co-immunoprecipitation (FBXO3-TMEM192), ubiquitination assays, TAX1BP1 interaction assays, lysophagy flux assays","journal":"Autophagy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — review/commentary of own findings, methods described briefly; primary data not fully detailed in abstract","pmids":["40083080"],"is_preprint":false},{"year":2022,"finding":"TAX1BP1 (T6BP) influences both autophagy-dependent and -independent endogenous MHC-II presentation of viral antigens. T6BP silencing induces mislocalization of MHC-II loading compartments and rapid degradation of the invariant chain (CD74) without altering MHC-II expression or internalization. T6BP interacts with calnexin via calnexin's cytosolic tail, and calnexin silencing replicates the functional consequences of T6BP silencing.","method":"siRNA silencing, immunopeptidome analysis (MHC-II ligandome), co-immunoprecipitation (TAX1BP1-calnexin), confocal microscopy, T cell activation assays","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — immunopeptidome, co-IP, functional T cell assays, parallel calnexin validation; single lab","pmids":["36215666"],"is_preprint":false},{"year":2025,"finding":"TAX1BP1 interacts with the SKICH domain-binding SINTBAD adaptor to recruit TBK1 kinase to ubiquitin condensates for autophagosome biogenesis initiation. TAX1BP1 is not a constitutive component of p62/NBR1-driven condensates but is recruited upon autophagy induction.","method":"In vitro reconstitution, SINTBAD co-IP, TAX1BP1 localization assays at condensates, ubiquitin load modulation","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with defined components, mechanistic demonstration of TBK1 recruitment via SINTBAD adaptor","pmids":["39448883"],"is_preprint":false}],"current_model":"TAX1BP1 is a multifunctional selective autophagy receptor and ubiquitin-binding adaptor that (1) mediates autophagic clearance of ubiquitinated cargo (protein aggregates, mitochondria, damaged lysosomes, pathogens, and signaling organelles) by binding ubiquitin via its tandem C-terminal zinc finger (UBZ) domains and recruiting the autophagy initiation machinery (FIP200/RB1CC1) via its SKICH domain through NAP1/SINTBAD adaptors; (2) terminates NF-κB and IRF3/antiviral signaling as an essential co-factor of the A20 ubiquitin-editing complex—assembled upon IKKα-mediated phosphorylation of TAX1BP1 on Ser593/Ser624—to deubiquitinate and inactivate RIP1, TRAF6, TBK1, and IKKi; (3) restrains virus-induced apoptosis and innate immune overactivation by targeting MAVS (via Itch-mediated ubiquitination) and STING1 (via K224 K63-ubiquitination and ESCRT-0/HGS-mediated microautophagy/Golgiphagy) for degradation; and (4) functions as a nuclear receptor coactivator and regulates T cell metabolic activation through LC3/GABARAP binding via its LIR motif."},"narrative":{"mechanistic_narrative":"TAX1BP1 is a multifunctional ubiquitin-binding adaptor that operates at the interface of selective autophagy and inflammatory/antiviral signaling termination [PMID:17703191, PMID:33207181]. As a selective autophagy receptor, it recognizes ubiquitinated cargo through its tandem C-terminal zinc-finger (UBZ) domains—whose structures and ubiquitin-binding mechanism have been defined—and its non-canonical LIR motif engages LC3/GABARAP, while its SKICH domain recruits the FIP200/RB1CC1 autophagy-initiation machinery directly and via NAP1/SINTBAD adaptors that also bring in TBK1 [PMID:24239949, PMID:29940186, PMID:34471133, PMID:38437556, PMID:39448883]. The zinc-finger ubiquitin-binding site overlaps the myosin VI binding site, so ubiquitin and myosin VI engage TAX1BP1 in a mutually exclusive manner [PMID:26451915, PMID:29940186]. Through this receptor activity TAX1BP1 mediates clearance of stress-induced protein aggregates—serving as the primary aggrephagy receptor in brain [PMID:33207181]—as well as xenophagy of intracellular bacteria recruited via galectin-8 and the LAMTOR1/2 complex [PMID:30428163, PMID:34225486], and within reconstituted ubiquitin condensates it is the principal driver of FIP200 recruitment to initiate autophagosome biogenesis [PMID:34471133, PMID:39448883]. In parallel, TAX1BP1 is an essential co-factor of the A20 ubiquitin-editing complex, acting as the adaptor linking A20 to its ubiquitinated substrates RIP1, TRAF6, TBK1 and IKKi to terminate NF-κB, JNK, and antiviral IRF3 signaling; this function requires IKKα-mediated phosphorylation of TAX1BP1 on Ser593/Ser624 to assemble the A20/Itch/RNF11 complex [PMID:17703191, PMID:18239685, PMID:20304918, PMID:21765415, PMID:21885437]. TAX1BP1 further restrains innate immune and antiviral responses by directing degradation of signaling organelles and adaptors—recruiting E3 ligases Itch and RNF34 to ubiquitinate MAVS for autophagic clearance and restraining NLRP3 inflammasome activation [PMID:27736772, PMID:36654301, PMID:39193925], and degrading STING1 via K63-ubiquitination, ESCRT-0/HGS-dependent microautophagy and Golgiphagy [PMID:40000606, PMID:41673009]. TBK1/IKKi phosphorylation of TAX1BP1 controls its own lysosomal turnover and its MAVS aggrephagy activity [PMID:39193925]. Distinct from these cytoplasmic roles, TAX1BP1 functions as a nuclear receptor coactivator that complexes with the glucocorticoid receptor and p300, and supports the metabolic activation of T cells through LIR-dependent autophagy [PMID:28314591, PMID:19109394, PMID:17283140].","teleology":[{"year":2007,"claim":"Established TAX1BP1's first defined function—as an essential regulator that enables A20 to terminate inflammatory signaling—answering whether the protein has a role in cytokine-induced NF-κB/JNK shutdown.","evidence":"TAX1BP1-deficient mouse fibroblasts with co-IP and ubiquitination assays across TNF-α/IL-1/LPS stimuli","pmids":["17703191"],"confidence":"High","gaps":["Did not define how TAX1BP1 physically bridges A20 to substrates","Mechanism of A20 recruitment regulation unresolved"]},{"year":2008,"claim":"Showed that ubiquitin binding via the C-terminal zinc fingers is required for TRAF6 association and NF-κB inhibition, and that loss causes inflammatory pathology in vivo, linking the molecular adaptor activity to organismal phenotype.","evidence":"TAX1BP1-KO mice plus zinc-finger ubiquitin-binding mutagenesis and co-IP","pmids":["18239685"],"confidence":"High","gaps":["Structural basis of ubiquitin recognition not yet defined","Did not address how the adaptor function is switched on"]},{"year":2010,"claim":"Extended A20/TAX1BP1 negative regulation to antiviral signaling by identifying TBK1 and IKKi as targets, answering whether the complex restrains type I interferon induction.","evidence":"Tax1bp1−/− MEFs with viral challenge, ubiquitination and IRF3 reporter assays","pmids":["20304918"],"confidence":"High","gaps":["How TAX1BP1 disrupts TRAF3-TBK1/IKKi ubiquitination mechanistically unclear","Recruitment to kinase complex not defined"]},{"year":2011,"claim":"Defined the upstream activating signal—IKKα phosphorylation of Ser593/Ser624—required to assemble the A20 editing complex, and identified ABIN1 as the adaptor recruiting TAX1BP1/A20 to TBK1/IKKi, establishing how the regulatory complex is triggered.","evidence":"In vitro kinase assays, phosphosite mutagenesis, IKKα KO, and ABIN1 co-IP/domain mutagenesis","pmids":["21765415","21885437"],"confidence":"High","gaps":["Whether other kinases phosphorylate the same sites in different contexts unaddressed","ABIN1 work from single lab at Medium confidence"]},{"year":2012,"claim":"Reframed TAX1BP1 as a bona fide selective autophagy cargo receptor, opening its second major functional domain and connecting autophagic sequestration to non-canonical NF-κB signaling.","evidence":"Autophagic flux assays and siRNA knockdown in K-Ras-dependent NSCLC","pmids":["23209807"],"confidence":"Medium","gaps":["Cargo specificity not defined","Single-lab functional knockdown"]},{"year":2013,"claim":"Provided the structural basis for ubiquitin recognition by solving the tandem UBZ1+2 domains, revealing inter-domain conformational flexibility relevant to partner recognition.","evidence":"X-ray crystallography and NMR relaxation analysis of the tandem zinc fingers","pmids":["24239949"],"confidence":"High","gaps":["Ubiquitin-bound complex structure not determined here","Functional consequence of flexibility untested"]},{"year":2015,"claim":"Demonstrated TAX1BP1 drives xenophagy of ubiquitylated Salmonella and that ubiquitin and myosin VI bind the zinc fingers mutually exclusively, defining a regulatory switch within the cargo-recognition module.","evidence":"Structural analysis, point mutagenesis, live imaging and Salmonella infection with TAX1BP1 KD","pmids":["26451915"],"confidence":"High","gaps":["Functional consequence of myosin VI/ubiquitin competition in vivo unclear","How autophagy machinery is recruited downstream not addressed"]},{"year":2016,"claim":"Showed TAX1BP1 restrains virus-induced apoptosis by recruiting Itch to ubiquitinate and degrade mitochondrial MAVS, establishing organelle/adaptor targeting as a distinct antiviral-restraining mode.","evidence":"TAX1BP1-KO and Itch-KO cells with fractionation, ubiquitination and apoptosis assays during VSV/Sendai infection","pmids":["27736772"],"confidence":"High","gaps":["Whether MAVS degradation is autophagic vs proteasomal here not fully resolved","Signal triggering mitochondrial relocalization undefined"]},{"year":2017,"claim":"Separated TAX1BP1's UBD-independent functions: a LIR-dependent specialized autophagy supporting T cell metabolic activation, and TRIM32-bridged selective degradation of TRIF to dampen TLR3/4 responses.","evidence":"TAX1BP1-KO T cells with LIR/UBD mutants and metabolic rescue; TRIM32-KO mice and domain mapping","pmids":["28314591","28898289"],"confidence":"High","gaps":["How LIR-only function bypasses cargo ubiquitin recognition unclear","TRIM32-TAX1BP1 cargo selectivity not generalized"]},{"year":2018,"claim":"Defined at atomic resolution how the SKICH domain engages the NAP1 adaptor and how tandem zinc-finger rigidity governs myosin VI binding, mechanistically linking the autophagy-machinery-recruiting and cargo-binding modules.","evidence":"Crystal structures of SKICH/NAP1, plus NMR and biochemistry of zinc fingers with ubiquitin/myosin VI","pmids":["30459273","29940186"],"confidence":"High","gaps":["FIP200 engagement mode not yet structurally resolved","Phospho-regulation of SKICH binding only evaluated with phosphomimetics"]},{"year":2020,"claim":"Identified TAX1BP1 as the primary autophagy receptor for stress-induced protein aggregate clearance, including in brain, answering which receptor handles proteotoxic aggregates.","evidence":"TAX1BP1-KO mice, iPSC-derived neurons, and comparison against OPTN/NBR1/p62/NDP52","pmids":["33207181"],"confidence":"High","gaps":["How TAX1BP1 is selectively recruited to aggregates not defined here","Relationship to disease aggregates untested"]},{"year":2021,"claim":"Reconstitution and KO studies placed TAX1BP1 within a receptor hierarchy—recruited to p62/NBR1 ubiquitin condensates as the primary driver of FIP200 recruitment—and identified galectin-8 and LAMTOR1/2 as upstream sensors/recruiters for pathogen autophagy, plus RNF34 for MAVS degradation.","evidence":"In vitro reconstitution with purified proteins; CRISPR galectin-8 KO and LAMTOR KO macrophages; RNF34 KD with ubiquitination assays","pmids":["34471133","34225486","30428163","36654301"],"confidence":"High","gaps":["How NBR1 hands TAX1BP1 to condensates mechanistically incomplete","RNF34/MAVS and LAMTOR findings single-lab Medium confidence"]},{"year":2024,"claim":"Resolved the SKICH-RB1CC1(FIP200) and GABARAP-LIR binding interfaces and showed RB1CC1 and NAP1 compete yet can form a ternary complex, while reconstitution showed cargo ubiquitin load acts as a switch recruiting TAX1BP1 and TBK1 (via SINTBAD) to initiate autophagosome biogenesis.","evidence":"Multiple crystal structures with biochemistry; in vitro reconstitution with domain mutagenesis and SINTBAD/NBR1 binding-site mapping","pmids":["38437556","39448883","33207181"],"confidence":"High","gaps":["In vivo confirmation of the condensation-to-sequestration switch lacking","Stoichiometry of ternary TAX1BP1/NAP1/RB1CC1 complex in cells unknown"]},{"year":2024,"claim":"Established phospho-regulation of TAX1BP1's autophagy function—TBK1/IKKi redundantly phosphorylate it to drive its own lysosomal turnover and MAVS aggrephagy—and explained pathological autophagy evasion by Tau fibrils whose ubiquitins are masked by excessive p62 coating.","evidence":"KO/KI MEFs with phosphosite mutagenesis and semi-denaturing aggregate assays; in vitro reconstitution with patient-derived Tau fibrils","pmids":["39193925","38865459"],"confidence":"High","gaps":["Physiological triggers of TAX1BP1 self-turnover unclear","Whether p62-masking generalizes to other fibrils untested"]},{"year":2025,"claim":"Extended TAX1BP1's organelle/adaptor degradation roles to STING1 (via coiled-coil/K224-ubiquitin recognition and ESCRT-0/HGS microautophagy plus Golgiphagy), to IFNAR1 (hijacked by ASFV p22), and to autophagy-independent MHC-II antigen presentation via calnexin, broadening its immunoregulatory reach.","evidence":"TAX1BP1-KO cells/macrophages with co-IP, K-to-R mutagenesis, ESCRT and Golgi assays; immunopeptidome analysis with calnexin co-IP","pmids":["40000606","41673009","40668839","36215666"],"confidence":"Medium","gaps":["Each substrate characterized in single labs","How TAX1BP1 selects micro- vs macroautophagy routes unresolved"]},{"year":null,"claim":"How TAX1BP1's distinct functional outputs—A20-complex signaling termination, ubiquitin/LIR-driven cargo autophagy, and nuclear receptor coactivation—are coordinated within a cell, and how post-translational modifications partition it among these roles, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking the signaling and autophagy functions","Parkin K549 mitophagy regulation only in preprint","Lysophagy axis (TMEM192) supported by Low-confidence evidence"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140097","term_label":"catalytic activity, acting on DNA","supporting_discovery_ids":[6,7,12]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,15,21]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,2,3]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[26,27]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[15,21]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[8,17]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[20,13]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[24,28]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[26,27]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[5,14,15,21]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,2,8,24]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,3]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[8]}],"complexes":["A20 ubiquitin-editing complex (TAX1BP1/A20/Itch/RNF11)"],"partners":["A20","TRAF6","TBK1","RB1CC1/FIP200","NBR1","MAVS","STING1","ITCH"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q86VP1","full_name":"Tax1-binding protein 1","aliases":["TRAF6-binding protein"],"length_aa":789,"mass_kda":90.9,"function":"Ubiquitin-binding adapter that participates in inflammatory, antiviral and innate immune processes as well as selective autophagy regulation (PubMed:29940186, PubMed:30459273, PubMed:30909570). Plays a key role in the negative regulation of NF-kappa-B and IRF3 signalings by acting as an adapter for the ubiquitin-editing enzyme A20/TNFAIP3 to bind and inactivate its substrates (PubMed:17703191). Disrupts the interactions between the E3 ubiquitin ligase TRAF3 and TBK1/IKBKE to attenuate 'Lys63'-linked polyubiquitination of TBK1 and thereby IFN-beta production (PubMed:21885437). Also recruits A20/TNFAIP3 to ubiquitinated signaling proteins TRAF6 and RIPK1, leading to their deubiquitination and disruption of IL-1 and TNF-induced NF-kappa-B signaling pathways (PubMed:17703191). Inhibits virus-induced apoptosis by inducing the 'Lys-48'-linked polyubiquitination and degradation of MAVS via recruitment of the E3 ligase ITCH, thereby attenuating MAVS-mediated apoptosis signaling (PubMed:27736772). As a macroautophagy/autophagy receptor, facilitates the xenophagic clearance of pathogenic bacteria such as Salmonella typhimurium and Mycobacterium tuberculosis (PubMed:26451915). Upon NBR1 recruitment to the SQSTM1-ubiquitin condensates, acts as the major recruiter of RB1CC1 to these ubiquitin condensates to promote their autophagic degradation (PubMed:33226137, PubMed:34471133). Mediates the autophagic degradation of other substrates including TICAM1 (PubMed:28898289)","subcellular_location":"Cytoplasm; Mitochondrion; Preautophagosomal structure; Cytoplasmic vesicle, autophagosome","url":"https://www.uniprot.org/uniprotkb/Q86VP1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TAX1BP1","classification":"Not Classified","n_dependent_lines":23,"n_total_lines":1208,"dependency_fraction":0.01903973509933775},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TAX1BP1","total_profiled":1310},"omim":[{"mim_id":"621078","title":"MYOPATHY, MYOFIBRILLAR, 13, WITH RIMMED VACUOLES; MFM13","url":"https://www.omim.org/entry/621078"},{"mim_id":"609866","title":"START DOMAIN-CONTAINING PROTEIN 13; STARD13","url":"https://www.omim.org/entry/609866"},{"mim_id":"608014","title":"HEAT-SHOCK 22-KD PROTEIN 8; HSPB8","url":"https://www.omim.org/entry/608014"},{"mim_id":"605326","title":"TAX1-BINDING PROTEIN 1; TAX1BP1","url":"https://www.omim.org/entry/605326"},{"mim_id":"603679","title":"UBIQUITIN-CONJUGATING ENZYME E2 N; UBE2N","url":"https://www.omim.org/entry/603679"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TAX1BP1"},"hgnc":{"alias_symbol":["TXBP151","CALCOCO3"],"prev_symbol":[]},"alphafold":{"accession":"Q86VP1","domains":[{"cath_id":"2.60.40.2840","chopping":"18-124","consensus_level":"high","plddt":92.914,"start":18,"end":124},{"cath_id":"-","chopping":"743-783","consensus_level":"high","plddt":84.6127,"start":743,"end":783}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86VP1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q86VP1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q86VP1-F1-predicted_aligned_error_v6.png","plddt_mean":75.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TAX1BP1","jax_strain_url":"https://www.jax.org/strain/search?query=TAX1BP1"},"sequence":{"accession":"Q86VP1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q86VP1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q86VP1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86VP1"}},"corpus_meta":[{"pmid":"34471133","id":"PMC_34471133","title":"Reconstitution 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In TAX1BP1-deficient mouse fibroblasts, IKK and JNK activation is elevated and persistent due to enhanced ubiquitination of RIP1 and TRAF6. In the absence of TAX1BP1, A20 is impaired in RIP1 binding and TRAF6 deubiquitination, establishing TAX1BP1 as an essential regulator of A20 function.\",\n      \"method\": \"TAX1BP1-deficient mouse fibroblasts (KO), co-immunoprecipitation, ubiquitination assays, NF-κB/JNK activation assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined cellular phenotype, co-IP showing A20/RIP1/TRAF6 interactions, replicated across multiple stimuli\",\n      \"pmids\": [\"17703191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TAX1BP1 acts as a negative regulator of TNF-α- and IL-1β-induced NF-κB activation. Ubiquitin binding via its C-terminal zinc finger domain is required for TRAF6 association and NF-κB inhibition. TAX1BP1-KO mice develop age-dependent inflammatory cardiac valvulitis, and TAX1BP1 functions as an essential adaptor between A20 and its ubiquitinated targets.\",\n      \"method\": \"TAX1BP1-KO mice, ubiquitin-binding zinc finger domain mutagenesis, NF-κB activation assays, co-immunoprecipitation\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse model with defined phenotype, domain mutagenesis establishing ubiquitin-binding requirement, replicated across multiple stimuli\",\n      \"pmids\": [\"18239685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TAX1BP1 and A20 inhibit antiviral signaling by targeting TBK1 and IKKi kinases. TAX1BP1-deficient MEFs show increased IFN-β production upon viral challenge. TAX1BP1 and A20 block antiviral signaling by disrupting K63-linked polyubiquitination of TBK1/IKKi independently of A20's deubiquitination domain. TRAF3 promotes TBK1-IKKi ubiquitination upstream. A20 requires TAX1BP1 to target and inactivate TBK1 and IKKi.\",\n      \"method\": \"Tax1bp1−/− MEFs, viral challenge assays, ubiquitination assays, co-immunoprecipitation, IRF3 activation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO MEFs, multiple orthogonal assays (IP, ubiquitination, reporter), identification of TBK1/IKKi as novel substrates\",\n      \"pmids\": [\"20304918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IKKα (but not IKKβ) phosphorylates TAX1BP1 on Ser593 and Ser624 in response to TNF or IL-1 stimulation. This phosphorylation is required for cytokine-dependent assembly of the A20 ubiquitin-editing complex (TAX1BP1, A20, Itch, RNF11) and subsequent downregulation of NF-κB canonical signaling.\",\n      \"method\": \"In vitro kinase assay, phospho-specific antibodies, IKKα KO/knockdown, co-immunoprecipitation, NF-κB reporter assays, site-directed mutagenesis (Ser593/Ser624)\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay with direct phosphorylation, mutagenesis of phosphosites, co-IP showing complex assembly, multiple orthogonal methods\",\n      \"pmids\": [\"21765415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ABIN1 interacts with TAX1BP1 and is essential for recruitment of TAX1BP1 and A20 to TBK1 and IKKi in response to poly(I:C). ABIN1 and TAX1BP1 together disrupt TRAF3-TBK1/IKKi interactions to attenuate K63-linked polyubiquitination of TBK1/IKKi. ABIN1's intact ubiquitin binding domain is required for interaction with TBK1/IKKi and IFN-β inhibition.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, ABIN1 ubiquitin-binding domain mutagenesis, IFN-β reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, domain mutagenesis, functional reporter assays, single lab\",\n      \"pmids\": [\"21885437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TAX1BP1 (as a paralogue of NDP52) functions as a bona fide cargo receptor for selective autophagy. Basal autophagy in K-Ras-dependent NSCLC is characterized by sequestration of TAX1BP1 (and NDP52), and this process promotes non-canonical NF-κB signaling in a TBK1-dependent manner.\",\n      \"method\": \"Autophagic flux assays, siRNA knockdown, non-canonical NF-κB reporter assays, TBK1 inhibition\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional KD with defined phenotype and pathway placement, single lab\",\n      \"pmids\": [\"23209807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Crystal and NMR solution structures of the tandem UBZ1+2 (ubiquitin-binding zinc finger) domains of TAX1BP1 were determined, revealing conformational flexibility between the two domains that may influence recognition of interacting partners including ubiquitinated signaling proteins.\",\n      \"method\": \"X-ray crystallography, NMR spectroscopy, NMR relaxation analysis\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal and NMR structures with relaxation data, single lab but two orthogonal structural methods\",\n      \"pmids\": [\"24239949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TAX1BP1 and myosin VI are recruited to ubiquitylated Salmonella and are required for xenophagic clearance. The ubiquitin-binding site of TAX1BP1 overlaps with the myosin VI binding site (in the zinc finger domains), such that ubiquitin and myosin VI bind TAX1BP1 in a mutually exclusive manner. Point mutations in the zinc finger domains that abrogate ubiquitin binding also ablate myosin VI binding. TAX1BP1 also associates with LC3 on the outer autophagosomal membrane.\",\n      \"method\": \"Structural analysis, point mutagenesis, co-immunoprecipitation, live-cell imaging, TAX1BP1 KD, Salmonella infection assays\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structural analysis plus mutagenesis plus functional xenophagy assays; mutually exclusive binding demonstrated biochemically\",\n      \"pmids\": [\"26451915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TAX1BP1 restrains virus-induced apoptosis by recruiting the E3 ligase Itch to MAVS on mitochondria, triggering MAVS ubiquitination and degradation. Virus infection promotes mitochondrial localization of TAX1BP1 and interaction with MAVS. Loss of TAX1BP1 or Itch results in increased MAVS protein levels and hypersensitivity to apoptosis. TAX1BP1 also undergoes degradation during RNA virus infection.\",\n      \"method\": \"TAX1BP1-KO and Itch-KO cells, co-immunoprecipitation, subcellular fractionation, apoptosis assays, ubiquitination assays, viral infection (VSV, Sendai virus)\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO cells with defined apoptosis phenotype, co-IP, fractionation showing mitochondrial localization, ubiquitination assays, two orthogonal methods\",\n      \"pmids\": [\"27736772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TRIM32 interacts with TRIF and mediates its selective autophagic degradation via TAX1BP1. TRIM32 links TRIF and TAX1BP1 through distinct domains, and poly(I:C)/LPS-induced TRIF degradation is inhibited by TAX1BP1 deficiency. This mechanism negatively regulates TLR3/4-mediated innate immune responses.\",\n      \"method\": \"Co-immunoprecipitation, TAX1BP1-deficient cells, domain mapping, autophagic flux assays, Trim32-KO mice, cytokine measurement\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse and KO cells, co-IP showing ternary complex, domain mapping, functional immune readout\",\n      \"pmids\": [\"28898289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TAX1BP1 drives a specialized form of autophagy required for the metabolic transition of activated T cells. TAX1BP1 binding to LC3/GABARAP via its LIR motif (but not its ubiquitin-binding domain) supports T cell proliferation and mTOR complex formation. TAX1BP1-deficient T cells stall in S phase due to bioenergetic and biosynthetic defects from defective autophagy induction and insufficient mTOR activation.\",\n      \"method\": \"TAX1BP1-KO T cells, LIR/UBD domain mutants, mTOR complex assays, metabolic assays, L-cysteine supplementation rescue\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined phenotype, domain-specific mutants separating UBD from LIR function, metabolic rescue experiment\",\n      \"pmids\": [\"28314591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Crystal structures of the SKICH domains of NDP52 and TAX1BP1 in complex with NAP1 were determined, revealing the mechanistic basis of NAP1-SKICH interaction and a general SKICH domain binding mode. TBK1-mediated phosphorylation sites in the SKICH domains of both receptors were evaluated with respect to their NAP1 interactions.\",\n      \"method\": \"X-ray crystallography, biochemical binding assays, phosphomimetic mutant analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — atomic-resolution crystal structures with biochemical validation, single lab\",\n      \"pmids\": [\"30459273\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Biochemical, NMR, and structural analyses defined the binding mechanism of TAX1BP1's tandem zinc fingers with ubiquitin, and showed that both tandem zinc fingers and the conformational rigidity between them are required for myosin VI binding. Ubiquitin and myosin VI bind TAX1BP1 in a mutually exclusive manner.\",\n      \"method\": \"NMR spectroscopy, biochemical assays, structural analysis, mutagenesis\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR and structural analysis with mutagenesis and biochemical validation of mutually exclusive binding\",\n      \"pmids\": [\"29940186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LAMTOR2/LAMTOR1 complex is required for TAX1BP1-mediated xenophagy. LAMTOR1 localizes to bacterium-containing endosomes, and LAMTOR2 is recruited to damaged endosomes in a LAMTOR1-dependent manner. LAMTOR2 interacts with TAX1BP1 (and NBR1, p62) and is necessary for TAX1BP1 recruitment to pathogen-containing autophagosomes. TAX1BP1 KO reduces autolysosome formation and subsequent bacterial degradation.\",\n      \"method\": \"LAMTOR1/2 KO cells, TAX1BP1 KO cells, co-immunoprecipitation, live imaging, GAS/Salmonella infection assays, autolysosome formation assays\",\n      \"journal\": \"Cellular microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO cells with defined xenophagy phenotype, co-IP showing interactions, single lab\",\n      \"pmids\": [\"30428163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Endogenous TAX1BP1 is recruited to and required for clearance of stress-induced protein aggregates via autophagy. TAX1BP1 depletion sensitizes cells to aggregate-induced proteotoxicity. Loss of TAX1BP1 in mice results in accumulation of high molecular weight ubiquitin conjugates and premature lipofuscin accumulation in brains, establishing TAX1BP1 as the primary autophagy receptor for aggregate clearance in the brain.\",\n      \"method\": \"TAX1BP1 KO mice, siRNA knockdown, autophagy receptor comparison (OPTN, NBR1, p62, NDP52, TAX1BP1), iPSC-derived neurons, viability assays, brain histology\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse model, iPSC-derived neurons, comparison across multiple receptors with defined phenotypic readouts\",\n      \"pmids\": [\"33207181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In vitro reconstitution defined that p62 is the major driver of ubiquitin condensate formation; NBR1 promotes condensation and recruits TAX1BP1 to condensates; TAX1BP1 is the main driver of FIP200 recruitment to the condensates, thereby initiating autophagic degradation. All three receptors interact with FIP200, but TAX1BP1 is the primary mediator of autophagy machinery recruitment.\",\n      \"method\": \"In vitro reconstitution with purified proteins, cell biology assays, co-IP, ubiquitin condensate formation assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified components, cell biology validation, multiple orthogonal approaches\",\n      \"pmids\": [\"34471133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Galectin-8 senses damaged Mtb-containing phagosomes and directly interacts with TAX1BP1. This galectin-8/TAX1BP1 interaction is necessary for efficient targeting of Mtb to selective autophagy in macrophages. Galectin-8 KO (but not galectin-3 or -9 KO alone) impairs TAX1BP1-mediated selective autophagy of Mtb.\",\n      \"method\": \"CRISPR/Cas9 KO macrophages (galectin-8-/-, galectin-3/8/9-/-), co-immunoprecipitation, confocal microscopy, Mtb replication assays\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with defined functional phenotype, co-IP identifying novel interaction, single lab\",\n      \"pmids\": [\"34225486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RNF34 is recruited to interact with TAX1BP1 and facilitates autophagic degradation of MAVS through K27-linked polyubiquitination. TAX1BP1 overexpression suppresses NLRP3 mitochondrial localization by inhibiting NLRP3 interaction with MAVS. Knockdown of RNF34 nullifies TAX1BP1-mediated protection against MAVS accumulation and NLRP3 inflammasome activation.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, TAX1BP1 overexpression (adenovirus), mitochondrial fractionation, ubiquitination assays, NLRP3 activation assays\",\n      \"journal\": \"Science bulletin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with domain-specific interactions, KD rescue experiments, ubiquitination assays, single lab\",\n      \"pmids\": [\"36654301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TNIP1 negatively regulates mitophagy rate through an evolutionarily conserved LIR motif (binding LC3/GABARAP) and an AHD3 domain that binds TAX1BP1. TNIP1 competes with autophagy receptors for FIP200 binding in a phosphorylation-dependent manner, providing a molecular basis for its inhibitory function during mitophagy.\",\n      \"method\": \"TNIP1 KO HeLa cells, ectopic expression, LIR/AHD3 domain mutants, co-immunoprecipitation, mitophagy rate assays, ULK1 complex interaction assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO and overexpression, domain mutagenesis establishing binding requirements, mechanistic competition assay for FIP200, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"36898370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Crystal structure of the TAX1BP1 SKICH domain in complex with the RB1CC1 (FIP200) coiled-coil region was determined. Two distinct binding sites between TAX1BP1 and RB1CC1 were identified: the SKICH/coiled-coil interaction and a CC1-domain/Claw interaction. RB1CC1 and NAP1 compete for SKICH binding, but NAP1's FIR motif can stabilize a ternary TAX1BP1/NAP1/RB1CC1 complex. The structure of GABARAP in complex with the non-canonical LIR motif of TAX1BP1 was also determined, revealing a unique binding mode.\",\n      \"method\": \"X-ray crystallography, biochemical binding assays, mutagenesis, ternary complex formation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple crystal structures with biochemical validation and mutagenesis, two orthogonal binding studies in one report\",\n      \"pmids\": [\"38437556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TBK1 and IKBKE/IKKi redundantly phosphorylate TAX1BP1 and regulate its autophagic turnover through canonical macroautophagy. TAX1BP1 phosphorylation promotes its localization to lysosomes resulting in degradation. TAX1BP1 plays a critical role in clearance of MAVS aggregates (aggrephagy), and its phosphorylation by TBK1/IKKi controls this MAVS aggrephagy function. During VSV infection, TAX1BP1 is targeted to lysosomes in an ATG8-family protein-independent manner.\",\n      \"method\": \"KO and KI MEFs, phospho-site mutagenesis, kinase assays, lysosomal localization assays, MAVS aggregate clearance assays (semi-denaturing AGE), VSV infection\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO/KI cells, phosphosite mutagenesis, multiple assays including semi-denaturing gel for aggregate clearance, lysosomal localization imaging\",\n      \"pmids\": [\"39193925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TAX1BP1 recruitment to ubiquitin-containing protein aggregates correlates with induction of autophagosome biogenesis and is not a constitutive component of condensates. TAX1BP1 is sufficient to recruit TBK1 kinase via the SINTBAD adaptor. The NBR1-TAX1BP1 binding site was defined and is adjacent to the GABARAP/LC3 interaction site. Increased ubiquitin load on condensates enhances TAX1BP1 recruitment, suggesting a cargo-sensing switch from condensation to sequestration.\",\n      \"method\": \"In vitro reconstitution, domain mutagenesis, SINTBAD interaction assays, NBR1-binding site mapping, ubiquitin condensate assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with domain mutagenesis, binding-site mapping, TBK1 recruitment assays\",\n      \"pmids\": [\"39448883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Tau fibrils from Alzheimer's disease brains are recognized by p62 but fail to recruit TAX1BP1 due to masking of ubiquitin moieties by excessive p62 coating. Monomeric Tau recruits both p62 and TAX1BP1. This irreversible, nonproductive p62-fibril interaction (due to fibril resistance to deubiquitylation) explains autophagy evasion by Tau aggregates.\",\n      \"method\": \"In vitro reconstitution with purified proteins and patient-derived Tau fibrils, ubiquitination assays, deubiquitylation resistance assays\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution with physiological and pathological substrates, mechanistic explanation of TAX1BP1 exclusion, single lab\",\n      \"pmids\": [\"38865459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TAX1BP1 acts as an autophagic receptor for STING1 degradation through its coiled-coil domain interacting with the cyclic dinucleotide binding domain of STING1. K63-ubiquitination of STING1 at K224 is required for TAX1BP1-dependent STING1 autophagic degradation. TAX1BP1 thus negatively regulates cGAS-STING-dependent antitumor immunity.\",\n      \"method\": \"Proteomic lysosomal analysis, co-immunoprecipitation, systematic K-to-R STING1 mutagenesis, ubiquitination assays, TAX1BP1 KO cells\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP domain mapping, systematic mutagenesis, proteomics, KO cells; single lab\",\n      \"pmids\": [\"40000606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"TAX1BP1 negatively regulates cGAS-STING signaling by promoting STING degradation through microautophagy via facilitating STING interaction with the ESCRT-0 protein HGS. TAX1BP1 also mediates autophagic degradation of fragmented Golgi (Golgiphagy) upon STING activation. TAX1BP1-deficient macrophages accumulate higher-order STING aggregates at the trans-Golgi network and show heightened type I IFN and proinflammatory cytokine production.\",\n      \"method\": \"TAX1BP1-KO macrophages, co-immunoprecipitation (STING-HGS interaction), ESCRT-pathway assays, Golgi morphology imaging, cytokine measurement, cGAS/STING agonist treatment\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO macrophages, co-IP identifying HGS interaction, Golgiphagy assays, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"41673009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Parkin-dependent K63-ubiquitination of TAX1BP1 at K549 within its third coiled-coil domain (CC3) regulates TAX1BP1's mitophagy function. This modification is not required for proteasomal degradation of TAX1BP1 but is a regulatory modification; ubiquitination-deficient TAX1BP1 (lacking CC3) reroutes mitochondria degradation to a less efficient endolysosomal pathway engaging VPS35.\",\n      \"method\": \"Mass spectrometry-based phosphoproteomics/ubiquitinomics, parkin WT vs catalytically inactive mutant, lysosomal inhibitor (bafilomycin A), TAX1BP1 ubiquitination-deficient mutant, mitophagy flux assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS identification of ubiquitination site, functional mutant analysis, mitophagy flux assays; preprint, single lab\",\n      \"pmids\": [\"40475537\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Tax1BP1 functions as a transcriptional coactivator for nuclear receptors (glucocorticoid receptor). It forms a complex with p300 and synergistically enhances E2-dependent viral transcription. Tax1BP1 prevents proteasomal degradation of HPV E2 protein, regulating E2 steady-state levels. The C-terminal region of Tax1BP1 interacts with the N-terminal transactivation domain of BPV1 E2.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, chromatin immunoprecipitation, transcriptional reporter assays, proteasome inhibitor experiments\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ChIP, reporter assays, proteasome inhibition; single lab with multiple methods\",\n      \"pmids\": [\"19109394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"TAX1BP1 is a nuclear receptor coactivator that forms a complex with the glucocorticoid receptor. HTLV-1 Tax protein binds TAX1BP1 directly, induces dissociation of TAX1BP1 from the glucocorticoid receptor complex, and represses TAX1BP1's coactivator function. Genetic knockout of Tax1bp1 in mice abrogates Tax's influence on nuclear receptor activation.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence colocalization, TAX1BP1 KO mice, nuclear receptor transcriptional assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse, co-IP, immunofluorescence, reporter assays; single lab\",\n      \"pmids\": [\"17283140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"NRP/Optineurin interacts with TAX1BP1 in a cooperative manner to modulate Tax1 ubiquitination and NF-κB activation. NRP requires Tax1's ubiquitination sites and its own ubiquitin-binding activity for interaction with Tax1. NRP, TAX1BP1, and Tax1 colocalize in Golgi-associated structures.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, ubiquitin-binding domain mutagenesis, NF-κB reporter assays\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, immunofluorescence localization, domain mutagenesis, reporter assays; single lab\",\n      \"pmids\": [\"19609363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TAX1BP1 and FIP200 mediate non-canonical autophagic degradation of p62 aggregates in neural stem cells (NSCs). Conditional deletion of Tax1bp1 in fip200 cKI mice (which have blocked canonical autophagy) leads to NSC deficiency and p62 aggregate accumulation phenocopying fip200 cKO mice. A TAX1BP1 mutant unable to bind FIP200 or NBR1/p62 fails to restore NSC maintenance.\",\n      \"method\": \"Conditional KO mouse models, TAX1BP1 domain mutants (FIP200-binding and NBR1/p62-binding deficient), NSC maintenance assays, p62 aggregate quantification\",\n      \"journal\": \"Zoological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO genetic epistasis in vivo, domain mutant rescue experiments, single lab\",\n      \"pmids\": [\"39021082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ASFV p22 promotes the association of TAX1BP1 with IFNAR1 via p22's transmembrane region, facilitating autophagic degradation of IFNAR1 and impairing JAK-STAT signaling. TAX1BP1 acts as the autophagy receptor mediating IFNAR1 degradation in this context.\",\n      \"method\": \"Co-immunoprecipitation, p22 domain mutagenesis (transmembrane region), IFNAR1 degradation assays, JAK-STAT signaling assays, TAX1BP1 interaction assays\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, domain mutagenesis, functional signaling assays; single lab\",\n      \"pmids\": [\"40668839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The TBK1-SCFFBXO3-TMEM192-TAX1BP1 regulatory axis orchestrates lysophagic flux. TBK1-dependent phosphorylation of FBXO3 facilitates FBXO3 interaction with TMEM192, promoting its ubiquitination, which is then recognized by TAX1BP1. Disruption of this pathway reduces lysophagic flux and causes accumulation of damaged lysosomes.\",\n      \"method\": \"TBK1 inhibition/KO, co-immunoprecipitation (FBXO3-TMEM192), ubiquitination assays, TAX1BP1 interaction assays, lysophagy flux assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — review/commentary of own findings, methods described briefly; primary data not fully detailed in abstract\",\n      \"pmids\": [\"40083080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TAX1BP1 (T6BP) influences both autophagy-dependent and -independent endogenous MHC-II presentation of viral antigens. T6BP silencing induces mislocalization of MHC-II loading compartments and rapid degradation of the invariant chain (CD74) without altering MHC-II expression or internalization. T6BP interacts with calnexin via calnexin's cytosolic tail, and calnexin silencing replicates the functional consequences of T6BP silencing.\",\n      \"method\": \"siRNA silencing, immunopeptidome analysis (MHC-II ligandome), co-immunoprecipitation (TAX1BP1-calnexin), confocal microscopy, T cell activation assays\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — immunopeptidome, co-IP, functional T cell assays, parallel calnexin validation; single lab\",\n      \"pmids\": [\"36215666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TAX1BP1 interacts with the SKICH domain-binding SINTBAD adaptor to recruit TBK1 kinase to ubiquitin condensates for autophagosome biogenesis initiation. TAX1BP1 is not a constitutive component of p62/NBR1-driven condensates but is recruited upon autophagy induction.\",\n      \"method\": \"In vitro reconstitution, SINTBAD co-IP, TAX1BP1 localization assays at condensates, ubiquitin load modulation\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with defined components, mechanistic demonstration of TBK1 recruitment via SINTBAD adaptor\",\n      \"pmids\": [\"39448883\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TAX1BP1 is a multifunctional selective autophagy receptor and ubiquitin-binding adaptor that (1) mediates autophagic clearance of ubiquitinated cargo (protein aggregates, mitochondria, damaged lysosomes, pathogens, and signaling organelles) by binding ubiquitin via its tandem C-terminal zinc finger (UBZ) domains and recruiting the autophagy initiation machinery (FIP200/RB1CC1) via its SKICH domain through NAP1/SINTBAD adaptors; (2) terminates NF-κB and IRF3/antiviral signaling as an essential co-factor of the A20 ubiquitin-editing complex—assembled upon IKKα-mediated phosphorylation of TAX1BP1 on Ser593/Ser624—to deubiquitinate and inactivate RIP1, TRAF6, TBK1, and IKKi; (3) restrains virus-induced apoptosis and innate immune overactivation by targeting MAVS (via Itch-mediated ubiquitination) and STING1 (via K224 K63-ubiquitination and ESCRT-0/HGS-mediated microautophagy/Golgiphagy) for degradation; and (4) functions as a nuclear receptor coactivator and regulates T cell metabolic activation through LC3/GABARAP binding via its LIR motif.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TAX1BP1 is a multifunctional ubiquitin-binding adaptor that operates at the interface of selective autophagy and inflammatory/antiviral signaling termination [#0, #14]. As a selective autophagy receptor, it recognizes ubiquitinated cargo through its tandem C-terminal zinc-finger (UBZ) domains—whose structures and ubiquitin-binding mechanism have been defined—and its non-canonical LIR motif engages LC3/GABARAP, while its SKICH domain recruits the FIP200/RB1CC1 autophagy-initiation machinery directly and via NAP1/SINTBAD adaptors that also bring in TBK1 [#6, #12, #15, #19, #21, #33]. The zinc-finger ubiquitin-binding site overlaps the myosin VI binding site, so ubiquitin and myosin VI engage TAX1BP1 in a mutually exclusive manner [#7, #12]. Through this receptor activity TAX1BP1 mediates clearance of stress-induced protein aggregates—serving as the primary aggrephagy receptor in brain [#14]—as well as xenophagy of intracellular bacteria recruited via galectin-8 and the LAMTOR1/2 complex [#13, #16], and within reconstituted ubiquitin condensates it is the principal driver of FIP200 recruitment to initiate autophagosome biogenesis [#15, #21]. In parallel, TAX1BP1 is an essential co-factor of the A20 ubiquitin-editing complex, acting as the adaptor linking A20 to its ubiquitinated substrates RIP1, TRAF6, TBK1 and IKKi to terminate NF-κB, JNK, and antiviral IRF3 signaling; this function requires IKKα-mediated phosphorylation of TAX1BP1 on Ser593/Ser624 to assemble the A20/Itch/RNF11 complex [#0, #1, #2, #3, #4]. TAX1BP1 further restrains innate immune and antiviral responses by directing degradation of signaling organelles and adaptors—recruiting E3 ligases Itch and RNF34 to ubiquitinate MAVS for autophagic clearance and restraining NLRP3 inflammasome activation [#8, #17, #20], and degrading STING1 via K63-ubiquitination, ESCRT-0/HGS-dependent microautophagy and Golgiphagy [#23, #24]. TBK1/IKKi phosphorylation of TAX1BP1 controls its own lysosomal turnover and its MAVS aggrephagy activity [#20]. Distinct from these cytoplasmic roles, TAX1BP1 functions as a nuclear receptor coactivator that complexes with the glucocorticoid receptor and p300, and supports the metabolic activation of T cells through LIR-dependent autophagy [#10, #26, #27].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established TAX1BP1's first defined function—as an essential regulator that enables A20 to terminate inflammatory signaling—answering whether the protein has a role in cytokine-induced NF-κB/JNK shutdown.\",\n      \"evidence\": \"TAX1BP1-deficient mouse fibroblasts with co-IP and ubiquitination assays across TNF-α/IL-1/LPS stimuli\",\n      \"pmids\": [\"17703191\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define how TAX1BP1 physically bridges A20 to substrates\", \"Mechanism of A20 recruitment regulation unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed that ubiquitin binding via the C-terminal zinc fingers is required for TRAF6 association and NF-κB inhibition, and that loss causes inflammatory pathology in vivo, linking the molecular adaptor activity to organismal phenotype.\",\n      \"evidence\": \"TAX1BP1-KO mice plus zinc-finger ubiquitin-binding mutagenesis and co-IP\",\n      \"pmids\": [\"18239685\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of ubiquitin recognition not yet defined\", \"Did not address how the adaptor function is switched on\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extended A20/TAX1BP1 negative regulation to antiviral signaling by identifying TBK1 and IKKi as targets, answering whether the complex restrains type I interferon induction.\",\n      \"evidence\": \"Tax1bp1−/− MEFs with viral challenge, ubiquitination and IRF3 reporter assays\",\n      \"pmids\": [\"20304918\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TAX1BP1 disrupts TRAF3-TBK1/IKKi ubiquitination mechanistically unclear\", \"Recruitment to kinase complex not defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined the upstream activating signal—IKKα phosphorylation of Ser593/Ser624—required to assemble the A20 editing complex, and identified ABIN1 as the adaptor recruiting TAX1BP1/A20 to TBK1/IKKi, establishing how the regulatory complex is triggered.\",\n      \"evidence\": \"In vitro kinase assays, phosphosite mutagenesis, IKKα KO, and ABIN1 co-IP/domain mutagenesis\",\n      \"pmids\": [\"21765415\", \"21885437\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other kinases phosphorylate the same sites in different contexts unaddressed\", \"ABIN1 work from single lab at Medium confidence\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Reframed TAX1BP1 as a bona fide selective autophagy cargo receptor, opening its second major functional domain and connecting autophagic sequestration to non-canonical NF-κB signaling.\",\n      \"evidence\": \"Autophagic flux assays and siRNA knockdown in K-Ras-dependent NSCLC\",\n      \"pmids\": [\"23209807\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cargo specificity not defined\", \"Single-lab functional knockdown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Provided the structural basis for ubiquitin recognition by solving the tandem UBZ1+2 domains, revealing inter-domain conformational flexibility relevant to partner recognition.\",\n      \"evidence\": \"X-ray crystallography and NMR relaxation analysis of the tandem zinc fingers\",\n      \"pmids\": [\"24239949\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitin-bound complex structure not determined here\", \"Functional consequence of flexibility untested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated TAX1BP1 drives xenophagy of ubiquitylated Salmonella and that ubiquitin and myosin VI bind the zinc fingers mutually exclusively, defining a regulatory switch within the cargo-recognition module.\",\n      \"evidence\": \"Structural analysis, point mutagenesis, live imaging and Salmonella infection with TAX1BP1 KD\",\n      \"pmids\": [\"26451915\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of myosin VI/ubiquitin competition in vivo unclear\", \"How autophagy machinery is recruited downstream not addressed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed TAX1BP1 restrains virus-induced apoptosis by recruiting Itch to ubiquitinate and degrade mitochondrial MAVS, establishing organelle/adaptor targeting as a distinct antiviral-restraining mode.\",\n      \"evidence\": \"TAX1BP1-KO and Itch-KO cells with fractionation, ubiquitination and apoptosis assays during VSV/Sendai infection\",\n      \"pmids\": [\"27736772\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MAVS degradation is autophagic vs proteasomal here not fully resolved\", \"Signal triggering mitochondrial relocalization undefined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Separated TAX1BP1's UBD-independent functions: a LIR-dependent specialized autophagy supporting T cell metabolic activation, and TRIM32-bridged selective degradation of TRIF to dampen TLR3/4 responses.\",\n      \"evidence\": \"TAX1BP1-KO T cells with LIR/UBD mutants and metabolic rescue; TRIM32-KO mice and domain mapping\",\n      \"pmids\": [\"28314591\", \"28898289\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How LIR-only function bypasses cargo ubiquitin recognition unclear\", \"TRIM32-TAX1BP1 cargo selectivity not generalized\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined at atomic resolution how the SKICH domain engages the NAP1 adaptor and how tandem zinc-finger rigidity governs myosin VI binding, mechanistically linking the autophagy-machinery-recruiting and cargo-binding modules.\",\n      \"evidence\": \"Crystal structures of SKICH/NAP1, plus NMR and biochemistry of zinc fingers with ubiquitin/myosin VI\",\n      \"pmids\": [\"30459273\", \"29940186\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"FIP200 engagement mode not yet structurally resolved\", \"Phospho-regulation of SKICH binding only evaluated with phosphomimetics\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified TAX1BP1 as the primary autophagy receptor for stress-induced protein aggregate clearance, including in brain, answering which receptor handles proteotoxic aggregates.\",\n      \"evidence\": \"TAX1BP1-KO mice, iPSC-derived neurons, and comparison against OPTN/NBR1/p62/NDP52\",\n      \"pmids\": [\"33207181\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TAX1BP1 is selectively recruited to aggregates not defined here\", \"Relationship to disease aggregates untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Reconstitution and KO studies placed TAX1BP1 within a receptor hierarchy—recruited to p62/NBR1 ubiquitin condensates as the primary driver of FIP200 recruitment—and identified galectin-8 and LAMTOR1/2 as upstream sensors/recruiters for pathogen autophagy, plus RNF34 for MAVS degradation.\",\n      \"evidence\": \"In vitro reconstitution with purified proteins; CRISPR galectin-8 KO and LAMTOR KO macrophages; RNF34 KD with ubiquitination assays\",\n      \"pmids\": [\"34471133\", \"34225486\", \"30428163\", \"36654301\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How NBR1 hands TAX1BP1 to condensates mechanistically incomplete\", \"RNF34/MAVS and LAMTOR findings single-lab Medium confidence\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved the SKICH-RB1CC1(FIP200) and GABARAP-LIR binding interfaces and showed RB1CC1 and NAP1 compete yet can form a ternary complex, while reconstitution showed cargo ubiquitin load acts as a switch recruiting TAX1BP1 and TBK1 (via SINTBAD) to initiate autophagosome biogenesis.\",\n      \"evidence\": \"Multiple crystal structures with biochemistry; in vitro reconstitution with domain mutagenesis and SINTBAD/NBR1 binding-site mapping\",\n      \"pmids\": [\"38437556\", \"39448883\", \"33207181\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo confirmation of the condensation-to-sequestration switch lacking\", \"Stoichiometry of ternary TAX1BP1/NAP1/RB1CC1 complex in cells unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established phospho-regulation of TAX1BP1's autophagy function—TBK1/IKKi redundantly phosphorylate it to drive its own lysosomal turnover and MAVS aggrephagy—and explained pathological autophagy evasion by Tau fibrils whose ubiquitins are masked by excessive p62 coating.\",\n      \"evidence\": \"KO/KI MEFs with phosphosite mutagenesis and semi-denaturing aggregate assays; in vitro reconstitution with patient-derived Tau fibrils\",\n      \"pmids\": [\"39193925\", \"38865459\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological triggers of TAX1BP1 self-turnover unclear\", \"Whether p62-masking generalizes to other fibrils untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended TAX1BP1's organelle/adaptor degradation roles to STING1 (via coiled-coil/K224-ubiquitin recognition and ESCRT-0/HGS microautophagy plus Golgiphagy), to IFNAR1 (hijacked by ASFV p22), and to autophagy-independent MHC-II antigen presentation via calnexin, broadening its immunoregulatory reach.\",\n      \"evidence\": \"TAX1BP1-KO cells/macrophages with co-IP, K-to-R mutagenesis, ESCRT and Golgi assays; immunopeptidome analysis with calnexin co-IP\",\n      \"pmids\": [\"40000606\", \"41673009\", \"40668839\", \"36215666\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Each substrate characterized in single labs\", \"How TAX1BP1 selects micro- vs macroautophagy routes unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TAX1BP1's distinct functional outputs—A20-complex signaling termination, ubiquitin/LIR-driven cargo autophagy, and nuclear receptor coactivation—are coordinated within a cell, and how post-translational modifications partition it among these roles, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking the signaling and autophagy functions\", \"Parkin K549 mitophagy regulation only in preprint\", \"Lysophagy axis (TMEM192) supported by Low-confidence evidence\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140097\", \"supporting_discovery_ids\": [6, 7, 12]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 15, 21]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [26, 27]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [15, 21]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [8, 17]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [20, 13]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [24, 28]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [26, 27]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [5, 14, 15, 21]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 2, 8, 24]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"complexes\": [\n      \"A20 ubiquitin-editing complex (TAX1BP1/A20/Itch/RNF11)\"\n    ],\n    \"partners\": [\n      \"A20\",\n      \"TRAF6\",\n      \"TBK1\",\n      \"RB1CC1/FIP200\",\n      \"NBR1\",\n      \"MAVS\",\n      \"STING1\",\n      \"ITCH\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}