{"gene":"PIP4P1","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2017,"finding":"TMEM55B (PIP4P1) recruits JIP4 to the lysosomal surface, inducing dynein-dependent retrograde transport of lysosomes toward the microtubule minus-end; TMEM55B overexpression causes perinuclear lysosomal collapse, while depletion of TMEM55B or JIP4 disperses lysosomes to the cell periphery.","method":"Overexpression, shRNA depletion, live imaging of lysosomal positioning, co-immunoprecipitation","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal functional experiments (OE and KD), replicated with two proteins (TMEM55B and JIP4), multiple orthogonal methods including live imaging and Co-IP, published in peer-reviewed journal","pmids":["29146937"],"is_preprint":false},{"year":2017,"finding":"TMEM55B expression is transcriptionally upregulated by TFEB and TFE3 upon starvation or cholesterol-induced lysosomal stress; depletion of TMEM55B or JIP4 abolishes starvation-induced retrograde lysosomal transport and prevents autophagosome-lysosome fusion.","method":"Reporter assays, qRT-PCR, TFEB/TFE3 overexpression, shRNA depletion, immunofluorescence","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (transcriptional reporter, KD, live imaging) in a single rigorous study","pmids":["29146937"],"is_preprint":false},{"year":2018,"finding":"TMEM55B interacts with components of the V-ATPase and Ragulator complexes at the lysosomal membrane; TMEM55B depletion attenuates amino acid-induced phosphorylation of mTORC1 substrates S6K and 4E-BP1, and abrogates recruitment of the V1 domain subcomplex of V-ATPase to lipid rafts.","method":"Proteomics, immunofluorescence, Co-IP, lipid raft fractionation, immunoblot for mTORC1 substrate phosphorylation","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods (proteomics, Co-IP, fractionation, functional KD) in a single lab study","pmids":["29644770"],"is_preprint":false},{"year":2018,"finding":"TMEM55B depletion evokes lysosomal stress as evidenced by translocation of TFEB to the nucleus, placing TMEM55B upstream of TFEB in a feedback loop.","method":"shRNA knockdown, immunofluorescence for TFEB localization","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, immunofluorescence localization with functional KD, no orthogonal method","pmids":["29644770"],"is_preprint":false},{"year":2019,"finding":"TMEM55B is phosphorylated by Erk/MAPK at Ser76 and Ser169 upon TLR ligand stimulation (blocked by MEK1/2 inhibitor U0126); phosphorylation-mimic mutants enhance perinuclear lysosomal clustering whereas phosphorylation-deficient mutants reduce it, although phosphorylation does not affect intrinsic phosphatase activity.","method":"Phosphosite mutagenesis, MEK1/2 inhibitor treatment, shRNA/CRISPR KO, immunofluorescence of LAMP1, immunoblot","journal":"Journal of biochemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — site-directed mutagenesis of phosphorylation sites combined with pharmacological inhibition and KO, multiple functional readouts in one study","pmids":["31329883"],"is_preprint":false},{"year":2021,"finding":"TMEM55B is S-palmitoylated at multiple cysteine residues; mutation of all cysteines prevents S-palmitoylation, causes retention of TMEM55B in the Golgi, and abolishes its ability to drive perinuclear lysosomal clustering. Additional mutagenesis of the dileucine-based lysosomal sorting motif in non-palmitoylated TMEM55B leads to partial missorting to the plasma membrane, implicating S-palmitoylation in AP-dependent lysosomal sorting.","method":"Acyl-RAC palmitoylation assay, cysteine mutagenesis, dileucine motif mutagenesis, immunofluorescence, subcellular fractionation","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — biochemical palmitoylation assay plus site-directed mutagenesis with functional localization readouts, multiple orthogonal methods","pmids":["34350967"],"is_preprint":false},{"year":2023,"finding":"The Parkinson's VPS35[D620N] mutation stimulates LRRK2-mediated recruitment and phosphorylation of Rab proteins at the lysosome, which recruits phospho-Rab effector RILPL1 to the lysosome where it binds directly to TMEM55B; conserved regions of RILPL1 and TMEM55B mediate this interaction, and mutations blocking binding were designed. Knockout of TMEM55B increases RILPL1 levels.","method":"Co-immunoprecipitation, mass spectrometry, mutagenesis, KO mouse fibroblasts/brain/lung, LRRK2 inhibitor treatment, proteasome inhibitor treatment","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, mutagenesis, KO in multiple tissues, pharmacological validation, replicated across cell types","pmids":["38091401"],"is_preprint":false},{"year":2024,"finding":"TMEM55B mediates NEDD4-dependent ubiquitination of PLEKHM1, causing its proteasomal degradation and halting autophagosome/lysosome fusion under oxidative stress.","method":"Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor treatment, KO cells, fusion assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — biochemical ubiquitination assay with Co-IP and functional KO readout, multiple orthogonal methods in one study","pmids":["38168055"],"is_preprint":false},{"year":2024,"finding":"TMEM55B promotes recruitment of ESCRT machinery components to lysosomal membranes to stimulate lysosomal repair in response to oxidative stress.","method":"Co-immunoprecipitation, immunofluorescence, KO cells, lysosomal damage assay","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and KO with functional repair readout, single lab, abstract-level detail","pmids":["38168055"],"is_preprint":false},{"year":2024,"finding":"TMEM55B sequesters the FLCN/FNIP complex to facilitate nuclear translocation of transcription factor TFE3, enabling transcriptional stress response programs.","method":"Co-immunoprecipitation, immunofluorescence of TFE3 localization, KO cells","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional KO with TFE3 localization readout, single lab","pmids":["38168055"],"is_preprint":false},{"year":2024,"finding":"Knockout of tmem55 genes in zebrafish embryos increases susceptibility to oxidative stress (arsenite toxicity), establishing an in vivo functional requirement.","method":"Zebrafish tmem55 KO, arsenite survival assay","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined in vivo phenotypic readout, single lab","pmids":["38168055"],"is_preprint":false},{"year":2025,"finding":"Crystal structures of the cytosolic region (residues 80–166) of TMEM55B alone and in complex with a C-terminal RILPL1 peptide (TMEM55B-binding motif, TBM) reveal two tandem RING-like domains, each forming a Zn2+-stabilized 40-residue β-sandwich; the RILPL1 TBM sits in a shallow groove and binding is mediated primarily by backbone hydrogen bonding anchored by two RILPL1 glutamate residues.","method":"X-ray crystallography, co-immunoprecipitation, mass spectrometry, mutagenesis","journal":"Structure (London, England : 1993)","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures of apo and complex forms, validated by Co-IP and mutagenesis, peer-reviewed","pmids":["41314214"],"is_preprint":false},{"year":2025,"finding":"TMEM55B acts as a central lysosomal hub, forming complexes (independently of phospho-Rabs) with multiple adaptor proteins containing a conserved TBM motif: JIP3, JIP4, OCRL, WDR81, and TBC1D9B.","method":"Co-immunoprecipitation, mass spectrometry, mutagenesis of TBM","journal":"Structure (London, England : 1993)","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with MS confirmation, mutagenesis blocking binding, structural validation, single lab but multiple client proteins","pmids":["41314214"],"is_preprint":false},{"year":2026,"finding":"TMEM55B binds to the GAP protein TBC1D9B, which directly interacts with ARL8B-GTP and stimulates its GTPase activity; knockout of TMEM55B causes lysosome dispersion, defective autophagic flux, and impaired adaptive degradative response — phenotypes occluded by co-depletion of ARL8.","method":"Co-immunoprecipitation, GTPase activity assay, KO cells, epistasis (double KO), immunofluorescence","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — biochemical GTPase assay, Co-IP, genetic epistasis with double KO, multiple functional readouts","pmids":["41832156"],"is_preprint":false},{"year":2025,"finding":"TMEM55B suppresses CTNS (cystinosin) levels through TMEM55B-dependent ubiquitylation of CTNS; JIP4 counteracts this by suppressing TMEM55B-dependent ubiquitylation, thereby maintaining CTNS abundance and lysosomal cystine efflux.","method":"Ubiquitylation assay, JIP4 KO cells and mice, CTNS protein level quantification, lysosomal cystine measurement","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — biochemical ubiquitylation assay and KO with defined metabolic readout, preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.06.06.657909"],"is_preprint":true},{"year":2025,"finding":"TMEM55B interacts with the lipid transfer protein PDZD8; TMEM55B suppression reduces lysosomal acidification, impairs lipid droplet turnover, attenuates lysosomal Ca2+ release and reuptake, and diminishes ATP-induced ER Ca2+ responses (CICR), implicating TMEM55B in coordinating lysosomal function at ER-lysosome membrane contact sites.","method":"Co-immunoprecipitation (PDZD8 pulldown), lysosomal pH assay, lipid droplet imaging, Ca2+ imaging, TMEM55B knockdown","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — multiple functional assays with KD, Co-IP for binding partner, preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.10.21.683636"],"is_preprint":true}],"current_model":"PIP4P1/TMEM55B is an integral lysosomal membrane protein that functions as a central scaffolding hub: its cytosolic domain (two tandem Zn2+-stabilized RING-like domains) recruits multiple adaptors bearing a conserved TMEM55B-binding motif (JIP4, JIP3, RILPL1, OCRL, WDR81, TBC1D9B) to orchestrate retrograde dynein-dependent lysosomal transport, mTORC1 activation via V-ATPase assembly, lysosomal repair via ESCRT recruitment, autophagy flux control via NEDD4-mediated PLEKHM1 ubiquitination and JIP4-regulated CTNS ubiquitination, and stress-responsive TFE3/TFEB transcription via FLCN/FNIP sequestration; its trafficking to lysosomes requires S-palmitoylation of cytoplasmic cysteines and a dileucine sorting motif, and its activity is further tuned by Erk/MAPK phosphorylation at Ser76/Ser169."},"narrative":{"mechanistic_narrative":"PIP4P1 (TMEM55B) is an integral lysosomal membrane protein that serves as a central scaffolding hub coordinating lysosomal positioning, stress responses, and degradative flux [PMID:29146937, PMID:41314214]. Its cytosolic region folds into two tandem RING-like domains, each a Zn2+-stabilized β-sandwich, that engage adaptor proteins through a shallow groove recognizing a conserved TMEM55B-binding motif (TBM); through this interface it recruits multiple clients including JIP3, JIP4, OCRL, WDR81, TBC1D9B, and RILPL1 [PMID:41314214]. By recruiting JIP4 to the lysosomal surface, TMEM55B drives dynein-dependent retrograde transport toward the microtubule minus-end, producing perinuclear lysosome clustering, while its loss disperses lysosomes to the cell periphery [PMID:29146937]. This positioning activity is regulated transcriptionally—TFEB and TFE3 upregulate TMEM55B upon starvation or lysosomal stress, and TMEM55B-driven retrograde transport is required for autophagosome–lysosome fusion [PMID:29146937]. TMEM55B also constrains lysosome dispersion via TBC1D9B, a GAP that stimulates the GTPase activity of ARL8B, with TMEM55B loss-of-function phenotypes occluded by ARL8 co-depletion [PMID:41832156]. Beyond positioning, TMEM55B participates in mTORC1 signaling through interactions with V-ATPase and Ragulator components [PMID:29644770], in oxidative-stress responses by promoting NEDD4-dependent ubiquitination of PLEKHM1 to halt fusion and by recruiting ESCRT machinery for lysosomal repair [PMID:38168055], and in transcriptional stress signaling by sequestering the FLCN/FNIP complex to enable TFE3 nuclear translocation [PMID:38168055]. The protein's lysosomal delivery depends on S-palmitoylation of cytoplasmic cysteines together with a dileucine sorting motif, and its lysosome-clustering activity is tuned by Erk/MAPK phosphorylation at Ser76 and Ser169 [PMID:31329883, PMID:34350967]. A zebrafish tmem55 knockout shows increased susceptibility to oxidative stress, establishing an in vivo requirement [PMID:38168055].","teleology":[{"year":2017,"claim":"Established TMEM55B as a lysosomal positioning factor by showing it recruits JIP4 to drive dynein-dependent retrograde transport, defining the first molecular function of the protein.","evidence":"Overexpression, shRNA depletion, live imaging of lysosome positioning, and Co-IP in cultured cells","pmids":["29146937"],"confidence":"High","gaps":["Did not resolve how TMEM55B physically links to dynein machinery beyond JIP4","Did not define the structural basis of the JIP4 interaction"]},{"year":2017,"claim":"Placed TMEM55B in a stress-responsive transcriptional circuit by showing TFEB/TFE3 upregulate it during starvation and that it is required for starvation-induced retrograde transport and autophagosome–lysosome fusion.","evidence":"Reporter assays, qRT-PCR, TFEB/TFE3 overexpression, shRNA depletion, immunofluorescence","pmids":["29146937"],"confidence":"High","gaps":["Did not establish whether the transcriptional regulation forms a closed feedback loop","Did not separate fusion defects from positioning defects mechanistically"]},{"year":2018,"claim":"Connected TMEM55B to nutrient signaling by linking it to V-ATPase/Ragulator assembly and amino acid-induced mTORC1 substrate phosphorylation, and identified a feedback relationship with TFEB.","evidence":"Proteomics, Co-IP, lipid raft fractionation, immunoblot for S6K/4E-BP1, and TFEB localization by IF after KD","pmids":["29644770"],"confidence":"Medium","gaps":["Single-lab study without orthogonal confirmation of the V-ATPase interaction","Direct versus indirect contribution to mTORC1 activation not dissected","TFEB feedback shown only by localization"]},{"year":2019,"claim":"Showed that TMEM55B activity is regulated post-translationally by Erk/MAPK phosphorylation at Ser76/Ser169 downstream of TLR signaling, modulating lysosome clustering independently of intrinsic phosphatase activity.","evidence":"Phosphosite mutagenesis, MEK1/2 inhibitor (U0126), shRNA/CRISPR KO, LAMP1 IF, immunoblot","pmids":["31329883"],"confidence":"High","gaps":["Mechanism by which phosphorylation alters clustering not defined","Functional link between TLR signaling and lysosome positioning physiology not established"]},{"year":2021,"claim":"Defined the trafficking determinants of TMEM55B, demonstrating that S-palmitoylation of cytoplasmic cysteines plus a dileucine motif route the protein to lysosomes and are required for its clustering activity.","evidence":"Acyl-RAC palmitoylation assay, cysteine and dileucine mutagenesis, IF, subcellular fractionation","pmids":["34350967"],"confidence":"High","gaps":["The palmitoyltransferase responsible was not identified","Whether palmitoylation is dynamically regulated was not addressed"]},{"year":2023,"claim":"Linked TMEM55B to Parkinson's disease pathways by showing VPS35[D620N]/LRRK2-driven phospho-Rab signaling recruits RILPL1 to lysosomes where it binds TMEM55B directly, and that TMEM55B regulates RILPL1 levels.","evidence":"Co-IP, mass spectrometry, mutagenesis, KO mouse tissues, LRRK2 and proteasome inhibitor treatment","pmids":["38091401"],"confidence":"High","gaps":["Functional consequence of the RILPL1–TMEM55B interaction for disease not resolved","Did not determine whether RILPL1 binds the same site as JIP4"]},{"year":2024,"claim":"Established TMEM55B as a master regulator of the oxidative-stress lysosomal response, coordinating NEDD4-dependent PLEKHM1 degradation to halt fusion, ESCRT-mediated repair, FLCN/FNIP sequestration for TFE3 activation, and an in vivo oxidative-stress requirement.","evidence":"Co-IP, ubiquitination assays, ESCRT recruitment IF, TFE3 localization, KO cells, lysosomal damage assays, zebrafish tmem55 KO arsenite survival","pmids":["38168055"],"confidence":"High","gaps":["How a single protein switches between these distinct outputs not resolved","ESCRT and FLCN/FNIP arms rest on single-lab Co-IP plus KO without reciprocal validation","Direct versus indirect role in PLEKHM1 ubiquitination not fully separated"]},{"year":2025,"claim":"Provided the structural basis for hub function, solving crystal structures of the cytosolic tandem RING-like domains and a RILPL1 TBM complex, and identifying a shared set of TBM-bearing adaptors (JIP3, JIP4, OCRL, WDR81, TBC1D9B).","evidence":"X-ray crystallography of apo and complex forms, Co-IP, mass spectrometry, TBM mutagenesis","pmids":["41314214"],"confidence":"High","gaps":["Did not determine whether adaptors compete for a single groove or bind simultaneously","Functional hierarchy among clients not established"]},{"year":2026,"claim":"Resolved how TMEM55B antagonizes lysosome dispersion mechanistically by recruiting the GAP TBC1D9B to stimulate ARL8B GTPase activity, with epistasis showing TMEM55B acts through ARL8.","evidence":"Co-IP, GTPase activity assay, KO cells, ARL8/TMEM55B double-KO epistasis, IF","pmids":["41832156"],"confidence":"High","gaps":["Spatiotemporal coordination between this GAP-based control and JIP4-dynein transport not defined"]},{"year":2025,"claim":"Extended TMEM55B function into lysosomal metabolite homeostasis and membrane contact sites, implicating it in CTNS/cystine regulation via ubiquitylation and in ER–lysosome lipid and Ca2+ coordination via PDZD8.","evidence":"Ubiquitylation assays, JIP4 KO cells/mice, cystine measurement (preprint); PDZD8 Co-IP, lysosomal pH, lipid droplet and Ca2+ imaging (preprint)","pmids":["bio_10.1101_2025.06.06.657909","bio_10.1101_2025.10.21.683636"],"confidence":"Medium","gaps":["Both findings are preprints not yet peer-reviewed","Whether TMEM55B is the direct E3-recruiting factor for CTNS not established","PDZD8 interaction not validated reciprocally"]},{"year":null,"claim":"It remains unknown how TMEM55B integrates and prioritizes its competing adaptor-driven outputs—positioning, repair, transcriptional stress, and metabolite control—at a single shared binding groove within an intact cell.","evidence":"","pmids":[],"confidence":"High","gaps":["No quantitative model of adaptor competition or hierarchy","No structural data on multivalent or simultaneous client engagement","Physiological triggers selecting each output are undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,11,12]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[13]}],"localization":[{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[0,5,8]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[1,7,13]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,13]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[8,9,10]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,4]}],"complexes":[],"partners":["JIP4","JIP3","RILPL1","OCRL","WDR81","TBC1D9B","PLEKHM1","PDZD8"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q86T03","full_name":"Type 1 phosphatidylinositol 4,5-bisphosphate 4-phosphatase","aliases":["PtdIns-4,5-P2 4-Ptase I","Transmembrane protein 55B"],"length_aa":277,"mass_kda":29.5,"function":"Catalyzes the hydrolysis of phosphatidylinositol-4,5-bisphosphate (PtdIns-4,5-P2) to phosphatidylinositol-4-phosphate (PtdIns-4-P) (PubMed:16365287). Does not hydrolyze phosphatidylinositol 3,4,5-trisphosphate, phosphatidylinositol 3,4-bisphosphate, inositol 3,5-bisphosphate, inositol 3,4-bisphosphate, phosphatidylinositol 5-monophosphate, phosphatidylinositol 4-monophosphate and phosphatidylinositol 3-monophosphate (PubMed:16365287). Regulates lysosomal positioning by recruiting JIP4 to lysosomal membranes, thus inducing retrograde transport of lysosomes along microtubules (PubMed:29146937). Contributes to assembly of the V-ATPase complex in lipid rafts of the lysosomal membrane and to subsequent amino acid-dependent activation of mTORC1 (PubMed:29644770). May play a role in the regulation of cellular cholesterol metabolism (PubMed:25035345)","subcellular_location":"Late endosome membrane; Lysosome membrane; Cytoplasmic vesicle, phagosome membrane; Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q86T03/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PIP4P1","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000165782","cell_line_id":"CID000152","localizations":[{"compartment":"vesicles","grade":3},{"compartment":"membrane","grade":2}],"interactors":[{"gene":"TMEM55B","stoichiometry":10.0},{"gene":"LAMTOR3","stoichiometry":10.0},{"gene":"LOH12CR1","stoichiometry":10.0},{"gene":"LAMTOR1","stoichiometry":10.0},{"gene":"C10ORF32-ASMT;C10ORF32","stoichiometry":10.0},{"gene":"LAMTOR5","stoichiometry":10.0},{"gene":"BLOC1S2","stoichiometry":10.0},{"gene":"LAMTOR2","stoichiometry":4.0},{"gene":"VPS13C","stoichiometry":0.2},{"gene":"TPD52","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000152","total_profiled":1310},"omim":[{"mim_id":"609865","title":"PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE 4-PHOSPHATASE, TYPE I; PIP4P1","url":"https://www.omim.org/entry/609865"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PIP4P1"},"hgnc":{"alias_symbol":["MGC26684"],"prev_symbol":["C14orf9","TMEM55B"]},"alphafold":{"accession":"Q86T03","domains":[{"cath_id":"-","chopping":"79-114","consensus_level":"medium","plddt":83.9808,"start":79,"end":114},{"cath_id":"-","chopping":"119-155","consensus_level":"medium","plddt":86.6335,"start":119,"end":155},{"cath_id":"-","chopping":"189-277","consensus_level":"medium","plddt":79.4017,"start":189,"end":277}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86T03","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q86T03-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q86T03-F1-predicted_aligned_error_v6.png","plddt_mean":69.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PIP4P1","jax_strain_url":"https://www.jax.org/strain/search?query=PIP4P1"},"sequence":{"accession":"Q86T03","fasta_url":"https://rest.uniprot.org/uniprotkb/Q86T03.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q86T03/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86T03"}},"corpus_meta":[{"pmid":"29146937","id":"PMC_29146937","title":"TFEB regulates lysosomal positioning by modulating TMEM55B expression and JIP4 recruitment to lysosomes.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/29146937","citation_count":160,"is_preprint":false},{"pmid":"38091401","id":"PMC_38091401","title":"Parkinson's VPS35[D620N] mutation induces LRRK2-mediated lysosomal association of RILPL1 and TMEM55B.","date":"2023","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/38091401","citation_count":32,"is_preprint":false},{"pmid":"29644770","id":"PMC_29644770","title":"TMEM55B contributes to lysosomal homeostasis and amino acid-induced mTORC1 activation.","date":"2018","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/29644770","citation_count":32,"is_preprint":false},{"pmid":"38168055","id":"PMC_38168055","title":"TMEM55B links autophagy flux, lysosomal repair, and TFE3 activation in response to oxidative stress.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/38168055","citation_count":22,"is_preprint":false},{"pmid":"31329883","id":"PMC_31329883","title":"Phosphorylation of TMEM55B by Erk/MAPK regulates lysosomal positioning.","date":"2019","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31329883","citation_count":22,"is_preprint":false},{"pmid":"34350967","id":"PMC_34350967","title":"S-palmitoylation determines TMEM55B-dependent positioning of lysosomes.","date":"2021","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/34350967","citation_count":11,"is_preprint":false},{"pmid":"33537719","id":"PMC_33537719","title":"Regulation of lysosomal positioning via TMEM55B phosphorylation.","date":"2021","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/33537719","citation_count":4,"is_preprint":false},{"pmid":"41314214","id":"PMC_41314214","title":"Structural basis for binding of RILPL1 to TMEM55B reveals a lysosomal platform for adaptor assembly through a conserved peptide motif.","date":"2025","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/41314214","citation_count":2,"is_preprint":false},{"pmid":"41513622","id":"PMC_41513622","title":"Loss of TMEM55B modulates lipid metabolism through dysregulated lipophagy and mitochondrial function.","date":"2026","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/41513622","citation_count":1,"is_preprint":false},{"pmid":"37961834","id":"PMC_37961834","title":"Hippocampal TMEM55B overexpression in the 5XFAD mouse model of Alzheimer's disease.","date":"2023","source":"Hippocampus","url":"https://pubmed.ncbi.nlm.nih.gov/37961834","citation_count":1,"is_preprint":false},{"pmid":"41650928","id":"PMC_41650928","title":"TMEM55B-Jack of all trades in the endo-lysosomal system?","date":"2026","source":"Structure (London, England : 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lipolysis","date":"2025-10-21","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.21.683636","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.06.06.657909","title":"JIP4 deficiency causes a lysosomal storage disease arising from impaired cystine efflux","date":"2025-06-09","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.06.657909","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.11.04.621986","title":"Small molecule modulator of neuronal lysosome positioning and function resolves Alzheimer’s Disease-linked pathologies in cultured human neurons","date":"2024-11-05","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.04.621986","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9278,"output_tokens":3879,"usd":0.043009,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11572,"output_tokens":4111,"usd":0.080318,"stage2_stop_reason":"end_turn"},"total_usd":0.123327,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2017,\n      \"finding\": \"TMEM55B (PIP4P1) recruits JIP4 to the lysosomal surface, inducing dynein-dependent retrograde transport of lysosomes toward the microtubule minus-end; TMEM55B overexpression causes perinuclear lysosomal collapse, while depletion of TMEM55B or JIP4 disperses lysosomes to the cell periphery.\",\n      \"method\": \"Overexpression, shRNA depletion, live imaging of lysosomal positioning, co-immunoprecipitation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal functional experiments (OE and KD), replicated with two proteins (TMEM55B and JIP4), multiple orthogonal methods including live imaging and Co-IP, published in peer-reviewed journal\",\n      \"pmids\": [\"29146937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TMEM55B expression is transcriptionally upregulated by TFEB and TFE3 upon starvation or cholesterol-induced lysosomal stress; depletion of TMEM55B or JIP4 abolishes starvation-induced retrograde lysosomal transport and prevents autophagosome-lysosome fusion.\",\n      \"method\": \"Reporter assays, qRT-PCR, TFEB/TFE3 overexpression, shRNA depletion, immunofluorescence\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (transcriptional reporter, KD, live imaging) in a single rigorous study\",\n      \"pmids\": [\"29146937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TMEM55B interacts with components of the V-ATPase and Ragulator complexes at the lysosomal membrane; TMEM55B depletion attenuates amino acid-induced phosphorylation of mTORC1 substrates S6K and 4E-BP1, and abrogates recruitment of the V1 domain subcomplex of V-ATPase to lipid rafts.\",\n      \"method\": \"Proteomics, immunofluorescence, Co-IP, lipid raft fractionation, immunoblot for mTORC1 substrate phosphorylation\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods (proteomics, Co-IP, fractionation, functional KD) in a single lab study\",\n      \"pmids\": [\"29644770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TMEM55B depletion evokes lysosomal stress as evidenced by translocation of TFEB to the nucleus, placing TMEM55B upstream of TFEB in a feedback loop.\",\n      \"method\": \"shRNA knockdown, immunofluorescence for TFEB localization\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, immunofluorescence localization with functional KD, no orthogonal method\",\n      \"pmids\": [\"29644770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TMEM55B is phosphorylated by Erk/MAPK at Ser76 and Ser169 upon TLR ligand stimulation (blocked by MEK1/2 inhibitor U0126); phosphorylation-mimic mutants enhance perinuclear lysosomal clustering whereas phosphorylation-deficient mutants reduce it, although phosphorylation does not affect intrinsic phosphatase activity.\",\n      \"method\": \"Phosphosite mutagenesis, MEK1/2 inhibitor treatment, shRNA/CRISPR KO, immunofluorescence of LAMP1, immunoblot\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — site-directed mutagenesis of phosphorylation sites combined with pharmacological inhibition and KO, multiple functional readouts in one study\",\n      \"pmids\": [\"31329883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TMEM55B is S-palmitoylated at multiple cysteine residues; mutation of all cysteines prevents S-palmitoylation, causes retention of TMEM55B in the Golgi, and abolishes its ability to drive perinuclear lysosomal clustering. Additional mutagenesis of the dileucine-based lysosomal sorting motif in non-palmitoylated TMEM55B leads to partial missorting to the plasma membrane, implicating S-palmitoylation in AP-dependent lysosomal sorting.\",\n      \"method\": \"Acyl-RAC palmitoylation assay, cysteine mutagenesis, dileucine motif mutagenesis, immunofluorescence, subcellular fractionation\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — biochemical palmitoylation assay plus site-directed mutagenesis with functional localization readouts, multiple orthogonal methods\",\n      \"pmids\": [\"34350967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The Parkinson's VPS35[D620N] mutation stimulates LRRK2-mediated recruitment and phosphorylation of Rab proteins at the lysosome, which recruits phospho-Rab effector RILPL1 to the lysosome where it binds directly to TMEM55B; conserved regions of RILPL1 and TMEM55B mediate this interaction, and mutations blocking binding were designed. Knockout of TMEM55B increases RILPL1 levels.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, mutagenesis, KO mouse fibroblasts/brain/lung, LRRK2 inhibitor treatment, proteasome inhibitor treatment\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, mutagenesis, KO in multiple tissues, pharmacological validation, replicated across cell types\",\n      \"pmids\": [\"38091401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TMEM55B mediates NEDD4-dependent ubiquitination of PLEKHM1, causing its proteasomal degradation and halting autophagosome/lysosome fusion under oxidative stress.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor treatment, KO cells, fusion assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical ubiquitination assay with Co-IP and functional KO readout, multiple orthogonal methods in one study\",\n      \"pmids\": [\"38168055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TMEM55B promotes recruitment of ESCRT machinery components to lysosomal membranes to stimulate lysosomal repair in response to oxidative stress.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, KO cells, lysosomal damage assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and KO with functional repair readout, single lab, abstract-level detail\",\n      \"pmids\": [\"38168055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TMEM55B sequesters the FLCN/FNIP complex to facilitate nuclear translocation of transcription factor TFE3, enabling transcriptional stress response programs.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence of TFE3 localization, KO cells\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional KO with TFE3 localization readout, single lab\",\n      \"pmids\": [\"38168055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Knockout of tmem55 genes in zebrafish embryos increases susceptibility to oxidative stress (arsenite toxicity), establishing an in vivo functional requirement.\",\n      \"method\": \"Zebrafish tmem55 KO, arsenite survival assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined in vivo phenotypic readout, single lab\",\n      \"pmids\": [\"38168055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Crystal structures of the cytosolic region (residues 80–166) of TMEM55B alone and in complex with a C-terminal RILPL1 peptide (TMEM55B-binding motif, TBM) reveal two tandem RING-like domains, each forming a Zn2+-stabilized 40-residue β-sandwich; the RILPL1 TBM sits in a shallow groove and binding is mediated primarily by backbone hydrogen bonding anchored by two RILPL1 glutamate residues.\",\n      \"method\": \"X-ray crystallography, co-immunoprecipitation, mass spectrometry, mutagenesis\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures of apo and complex forms, validated by Co-IP and mutagenesis, peer-reviewed\",\n      \"pmids\": [\"41314214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TMEM55B acts as a central lysosomal hub, forming complexes (independently of phospho-Rabs) with multiple adaptor proteins containing a conserved TBM motif: JIP3, JIP4, OCRL, WDR81, and TBC1D9B.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, mutagenesis of TBM\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with MS confirmation, mutagenesis blocking binding, structural validation, single lab but multiple client proteins\",\n      \"pmids\": [\"41314214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"TMEM55B binds to the GAP protein TBC1D9B, which directly interacts with ARL8B-GTP and stimulates its GTPase activity; knockout of TMEM55B causes lysosome dispersion, defective autophagic flux, and impaired adaptive degradative response — phenotypes occluded by co-depletion of ARL8.\",\n      \"method\": \"Co-immunoprecipitation, GTPase activity assay, KO cells, epistasis (double KO), immunofluorescence\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — biochemical GTPase assay, Co-IP, genetic epistasis with double KO, multiple functional readouts\",\n      \"pmids\": [\"41832156\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TMEM55B suppresses CTNS (cystinosin) levels through TMEM55B-dependent ubiquitylation of CTNS; JIP4 counteracts this by suppressing TMEM55B-dependent ubiquitylation, thereby maintaining CTNS abundance and lysosomal cystine efflux.\",\n      \"method\": \"Ubiquitylation assay, JIP4 KO cells and mice, CTNS protein level quantification, lysosomal cystine measurement\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — biochemical ubiquitylation assay and KO with defined metabolic readout, preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.06.06.657909\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TMEM55B interacts with the lipid transfer protein PDZD8; TMEM55B suppression reduces lysosomal acidification, impairs lipid droplet turnover, attenuates lysosomal Ca2+ release and reuptake, and diminishes ATP-induced ER Ca2+ responses (CICR), implicating TMEM55B in coordinating lysosomal function at ER-lysosome membrane contact sites.\",\n      \"method\": \"Co-immunoprecipitation (PDZD8 pulldown), lysosomal pH assay, lipid droplet imaging, Ca2+ imaging, TMEM55B knockdown\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — multiple functional assays with KD, Co-IP for binding partner, preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.10.21.683636\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"PIP4P1/TMEM55B is an integral lysosomal membrane protein that functions as a central scaffolding hub: its cytosolic domain (two tandem Zn2+-stabilized RING-like domains) recruits multiple adaptors bearing a conserved TMEM55B-binding motif (JIP4, JIP3, RILPL1, OCRL, WDR81, TBC1D9B) to orchestrate retrograde dynein-dependent lysosomal transport, mTORC1 activation via V-ATPase assembly, lysosomal repair via ESCRT recruitment, autophagy flux control via NEDD4-mediated PLEKHM1 ubiquitination and JIP4-regulated CTNS ubiquitination, and stress-responsive TFE3/TFEB transcription via FLCN/FNIP sequestration; its trafficking to lysosomes requires S-palmitoylation of cytoplasmic cysteines and a dileucine sorting motif, and its activity is further tuned by Erk/MAPK phosphorylation at Ser76/Ser169.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PIP4P1 (TMEM55B) is an integral lysosomal membrane protein that serves as a central scaffolding hub coordinating lysosomal positioning, stress responses, and degradative flux [#0, #12]. Its cytosolic region folds into two tandem RING-like domains, each a Zn2+-stabilized β-sandwich, that engage adaptor proteins through a shallow groove recognizing a conserved TMEM55B-binding motif (TBM); through this interface it recruits multiple clients including JIP3, JIP4, OCRL, WDR81, TBC1D9B, and RILPL1 [#11, #12]. By recruiting JIP4 to the lysosomal surface, TMEM55B drives dynein-dependent retrograde transport toward the microtubule minus-end, producing perinuclear lysosome clustering, while its loss disperses lysosomes to the cell periphery [#0]. This positioning activity is regulated transcriptionally—TFEB and TFE3 upregulate TMEM55B upon starvation or lysosomal stress, and TMEM55B-driven retrograde transport is required for autophagosome–lysosome fusion [#1]. TMEM55B also constrains lysosome dispersion via TBC1D9B, a GAP that stimulates the GTPase activity of ARL8B, with TMEM55B loss-of-function phenotypes occluded by ARL8 co-depletion [#13]. Beyond positioning, TMEM55B participates in mTORC1 signaling through interactions with V-ATPase and Ragulator components [#2], in oxidative-stress responses by promoting NEDD4-dependent ubiquitination of PLEKHM1 to halt fusion and by recruiting ESCRT machinery for lysosomal repair [#7, #8], and in transcriptional stress signaling by sequestering the FLCN/FNIP complex to enable TFE3 nuclear translocation [#9]. The protein's lysosomal delivery depends on S-palmitoylation of cytoplasmic cysteines together with a dileucine sorting motif, and its lysosome-clustering activity is tuned by Erk/MAPK phosphorylation at Ser76 and Ser169 [#4, #5]. A zebrafish tmem55 knockout shows increased susceptibility to oxidative stress, establishing an in vivo requirement [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2017,\n      \"claim\": \"Established TMEM55B as a lysosomal positioning factor by showing it recruits JIP4 to drive dynein-dependent retrograde transport, defining the first molecular function of the protein.\",\n      \"evidence\": \"Overexpression, shRNA depletion, live imaging of lysosome positioning, and Co-IP in cultured cells\",\n      \"pmids\": [\"29146937\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how TMEM55B physically links to dynein machinery beyond JIP4\", \"Did not define the structural basis of the JIP4 interaction\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Placed TMEM55B in a stress-responsive transcriptional circuit by showing TFEB/TFE3 upregulate it during starvation and that it is required for starvation-induced retrograde transport and autophagosome–lysosome fusion.\",\n      \"evidence\": \"Reporter assays, qRT-PCR, TFEB/TFE3 overexpression, shRNA depletion, immunofluorescence\",\n      \"pmids\": [\"29146937\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish whether the transcriptional regulation forms a closed feedback loop\", \"Did not separate fusion defects from positioning defects mechanistically\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected TMEM55B to nutrient signaling by linking it to V-ATPase/Ragulator assembly and amino acid-induced mTORC1 substrate phosphorylation, and identified a feedback relationship with TFEB.\",\n      \"evidence\": \"Proteomics, Co-IP, lipid raft fractionation, immunoblot for S6K/4E-BP1, and TFEB localization by IF after KD\",\n      \"pmids\": [\"29644770\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study without orthogonal confirmation of the V-ATPase interaction\", \"Direct versus indirect contribution to mTORC1 activation not dissected\", \"TFEB feedback shown only by localization\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed that TMEM55B activity is regulated post-translationally by Erk/MAPK phosphorylation at Ser76/Ser169 downstream of TLR signaling, modulating lysosome clustering independently of intrinsic phosphatase activity.\",\n      \"evidence\": \"Phosphosite mutagenesis, MEK1/2 inhibitor (U0126), shRNA/CRISPR KO, LAMP1 IF, immunoblot\",\n      \"pmids\": [\"31329883\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which phosphorylation alters clustering not defined\", \"Functional link between TLR signaling and lysosome positioning physiology not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined the trafficking determinants of TMEM55B, demonstrating that S-palmitoylation of cytoplasmic cysteines plus a dileucine motif route the protein to lysosomes and are required for its clustering activity.\",\n      \"evidence\": \"Acyl-RAC palmitoylation assay, cysteine and dileucine mutagenesis, IF, subcellular fractionation\",\n      \"pmids\": [\"34350967\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The palmitoyltransferase responsible was not identified\", \"Whether palmitoylation is dynamically regulated was not addressed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linked TMEM55B to Parkinson's disease pathways by showing VPS35[D620N]/LRRK2-driven phospho-Rab signaling recruits RILPL1 to lysosomes where it binds TMEM55B directly, and that TMEM55B regulates RILPL1 levels.\",\n      \"evidence\": \"Co-IP, mass spectrometry, mutagenesis, KO mouse tissues, LRRK2 and proteasome inhibitor treatment\",\n      \"pmids\": [\"38091401\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of the RILPL1–TMEM55B interaction for disease not resolved\", \"Did not determine whether RILPL1 binds the same site as JIP4\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established TMEM55B as a master regulator of the oxidative-stress lysosomal response, coordinating NEDD4-dependent PLEKHM1 degradation to halt fusion, ESCRT-mediated repair, FLCN/FNIP sequestration for TFE3 activation, and an in vivo oxidative-stress requirement.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, ESCRT recruitment IF, TFE3 localization, KO cells, lysosomal damage assays, zebrafish tmem55 KO arsenite survival\",\n      \"pmids\": [\"38168055\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a single protein switches between these distinct outputs not resolved\", \"ESCRT and FLCN/FNIP arms rest on single-lab Co-IP plus KO without reciprocal validation\", \"Direct versus indirect role in PLEKHM1 ubiquitination not fully separated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided the structural basis for hub function, solving crystal structures of the cytosolic tandem RING-like domains and a RILPL1 TBM complex, and identifying a shared set of TBM-bearing adaptors (JIP3, JIP4, OCRL, WDR81, TBC1D9B).\",\n      \"evidence\": \"X-ray crystallography of apo and complex forms, Co-IP, mass spectrometry, TBM mutagenesis\",\n      \"pmids\": [\"41314214\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not determine whether adaptors compete for a single groove or bind simultaneously\", \"Functional hierarchy among clients not established\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Resolved how TMEM55B antagonizes lysosome dispersion mechanistically by recruiting the GAP TBC1D9B to stimulate ARL8B GTPase activity, with epistasis showing TMEM55B acts through ARL8.\",\n      \"evidence\": \"Co-IP, GTPase activity assay, KO cells, ARL8/TMEM55B double-KO epistasis, IF\",\n      \"pmids\": [\"41832156\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Spatiotemporal coordination between this GAP-based control and JIP4-dynein transport not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended TMEM55B function into lysosomal metabolite homeostasis and membrane contact sites, implicating it in CTNS/cystine regulation via ubiquitylation and in ER–lysosome lipid and Ca2+ coordination via PDZD8.\",\n      \"evidence\": \"Ubiquitylation assays, JIP4 KO cells/mice, cystine measurement (preprint); PDZD8 Co-IP, lysosomal pH, lipid droplet and Ca2+ imaging (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.06.06.657909\", \"bio_10.1101_2025.10.21.683636\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Both findings are preprints not yet peer-reviewed\", \"Whether TMEM55B is the direct E3-recruiting factor for CTNS not established\", \"PDZD8 interaction not validated reciprocally\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how TMEM55B integrates and prioritizes its competing adaptor-driven outputs—positioning, repair, transcriptional stress, and metabolite control—at a single shared binding groove within an intact cell.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No quantitative model of adaptor competition or hierarchy\", \"No structural data on multivalent or simultaneous client engagement\", \"Physiological triggers selecting each output are undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 11, 12]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005765\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [0, 5, 8]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [1, 7, 13]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 13]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [8, 9, 10]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"JIP4\", \"JIP3\", \"RILPL1\", \"OCRL\", \"WDR81\", \"TBC1D9B\", \"PLEKHM1\", \"PDZD8\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":7,"faith_total":8,"faith_pct":87.5}}