{"gene":"RILPL1","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2012,"finding":"RILPL1 localizes specifically to the distal end of the mother centriole and to the primary cilium. Depletion of RILPL1 (and RILPL2) causes accumulation of signaling proteins in the ciliary membrane and prevents proper epithelial cell organization in 3D culture, indicating RILPL1 functions in regulating ciliary membrane protein concentration by promoting protein removal from the primary cilium.","method":"Live-cell microscopy, RNAi depletion, 3D culture assays, immunofluorescence localization","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional consequence, depletion phenotype with specific cellular readout, single lab with two orthogonal methods","pmids":["23264467"],"is_preprint":false},{"year":2019,"finding":"LRRK2-phosphorylated RAB8 and RAB10 are recruited to centrosome-localized RILPL1, causing centrosomal cohesion deficits in dividing cells. Both RAB8 and RAB10 contribute to LRRK2-mediated centrosomal cohesion defects, and both defects require RILPL1. The same phospho-RAB8/RAB10/RILPL1 nexus also underlies LRRK2-mediated ciliogenesis defects.","method":"RNAi knockdown, LRRK2 kinase inhibition, immunofluorescence in patient-derived peripheral cells and primary astrocytes from mutant LRRK2 mice, genetic epistasis (RAB8, RAB10, RILPL1 depletion)","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal epistasis with multiple Rab proteins and RILPL1, replicated in patient-derived cells and mouse primary astrocytes, multiple orthogonal methods","pmids":["31428781"],"is_preprint":false},{"year":2021,"finding":"LRRK2-phosphorylated RAB10 enhances binding to RILPL1; together they block cilia formation by preventing CP110 release from the mother centriole, a step normally required for early ciliogenesis. LRRK2 blockade of CP110 uncapping requires both RAB10 and RILPL1, and is due to failure to recruit TTBK2 (a kinase needed for CP110 release). Overexpression of RILPL1 alone is sufficient to block CP110 release.","method":"Live-cell fluorescence microscopy, genetic epistasis (Rab10 and RILPL1 knockout MEF cells), RILPL1 overexpression, serum starvation/readdition ciliation assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis with clean KO cells, live-cell imaging, RILPL1 overexpression phenocopy, mechanistic placement upstream of TTBK2, multiple orthogonal approaches","pmids":["33653948"],"is_preprint":false},{"year":2022,"finding":"RILPL1 localizes to the subdistal appendage of the mother centriole and mediates centrosomal accumulation of LRRK2-phosphorylated RAB10 (and RAB8), causing centrosomal cohesion deficits and impaired cell polarization (monitored by scratch wound assay). The centrosomal deficits require RILPL1 but not RILPL2, RAB12, RAB35, or RAB43, establishing specificity within the LRRK2 signaling network. VPS35 and PPM1H converge on the same phospho-Rab10/RILPL1 centrosomal axis.","method":"Immunofluorescence localization, RNAi/knockout epistasis for multiple Rab proteins, LRRK2 kinase inhibition, scratch wound polarization assay","journal":"Biology open","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic epistasis across multiple Rab substrates, specific localization of RILPL1 to subdistal appendage, functional polarization readout, consistent with multiple prior studies","pmids":["35776681"],"is_preprint":false},{"year":2022,"finding":"Pathogenic LRRK2 causes centrosomal displacement of CDK5RAP2 (a protein critical for centrosome cohesion) via RILPL1 and phospho-Rab proteins. Centrosomal cohesion deficits require both the GTP conformation and phosphorylation status of Rab proteins; LRRK2 does not displace proteinaceous linker proteins but specifically displaces CDK5RAP2 in a RILPL1- and phospho-Rab-dependent manner.","method":"Transient transfection, immunofluorescence, patient-derived iPS cells, dominant-negative Rab mutants, RILPL1 requirement established by depletion","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic dissection of CDK5RAP2 displacement via RILPL1/phospho-Rab, iPS cell validation, single lab with multiple approaches","pmids":["35721463"],"is_preprint":false},{"year":2023,"finding":"Pathogenic LRRK2 causes perinuclear clustering of lysosomes dependent on RAB12 phosphorylation at Ser106 and its effector RILPL1. LRRK2-mediated phosphorylation of RAB12 increases its interaction with RILPL1, and both RAB12 knockout and RILPL1 knockout abolish lysosomal clustering, indicating RILPL1 acts as a RAB12 effector to compromise intracellular lysosomal transport.","method":"Organelle distribution imaging, RAB12 and RILPL1 knockout/re-expression, phosphomimetic/phospho-dead Rab12 mutants, Co-immunoprecipitation","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout epistasis, phospho-mutant rescue, Co-IP interaction, single lab with multiple orthogonal methods","pmids":["37086089"],"is_preprint":false},{"year":2023,"finding":"The Parkinson's disease VPS35[D620N] mutation stimulates LRRK2-mediated phosphorylation of Rab proteins at the lysosome, recruiting RILPL1 to the lysosome where it binds to the lysosomal integral membrane protein TMEM55B via conserved interacting regions. VPS35[D620N] mutation reduces RILPL1 protein levels in mouse fibroblasts, brain, and lung in a manner reversed by LRRK2 inhibition and proteasome inhibitors. Knockout of RILPL1 enhances phosphorylation of Rab substrates; knockout of TMEM55B increases RILPL1 levels.","method":"Lysosomal proteomics, Co-immunoprecipitation, interaction-blocking mutagenesis, LRRK2 inhibitor treatment, proteasome inhibition, RILPL1 and TMEM55B knockout cell lines, tissue analysis from mouse models","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (proteomics, Co-IP, mutagenesis, KO), validated in multiple tissues and cell types, single comprehensive study","pmids":["38091401"],"is_preprint":false},{"year":2024,"finding":"RILPL1 is recruited to ruptured/dysfunctional lysosomes via LRRK2 kinase activity and pRAB proteins, where it binds p150Glued (a dynactin subunit) to facilitate transport of lysosomes and lysosomal tubules toward the minus-end of microtubules, causing LYTL tubule retraction. This opposes JIP4-mediated tubule extension toward the plus-end, creating antagonistic motor forces that dynamically regulate lysosomal tubulation.","method":"Lysosomal proteomics, live-cell imaging, RILPL1 interaction with p150Glued (Co-IP/pulldown), LRRK2 kinase inhibition, overexpression studies, microtubule dynamics analysis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics plus live imaging plus p150Glued binding, replicated in peer-reviewed follow-up (PMID:40990465), preprint version","pmids":["38903076"],"is_preprint":true},{"year":2025,"finding":"RILPL1 is recruited to dysfunctional lysosomes in an LRRK2 kinase activity-dependent manner via pRAB proteins, binds p150Glued dynactin subunit, and drives retraction of lysosomal tubulation/sorting (LYTL) tubules toward the minus-end of microtubules, opposing JIP4-mediated plus-end extension to create a metastable membrane deformation enabling dynamic tubulation.","method":"Lysosomal proteome mapping after LRRK2 inhibition, live-cell imaging of LYTL tubules, p150Glued binding assay, LRRK2 kinase inhibition, functional comparison with JIP4","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — peer-reviewed, proteomics plus live imaging plus mechanistic binding to p150Glued, replicates preprint findings with additional validation","pmids":["40990465"],"is_preprint":false},{"year":2025,"finding":"Crystal structures of the cytosolic region of TMEM55B alone and in complex with a C-terminal RILPL1 peptide (TMEM55B-binding motif, TBM) reveal that the RILPL1 TBM sits in a shallow groove across two tandem RING-like Zn2+-stabilized β-sandwich domains of TMEM55B. Binding is mediated primarily by backbone hydrogen bonding anchored by two glutamate residues from RILPL1. RILPL1 is recruited to phospho-Rab8A-positive lysosomes prior to TMEM55B engagement. TMEM55B also forms complexes (independently of phospho-Rabs) with other TBM-containing proteins including JIP3, JIP4, OCRL, WDR81, and TBC1D9B.","method":"X-ray crystallography, co-immunoprecipitation, mass spectrometry, mutagenesis of interaction interface","journal":"Structure (London, England : 1993)","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure of RILPL1 TBM–TMEM55B complex with mutagenesis validation and Co-IP/MS confirmation, peer-reviewed","pmids":["41314214"],"is_preprint":false},{"year":2024,"finding":"RAB12 cooperates with LRRK2 to inhibit primary ciliogenesis and regulate centrosome homeostasis in astrocytes by enhancing phosphorylation of RAB10 and recruiting RILPL1. The functions of RAB12 in this context require direct interaction with LRRK2 and LRRK2 kinase activity. Deletion of Rab12 in astrocytes prevents ciliary deficits and centrosome alterations caused by the PD-linked LRRK2-G2019S mutation.","method":"Cryo-EM structure of RAB12-LRRK2 complex, phosphoproteomics, conditional Rab12 knockout in astrocytes, ciliogenesis/centrosome assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RILPL1 role established by recruitment assay in Rab12 KO context, supported by Cryo-EM structural data for RAB12-LRRK2; RILPL1-specific mechanistic detail is indirect (preprint, single lab)","pmids":["bio_10.1101_2024.07.17.603999"],"is_preprint":true}],"current_model":"RILPL1 is a phospho-Rab effector that localizes to the subdistal appendage of the mother centriole and is recruited to lysosomes via LRRK2-phosphorylated RAB proteins (RAB8, RAB10, RAB12); at the centriole, accumulation of phospho-Rab/RILPL1 blocks CP110 uncapping (preventing TTBK2 recruitment) to inhibit ciliogenesis and displaces CDK5RAP2 to disrupt centrosome cohesion, while at the lysosome RILPL1 binds TMEM55B (via a structurally defined TBM motif in a shallow groove of tandem RING-like Zn2+-β-sandwich domains) and binds p150Glued dynactin to drive minus-end-directed lysosomal transport and retraction of LYTL tubules, opposing JIP4-mediated tubule extension."},"narrative":{"mechanistic_narrative":"RILPL1 is a phospho-Rab effector that couples LRRK2 kinase signaling to centriolar and lysosomal membrane dynamics [PMID:35776681, PMID:38091401]. It localizes to the subdistal appendage of the mother centriole, where it captures LRRK2-phosphorylated RAB8 and RAB10 [PMID:35776681]; the resulting phospho-Rab/RILPL1 accumulation blocks CP110 release from the mother centriole by preventing TTBK2 recruitment, thereby inhibiting early ciliogenesis, and RILPL1 overexpression alone is sufficient to block CP110 uncapping [PMID:33653948]. The same axis displaces CDK5RAP2 from the centrosome to produce centrosome cohesion deficits and impaired cell polarization, in a manner requiring both the GTP and phosphorylation status of the Rab substrate [PMID:35776681, PMID:35721463]. At lysosomes, RILPL1 acts as an effector of phosphorylated RAB12, RAB8, and RAB10 to drive perinuclear lysosomal clustering and to compromise lysosomal transport [PMID:37086089, PMID:38091401]. Once recruited, RILPL1 engages the lysosomal integral membrane protein TMEM55B through a C-terminal TMEM55B-binding motif (TBM) that inserts into a shallow groove spanning two tandem RING-like Zn2+-stabilized β-sandwich domains, anchored largely by backbone hydrogen bonding from two RILPL1 glutamate residues [PMID:41314214]. RILPL1 also binds the dynactin subunit p150Glued to power minus-end-directed transport and retraction of lysosomal (LYTL) tubules, opposing JIP4-mediated plus-end tubule extension to create antagonistic motor forces that govern dynamic lysosomal tubulation [PMID:40990465]. Its recruitment to all of these sites depends on the Parkinson's-disease-associated LRRK2 kinase pathway, and the PD-linked VPS35[D620N] mutation feeds into the same phospho-Rab/RILPL1 axis [PMID:35776681, PMID:38091401].","teleology":[{"year":2012,"claim":"Established that RILPL1 is a centriolar/ciliary protein whose loss causes abnormal accumulation of ciliary membrane proteins, framing it as a regulator of ciliary protein content.","evidence":"Live-cell microscopy, RNAi depletion, and 3D culture assays localizing RILPL1 to the mother centriole and primary cilium","pmids":["23264467"],"confidence":"Medium","gaps":["No molecular partner or recruitment mechanism identified","Link to phospho-Rab/LRRK2 signaling not yet known"]},{"year":2019,"claim":"Placed RILPL1 downstream of LRRK2 by showing LRRK2-phosphorylated RAB8 and RAB10 are recruited to centrosomal RILPL1, and that RILPL1 is required for LRRK2-driven cohesion and ciliogenesis defects.","evidence":"RNAi epistasis with RAB8/RAB10/RILPL1, LRRK2 kinase inhibition in patient-derived cells and mutant LRRK2 mouse astrocytes","pmids":["31428781"],"confidence":"High","gaps":["Molecular mechanism of cohesion disruption not defined","Direct binding of phospho-Rab to RILPL1 not structurally resolved"]},{"year":2021,"claim":"Defined the ciliogenesis-blocking mechanism: phospho-RAB10/RILPL1 prevents CP110 uncapping by failing to recruit TTBK2, the kinase that triggers CP110 release.","evidence":"Live-cell imaging, Rab10/RILPL1 knockout MEFs, RILPL1 overexpression phenocopy, serum-starvation ciliation assays","pmids":["33653948"],"confidence":"High","gaps":["How RILPL1 physically blocks TTBK2 recruitment is unresolved","Stoichiometry of phospho-Rab/RILPL1 at the centriole unknown"]},{"year":2022,"claim":"Refined RILPL1's centriolar position to the subdistal appendage and established Rab-substrate specificity, identifying CDK5RAP2 displacement as the cohesion-disrupting event.","evidence":"Immunofluorescence localization, systematic Rab knockout/RNAi epistasis, scratch-wound polarization assays, iPS cell validation","pmids":["35776681","35721463"],"confidence":"High","gaps":["Direct interaction between RILPL1 and CDK5RAP2 not demonstrated","Mechanism linking RILPL1 to CDK5RAP2 eviction unclear"]},{"year":2023,"claim":"Extended RILPL1 function to lysosomes, showing it acts as a phospho-RAB12 effector driving perinuclear lysosomal clustering and binds the lysosomal protein TMEM55B upon LRRK2/VPS35[D620N] activation.","evidence":"Organelle imaging, RAB12/RILPL1 knockout and re-expression, phospho-mutant Rab12, lysosomal proteomics, Co-IP, interaction-blocking mutagenesis, mouse tissue analysis","pmids":["37086089","38091401"],"confidence":"High","gaps":["Functional role of TMEM55B binding in transport not fully defined","Mechanism of VPS35[D620N]-driven RILPL1 destabilization unresolved"]},{"year":2025,"claim":"Identified the motor mechanism: RILPL1 binds p150Glued dynactin to drive minus-end lysosomal tubule retraction, antagonizing JIP4 to create dynamic, metastable lysosomal tubulation.","evidence":"Lysosomal proteome mapping after LRRK2 inhibition, live-cell LYTL tubule imaging, p150Glued binding assays, functional comparison with JIP4","pmids":["40990465","38903076"],"confidence":"High","gaps":["Quantitative balance of JIP4 vs RILPL1 forces not modeled","Whether centriolar and lysosomal pools of RILPL1 are functionally interchangeable is unknown"]},{"year":2025,"claim":"Provided atomic detail of the RILPL1–TMEM55B interface, defining a C-terminal TBM that docks into a groove across tandem RING-like Zn2+ β-sandwich domains and revealing TMEM55B as a hub for multiple TBM-containing proteins.","evidence":"X-ray crystallography of TMEM55B alone and bound to the RILPL1 TBM peptide, interface mutagenesis, Co-IP/MS","pmids":["41314214"],"confidence":"High","gaps":["Functional consequence of competition among TBM-containing TMEM55B partners not established","Affinity/regulation of TBM engagement relative to phospho-Rab binding not quantified"]},{"year":null,"claim":"How RILPL1 mechanistically partitions between its centriolar (ciliogenesis/cohesion) and lysosomal (transport/tubulation) roles, and how these contribute to LRRK2-driven Parkinson's pathology, remains open.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model coordinating centriolar and lysosomal RILPL1 pools","In vivo consequence of RILPL1 loss for disease phenotypes not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[5,6,7,8]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[7,8]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0,3]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[0]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[5,6,7,8]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[7,8]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[5,7,8]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,2,3]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,3,6]}],"complexes":[],"partners":["TMEM55B","RAB10","RAB8A","RAB12","DCTN1","LRRK2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q5EBL4","full_name":"RILP-like protein 1","aliases":["Rab-interacting lysosomal-like protein 1"],"length_aa":403,"mass_kda":47.1,"function":"Plays a role in the regulation of cell shape and polarity (By similarity). Plays a role in cellular protein transport, including protein transport away from primary cilia (By similarity). Neuroprotective protein, which acts by sequestring GAPDH in the cytosol and prevent the apoptotic function of GAPDH in the nucleus (By similarity). Competes with SIAH1 for binding GAPDH (By similarity). Does not regulate lysosomal morphology and distribution (PubMed:14668488). Binds to RAB10 following LRRK2-mediated RAB10 phosphorylation which leads to inhibition of ciliogenesis (PubMed:30398148)","subcellular_location":"Cytoplasm, cytosol; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriole; Cytoplasm, cytoskeleton, cilium basal body","url":"https://www.uniprot.org/uniprotkb/Q5EBL4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RILPL1","classification":"Not Classified","n_dependent_lines":11,"n_total_lines":1208,"dependency_fraction":0.009105960264900662},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/RILPL1","total_profiled":1310},"omim":[{"mim_id":"619790","title":"OCULOPHARYNGODISTAL MYOPATHY 4; OPDM4","url":"https://www.omim.org/entry/619790"},{"mim_id":"614093","title":"RAB-INTERACTING LYSOSOMAL PROTEIN-LIKE 2; RILPL2","url":"https://www.omim.org/entry/614093"},{"mim_id":"614092","title":"RAB-INTERACTING LYSOSOMAL PROTEIN-LIKE 1; RILPL1","url":"https://www.omim.org/entry/614092"},{"mim_id":"607848","title":"RAB-INTERACTING LYSOSOMAL PROTEIN; RILP","url":"https://www.omim.org/entry/607848"},{"mim_id":"164310","title":"OCULOPHARYNGODISTAL MYOPATHY 1; OPDM1","url":"https://www.omim.org/entry/164310"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Primary cilium","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Centrosome","reliability":"Additional"},{"location":"Basal body","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"heart muscle","ntpm":59.0},{"tissue":"skeletal muscle","ntpm":83.2}],"url":"https://www.proteinatlas.org/search/RILPL1"},"hgnc":{"alias_symbol":["FLJ39378"],"prev_symbol":[]},"alphafold":{"accession":"Q5EBL4","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5EBL4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5EBL4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5EBL4-F1-predicted_aligned_error_v6.png","plddt_mean":75.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RILPL1","jax_strain_url":"https://www.jax.org/strain/search?query=RILPL1"},"sequence":{"accession":"Q5EBL4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5EBL4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5EBL4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5EBL4"}},"corpus_meta":[{"pmid":"31428781","id":"PMC_31428781","title":"RAB8, RAB10 and RILPL1 contribute to both LRRK2 kinase-mediated centrosomal cohesion and ciliogenesis deficits.","date":"2019","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31428781","citation_count":74,"is_preprint":false},{"pmid":"33653948","id":"PMC_33653948","title":"Pathogenic LRRK2 regulates ciliation probability upstream of tau tubulin kinase 2 via Rab10 and RILPL1 proteins.","date":"2021","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/33653948","citation_count":68,"is_preprint":false},{"pmid":"35148830","id":"PMC_35148830","title":"The CGG repeat expansion in RILPL1 is associated with oculopharyngodistal myopathy type 4.","date":"2022","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35148830","citation_count":59,"is_preprint":false},{"pmid":"23264467","id":"PMC_23264467","title":"The Rilp-like proteins Rilpl1 and Rilpl2 regulate ciliary membrane content.","date":"2012","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/23264467","citation_count":52,"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":"35700120","id":"PMC_35700120","title":"GGC Repeat Expansion of RILPL1 is Associated with Oculopharyngodistal Myopathy.","date":"2022","source":"Annals of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/35700120","citation_count":30,"is_preprint":false},{"pmid":"35776681","id":"PMC_35776681","title":"The LRRK2 signaling network converges on a centriolar phospho-Rab10/RILPL1 complex to cause deficits in centrosome cohesion and cell polarization.","date":"2022","source":"Biology 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sclerosis","date":"2025-05-23","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.22.25328088","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.07.17.603999","title":"RAB12-LRRK2 Complex Suppresses Primary Ciliogenesis and Regulates Centrosome Homeostasis in Astrocytes","date":"2024-07-19","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.17.603999","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11070,"output_tokens":3582,"usd":0.04347,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11078,"output_tokens":3227,"usd":0.068032,"stage2_stop_reason":"end_turn"},"total_usd":0.111502,"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\": 2012,\n      \"finding\": \"RILPL1 localizes specifically to the distal end of the mother centriole and to the primary cilium. Depletion of RILPL1 (and RILPL2) causes accumulation of signaling proteins in the ciliary membrane and prevents proper epithelial cell organization in 3D culture, indicating RILPL1 functions in regulating ciliary membrane protein concentration by promoting protein removal from the primary cilium.\",\n      \"method\": \"Live-cell microscopy, RNAi depletion, 3D culture assays, immunofluorescence localization\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional consequence, depletion phenotype with specific cellular readout, single lab with two orthogonal methods\",\n      \"pmids\": [\"23264467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LRRK2-phosphorylated RAB8 and RAB10 are recruited to centrosome-localized RILPL1, causing centrosomal cohesion deficits in dividing cells. Both RAB8 and RAB10 contribute to LRRK2-mediated centrosomal cohesion defects, and both defects require RILPL1. The same phospho-RAB8/RAB10/RILPL1 nexus also underlies LRRK2-mediated ciliogenesis defects.\",\n      \"method\": \"RNAi knockdown, LRRK2 kinase inhibition, immunofluorescence in patient-derived peripheral cells and primary astrocytes from mutant LRRK2 mice, genetic epistasis (RAB8, RAB10, RILPL1 depletion)\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal epistasis with multiple Rab proteins and RILPL1, replicated in patient-derived cells and mouse primary astrocytes, multiple orthogonal methods\",\n      \"pmids\": [\"31428781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LRRK2-phosphorylated RAB10 enhances binding to RILPL1; together they block cilia formation by preventing CP110 release from the mother centriole, a step normally required for early ciliogenesis. LRRK2 blockade of CP110 uncapping requires both RAB10 and RILPL1, and is due to failure to recruit TTBK2 (a kinase needed for CP110 release). Overexpression of RILPL1 alone is sufficient to block CP110 release.\",\n      \"method\": \"Live-cell fluorescence microscopy, genetic epistasis (Rab10 and RILPL1 knockout MEF cells), RILPL1 overexpression, serum starvation/readdition ciliation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis with clean KO cells, live-cell imaging, RILPL1 overexpression phenocopy, mechanistic placement upstream of TTBK2, multiple orthogonal approaches\",\n      \"pmids\": [\"33653948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RILPL1 localizes to the subdistal appendage of the mother centriole and mediates centrosomal accumulation of LRRK2-phosphorylated RAB10 (and RAB8), causing centrosomal cohesion deficits and impaired cell polarization (monitored by scratch wound assay). The centrosomal deficits require RILPL1 but not RILPL2, RAB12, RAB35, or RAB43, establishing specificity within the LRRK2 signaling network. VPS35 and PPM1H converge on the same phospho-Rab10/RILPL1 centrosomal axis.\",\n      \"method\": \"Immunofluorescence localization, RNAi/knockout epistasis for multiple Rab proteins, LRRK2 kinase inhibition, scratch wound polarization assay\",\n      \"journal\": \"Biology open\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic epistasis across multiple Rab substrates, specific localization of RILPL1 to subdistal appendage, functional polarization readout, consistent with multiple prior studies\",\n      \"pmids\": [\"35776681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Pathogenic LRRK2 causes centrosomal displacement of CDK5RAP2 (a protein critical for centrosome cohesion) via RILPL1 and phospho-Rab proteins. Centrosomal cohesion deficits require both the GTP conformation and phosphorylation status of Rab proteins; LRRK2 does not displace proteinaceous linker proteins but specifically displaces CDK5RAP2 in a RILPL1- and phospho-Rab-dependent manner.\",\n      \"method\": \"Transient transfection, immunofluorescence, patient-derived iPS cells, dominant-negative Rab mutants, RILPL1 requirement established by depletion\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic dissection of CDK5RAP2 displacement via RILPL1/phospho-Rab, iPS cell validation, single lab with multiple approaches\",\n      \"pmids\": [\"35721463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Pathogenic LRRK2 causes perinuclear clustering of lysosomes dependent on RAB12 phosphorylation at Ser106 and its effector RILPL1. LRRK2-mediated phosphorylation of RAB12 increases its interaction with RILPL1, and both RAB12 knockout and RILPL1 knockout abolish lysosomal clustering, indicating RILPL1 acts as a RAB12 effector to compromise intracellular lysosomal transport.\",\n      \"method\": \"Organelle distribution imaging, RAB12 and RILPL1 knockout/re-expression, phosphomimetic/phospho-dead Rab12 mutants, Co-immunoprecipitation\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout epistasis, phospho-mutant rescue, Co-IP interaction, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"37086089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The Parkinson's disease VPS35[D620N] mutation stimulates LRRK2-mediated phosphorylation of Rab proteins at the lysosome, recruiting RILPL1 to the lysosome where it binds to the lysosomal integral membrane protein TMEM55B via conserved interacting regions. VPS35[D620N] mutation reduces RILPL1 protein levels in mouse fibroblasts, brain, and lung in a manner reversed by LRRK2 inhibition and proteasome inhibitors. Knockout of RILPL1 enhances phosphorylation of Rab substrates; knockout of TMEM55B increases RILPL1 levels.\",\n      \"method\": \"Lysosomal proteomics, Co-immunoprecipitation, interaction-blocking mutagenesis, LRRK2 inhibitor treatment, proteasome inhibition, RILPL1 and TMEM55B knockout cell lines, tissue analysis from mouse models\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (proteomics, Co-IP, mutagenesis, KO), validated in multiple tissues and cell types, single comprehensive study\",\n      \"pmids\": [\"38091401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RILPL1 is recruited to ruptured/dysfunctional lysosomes via LRRK2 kinase activity and pRAB proteins, where it binds p150Glued (a dynactin subunit) to facilitate transport of lysosomes and lysosomal tubules toward the minus-end of microtubules, causing LYTL tubule retraction. This opposes JIP4-mediated tubule extension toward the plus-end, creating antagonistic motor forces that dynamically regulate lysosomal tubulation.\",\n      \"method\": \"Lysosomal proteomics, live-cell imaging, RILPL1 interaction with p150Glued (Co-IP/pulldown), LRRK2 kinase inhibition, overexpression studies, microtubule dynamics analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics plus live imaging plus p150Glued binding, replicated in peer-reviewed follow-up (PMID:40990465), preprint version\",\n      \"pmids\": [\"38903076\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RILPL1 is recruited to dysfunctional lysosomes in an LRRK2 kinase activity-dependent manner via pRAB proteins, binds p150Glued dynactin subunit, and drives retraction of lysosomal tubulation/sorting (LYTL) tubules toward the minus-end of microtubules, opposing JIP4-mediated plus-end extension to create a metastable membrane deformation enabling dynamic tubulation.\",\n      \"method\": \"Lysosomal proteome mapping after LRRK2 inhibition, live-cell imaging of LYTL tubules, p150Glued binding assay, LRRK2 kinase inhibition, functional comparison with JIP4\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — peer-reviewed, proteomics plus live imaging plus mechanistic binding to p150Glued, replicates preprint findings with additional validation\",\n      \"pmids\": [\"40990465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Crystal structures of the cytosolic region of TMEM55B alone and in complex with a C-terminal RILPL1 peptide (TMEM55B-binding motif, TBM) reveal that the RILPL1 TBM sits in a shallow groove across two tandem RING-like Zn2+-stabilized β-sandwich domains of TMEM55B. Binding is mediated primarily by backbone hydrogen bonding anchored by two glutamate residues from RILPL1. RILPL1 is recruited to phospho-Rab8A-positive lysosomes prior to TMEM55B engagement. TMEM55B also forms complexes (independently of phospho-Rabs) with other TBM-containing proteins including JIP3, JIP4, OCRL, WDR81, and TBC1D9B.\",\n      \"method\": \"X-ray crystallography, co-immunoprecipitation, mass spectrometry, mutagenesis of interaction interface\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure of RILPL1 TBM–TMEM55B complex with mutagenesis validation and Co-IP/MS confirmation, peer-reviewed\",\n      \"pmids\": [\"41314214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RAB12 cooperates with LRRK2 to inhibit primary ciliogenesis and regulate centrosome homeostasis in astrocytes by enhancing phosphorylation of RAB10 and recruiting RILPL1. The functions of RAB12 in this context require direct interaction with LRRK2 and LRRK2 kinase activity. Deletion of Rab12 in astrocytes prevents ciliary deficits and centrosome alterations caused by the PD-linked LRRK2-G2019S mutation.\",\n      \"method\": \"Cryo-EM structure of RAB12-LRRK2 complex, phosphoproteomics, conditional Rab12 knockout in astrocytes, ciliogenesis/centrosome assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RILPL1 role established by recruitment assay in Rab12 KO context, supported by Cryo-EM structural data for RAB12-LRRK2; RILPL1-specific mechanistic detail is indirect (preprint, single lab)\",\n      \"pmids\": [\"bio_10.1101_2024.07.17.603999\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"RILPL1 is a phospho-Rab effector that localizes to the subdistal appendage of the mother centriole and is recruited to lysosomes via LRRK2-phosphorylated RAB proteins (RAB8, RAB10, RAB12); at the centriole, accumulation of phospho-Rab/RILPL1 blocks CP110 uncapping (preventing TTBK2 recruitment) to inhibit ciliogenesis and displaces CDK5RAP2 to disrupt centrosome cohesion, while at the lysosome RILPL1 binds TMEM55B (via a structurally defined TBM motif in a shallow groove of tandem RING-like Zn2+-β-sandwich domains) and binds p150Glued dynactin to drive minus-end-directed lysosomal transport and retraction of LYTL tubules, opposing JIP4-mediated tubule extension.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RILPL1 is a phospho-Rab effector that couples LRRK2 kinase signaling to centriolar and lysosomal membrane dynamics [#3, #6]. It localizes to the subdistal appendage of the mother centriole, where it captures LRRK2-phosphorylated RAB8 and RAB10 [#3]; the resulting phospho-Rab/RILPL1 accumulation blocks CP110 release from the mother centriole by preventing TTBK2 recruitment, thereby inhibiting early ciliogenesis, and RILPL1 overexpression alone is sufficient to block CP110 uncapping [#2]. The same axis displaces CDK5RAP2 from the centrosome to produce centrosome cohesion deficits and impaired cell polarization, in a manner requiring both the GTP and phosphorylation status of the Rab substrate [#3, #4]. At lysosomes, RILPL1 acts as an effector of phosphorylated RAB12, RAB8, and RAB10 to drive perinuclear lysosomal clustering and to compromise lysosomal transport [#5, #6]. Once recruited, RILPL1 engages the lysosomal integral membrane protein TMEM55B through a C-terminal TMEM55B-binding motif (TBM) that inserts into a shallow groove spanning two tandem RING-like Zn2+-stabilized β-sandwich domains, anchored largely by backbone hydrogen bonding from two RILPL1 glutamate residues [#9]. RILPL1 also binds the dynactin subunit p150Glued to power minus-end-directed transport and retraction of lysosomal (LYTL) tubules, opposing JIP4-mediated plus-end tubule extension to create antagonistic motor forces that govern dynamic lysosomal tubulation [#8]. Its recruitment to all of these sites depends on the Parkinson's-disease-associated LRRK2 kinase pathway, and the PD-linked VPS35[D620N] mutation feeds into the same phospho-Rab/RILPL1 axis [#3, #6].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established that RILPL1 is a centriolar/ciliary protein whose loss causes abnormal accumulation of ciliary membrane proteins, framing it as a regulator of ciliary protein content.\",\n      \"evidence\": \"Live-cell microscopy, RNAi depletion, and 3D culture assays localizing RILPL1 to the mother centriole and primary cilium\",\n      \"pmids\": [\"23264467\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular partner or recruitment mechanism identified\", \"Link to phospho-Rab/LRRK2 signaling not yet known\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed RILPL1 downstream of LRRK2 by showing LRRK2-phosphorylated RAB8 and RAB10 are recruited to centrosomal RILPL1, and that RILPL1 is required for LRRK2-driven cohesion and ciliogenesis defects.\",\n      \"evidence\": \"RNAi epistasis with RAB8/RAB10/RILPL1, LRRK2 kinase inhibition in patient-derived cells and mutant LRRK2 mouse astrocytes\",\n      \"pmids\": [\"31428781\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of cohesion disruption not defined\", \"Direct binding of phospho-Rab to RILPL1 not structurally resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined the ciliogenesis-blocking mechanism: phospho-RAB10/RILPL1 prevents CP110 uncapping by failing to recruit TTBK2, the kinase that triggers CP110 release.\",\n      \"evidence\": \"Live-cell imaging, Rab10/RILPL1 knockout MEFs, RILPL1 overexpression phenocopy, serum-starvation ciliation assays\",\n      \"pmids\": [\"33653948\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How RILPL1 physically blocks TTBK2 recruitment is unresolved\", \"Stoichiometry of phospho-Rab/RILPL1 at the centriole unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Refined RILPL1's centriolar position to the subdistal appendage and established Rab-substrate specificity, identifying CDK5RAP2 displacement as the cohesion-disrupting event.\",\n      \"evidence\": \"Immunofluorescence localization, systematic Rab knockout/RNAi epistasis, scratch-wound polarization assays, iPS cell validation\",\n      \"pmids\": [\"35776681\", \"35721463\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct interaction between RILPL1 and CDK5RAP2 not demonstrated\", \"Mechanism linking RILPL1 to CDK5RAP2 eviction unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended RILPL1 function to lysosomes, showing it acts as a phospho-RAB12 effector driving perinuclear lysosomal clustering and binds the lysosomal protein TMEM55B upon LRRK2/VPS35[D620N] activation.\",\n      \"evidence\": \"Organelle imaging, RAB12/RILPL1 knockout and re-expression, phospho-mutant Rab12, lysosomal proteomics, Co-IP, interaction-blocking mutagenesis, mouse tissue analysis\",\n      \"pmids\": [\"37086089\", \"38091401\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional role of TMEM55B binding in transport not fully defined\", \"Mechanism of VPS35[D620N]-driven RILPL1 destabilization unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified the motor mechanism: RILPL1 binds p150Glued dynactin to drive minus-end lysosomal tubule retraction, antagonizing JIP4 to create dynamic, metastable lysosomal tubulation.\",\n      \"evidence\": \"Lysosomal proteome mapping after LRRK2 inhibition, live-cell LYTL tubule imaging, p150Glued binding assays, functional comparison with JIP4\",\n      \"pmids\": [\"40990465\", \"38903076\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative balance of JIP4 vs RILPL1 forces not modeled\", \"Whether centriolar and lysosomal pools of RILPL1 are functionally interchangeable is unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided atomic detail of the RILPL1–TMEM55B interface, defining a C-terminal TBM that docks into a groove across tandem RING-like Zn2+ β-sandwich domains and revealing TMEM55B as a hub for multiple TBM-containing proteins.\",\n      \"evidence\": \"X-ray crystallography of TMEM55B alone and bound to the RILPL1 TBM peptide, interface mutagenesis, Co-IP/MS\",\n      \"pmids\": [\"41314214\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of competition among TBM-containing TMEM55B partners not established\", \"Affinity/regulation of TBM engagement relative to phospho-Rab binding not quantified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RILPL1 mechanistically partitions between its centriolar (ciliogenesis/cohesion) and lysosomal (transport/tubulation) roles, and how these contribute to LRRK2-driven Parkinson's pathology, remains open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model coordinating centriolar and lysosomal RILPL1 pools\", \"In vivo consequence of RILPL1 loss for disease phenotypes not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [5, 6, 7, 8]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [7, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [5, 6, 7, 8]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [7, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [5, 7, 8]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 3, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TMEM55B\", \"RAB10\", \"RAB8A\", \"RAB12\", \"DCTN1\", \"LRRK2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}