{"gene":"RILP","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":2001,"finding":"RILP (Rab7-interacting lysosomal protein) specifically binds GTP-bound Rab7 and recruits functional dynein-dynactin motor complexes to late endosomes and lysosomes, causing their transport toward microtubule minus ends and inhibiting peripheral trafficking.","method":"Co-immunoprecipitation, overexpression in mammalian cells, fluorescence microscopy, dominant-negative constructs","journal":"Current Biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal interaction demonstrated, replicated across two independent labs simultaneously","pmids":["11696325"],"is_preprint":false},{"year":2001,"finding":"RILP is a 45 kDa protein containing two coiled-coil regions, found mainly in cytosol, that is recruited to late endosomal/lysosomal membranes by Rab7-GTP via its C-terminus; RILP-C33 (truncated C-terminal form lacking N-terminal half) acts as dominant negative, inhibiting EGF and LDL degradation and dispersing lysosomes similarly to dominant-negative Rab7.","method":"Yeast two-hybrid, GST pulldown, overexpression of truncation mutants, degradation assays","journal":"The EMBO Journal","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods, foundational paper replicated by others","pmids":["11179213"],"is_preprint":false},{"year":2003,"finding":"RILP promotes extension of phagosomal tubules toward late endocytic compartments by recruiting dynein-dynactin; a truncated RILP lacking the dynein-dynactin-recruiting domain prevents tubule extension and phagosome-lysosome fusion, establishing RILP as essential for phagosome maturation.","method":"Fluorescence microscopy, electron microscopy, overexpression of RILP truncation mutants, functional phagosome maturation assays","journal":"Molecular and Cellular Biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods with defined phenotypic readout, high citation count","pmids":["12944476"],"is_preprint":false},{"year":2003,"finding":"A unique 62-residue region (amino acids 272–333) in RILP is necessary and sufficient for regulating lysosomal morphology and for interaction with GTP-bound Rab7 and Rab34; transferring this region into the related protein RLP1 confers lysosome-regulatory activity.","method":"Domain swapping/chimeric protein expression, GTPase interaction assays, lysosome morphology readout in mammalian cells","journal":"Molecular Biology of the Cell","confidence":"High","confidence_rationale":"Tier 1–2 — mutagenesis and domain transfer with functional validation","pmids":["14668488"],"is_preprint":false},{"year":2004,"finding":"Salmonella effector SifA disrupts the Rab7–RILP interaction on Salmonella-containing vacuoles, preventing dynein recruitment; this uncoupling allows kinesin-dependent centrifugal extension of Salmonella-induced filaments, promoting bacterial replication in a protected compartment.","method":"Co-transfection, immunofluorescence, immobilized RILP pulldown of active Rab7, cell-free system with BCG supernatant","journal":"Molecular Biology of the Cell","confidence":"High","confidence_rationale":"Tier 2 — in vitro pulldown, cell-based imaging, epistasis with SifA","pmids":["15121880"],"is_preprint":false},{"year":2007,"finding":"GTP-bound Rab7 simultaneously binds RILP and ORP1L to form a tripartite RILP-Rab7-ORP1L complex; RILP directly contacts the C-terminal 25-kDa region of dynactin p150Glued; ORP1L and betaIII spectrin are additionally required for dynein motor activity, establishing a stepwise assembly cascade for minus-end endosomal transport.","method":"Co-immunoprecipitation, GST pulldown, siRNA knockdown, live-cell imaging, dominant-negative constructs","journal":"The Journal of Cell Biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods, direct binding mapped to specific domain, replicated","pmids":["17283181"],"is_preprint":false},{"year":2007,"finding":"RILP is required for biogenesis of multivesicular endosomes (MVEs): RILP depletion by siRNA reduces intralumenal vesicle content, impairs EGFR degradation (but not transferrin recycling), and causes elevated levels of late-endosomal markers. RILP interacts with ESCRT-II subunits Vps22 and Vps36.","method":"siRNA knockdown, electron microscopy, degradation assays for EGFR vs. transferrin, co-immunoprecipitation with ESCRT-II subunits","journal":"Journal of Cell Science","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function with specific phenotype and direct interaction data, multiple orthogonal methods","pmids":["17959629"],"is_preprint":false},{"year":2006,"finding":"RILP interacts with VPS22 (EAP30/SNF8) of ESCRT-II via its N-terminal half, and with VPS36 (EAP45) via its C-terminal half; RILP overexpression causes enlarged, clustered MVBs and retards EGF sorting at sorting endosomes, suggesting a regulatory loop between early and late endocytic machinery.","method":"Yeast two-hybrid, co-immunoprecipitation, confocal immunofluorescence, RILP domain truncation analysis","journal":"Biochemical and Biophysical Research Communications","confidence":"Medium","confidence_rationale":"Tier 3 — co-IP and colocalization, single lab, moderate follow-up","pmids":["17010938","16857164"],"is_preprint":false},{"year":2007,"finding":"Mycobacterium bovis BCG inhibits phagosome maturation by preventing RILP recruitment to Rab7 on phagosomal membranes; BCG culture supernatant contains a factor that catalyzes GTP→GDP conversion on Rab7, maintaining Rab7 in inactive GDP-bound form and blocking RILP-mediated lysosomal fusion.","method":"Co-transfection, immobilized RILP pulldown of GTP-bound Rab7, cell-free GTPase activity assay","journal":"Journal of Leukocyte Biology","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro and cell-based assays, direct mechanistic link established","pmids":["18040083"],"is_preprint":false},{"year":2008,"finding":"Huntingtin regulates REST/NRSF nuclear trafficking indirectly through a complex containing REST/NRSF, RILP, dynactin p150Glued, huntingtin, and HAP1; RILP directly binds p150Glued and REST/NRSF; mutant huntingtin weakens the dynactin p150Glued–RILP interaction; HAP1 prevents the complex from translocating REST/NRSF to the nucleus.","method":"Yeast two-hybrid, co-immunoprecipitation of in vitro translated proteins, complex characterization","journal":"The Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 3 — co-IP and two-hybrid, single lab, single paper","pmids":["18922795"],"is_preprint":false},{"year":2009,"finding":"Cholesterol levels in late endosomes are sensed by ORP1L; under low cholesterol, ORP1L conformation induces formation of ER-late endosome membrane contact sites where VAP (ER protein) interacts in trans with the Rab7-RILP complex to remove p150Glued and associated motors, causing plus-end directed movement. High cholesterol (as in Niemann-Pick C) prevents this, locking LEs at minus-end via dynein-RILP.","method":"Co-immunoprecipitation, dominant-negative constructs, fluorescence microscopy, fractionation, cholesterol manipulation","journal":"The Journal of Cell Biology","confidence":"High","confidence_rationale":"Tier 2 — mechanistic epistasis with multiple orthogonal methods, high citation count, replicated by multiple labs","pmids":["19564404"],"is_preprint":false},{"year":2012,"finding":"RILP functions as an effector of Rab36 (in addition to Rab7) via its RILP homology domain (RHD, a coiled-coil domain); site-directed mutagenesis of RHD revealed differential amino acid contributions to Rab7 vs. Rab36 binding; Rab36-RILP interaction mediates retrograde melanosome transport in melanocytes, independent of Rab7.","method":"Yeast two-hybrid screen, GST pulldown, site-directed mutagenesis, knockdown in melanocytes, melanosome distribution assays","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — mutagenesis plus functional cellular assays with defined phenotype","pmids":["22740695"],"is_preprint":false},{"year":2012,"finding":"Melanoregulin (Mreg) interacts with the C-terminal domain of RILP and forms a trimeric complex with RILP and p150Glued, mediating dynein-dynactin-dependent retrograde melanosome transport; Mreg knockdown or dynein-dynactin disruption restores peripheral melanosome distribution in Rab27A-deficient melanocytes.","method":"Co-immunoprecipitation, siRNA knockdown, overexpression, melanosome distribution assays","journal":"Journal of Cell Science","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal co-IP and KD with defined phenotype, single lab","pmids":["22275436"],"is_preprint":false},{"year":2013,"finding":"RILP simultaneously and directly binds both the HOPS tethering complex and p150Glued subunit of dynein-dynactin, coupling late endosomal transport and tethering into a single RAB7-RILP-ORP1L multiprotein complex; ORP1L acts as a cholesterol-sensing switch controlling RILP-HOPS-p150Glued interactions.","method":"Co-immunoprecipitation, siRNA knockdown, genetic epistasis (haploid cell screen), Ebola infection assay, in vitro binding","journal":"Journal of Cell Science","confidence":"High","confidence_rationale":"Tier 2 — direct binding, epistasis, functional assays with multiple methods","pmids":["23729732"],"is_preprint":false},{"year":2014,"finding":"RILP interacts with the V1G1 subunit (ATP6V1G1) of vacuolar ATPase, controls V1G1 recruitment to late endosomal/lysosomal membranes, promotes proteasomal degradation of V1G1 (via ubiquitylation), and thereby regulates V-ATPase assembly and activity.","method":"Co-immunoprecipitation, siRNA knockdown, V-ATPase activity assay, ubiquitylation assay, fluorescence microscopy","journal":"Journal of Cell Science","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods, direct interaction with functional consequence on V-ATPase activity","pmids":["24762812"],"is_preprint":false},{"year":2015,"finding":"RILP suppresses breast cancer cell invasion by interacting with RalGDS (Ral guanine nucleotide dissociation stimulator) via its N-terminal region; this interaction recruits RalGDS to late endosomes, inhibiting its GEF activity toward RalA and thereby suppressing invasion.","method":"Co-immunoprecipitation, truncation analysis, immunofluorescence, RalA activity assay, siRNA knockdown, migration/invasion assays","journal":"Cell Death & Disease","confidence":"Medium","confidence_rationale":"Tier 2 — direct interaction mapped, GEF activity measured, functional phenotype demonstrated","pmids":["26469971"],"is_preprint":false},{"year":2016,"finding":"Folliculin (FLCN) promotes perinuclear lysosome clustering by interacting directly via its C-terminal DENN domain with RILP; purified FLCN-DENN domain loads active Rab34 onto RILP (but does not act as a GEF for Rab34); this drives formation of Rab34-positive membrane contacts with lysosomes reducing their motility.","method":"Purified recombinant protein in vitro binding assay, siRNA knockdown, live-cell imaging, co-immunoprecipitation","journal":"EMBO Reports","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with purified proteins plus cellular functional assays","pmids":["27113757"],"is_preprint":false},{"year":2016,"finding":"HCV (and Sendai virus) infection causes NS3/4A protease-dependent cleavage of RILP, generating a C-terminal fragment (cRILP) that lacks the N-terminus; cRILP redistributes to the cell periphery, releases from dynein p150Glued, and redirects Rab7 vesicles to kinesin-dependent trafficking, promoting virion secretion.","method":"Viral infection, western blot for RILP cleavage, siRNA knockdown, cRILP expression, kinesin inhibitor, trafficking assays","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 — multiple mechanistic orthogonal approaches, defined biochemical cleavage site, functional rescue","pmids":["27791088"],"is_preprint":false},{"year":2016,"finding":"Rab12 is a novel binding partner and cargo of RILP; activated Rab12 interacts with RILP to mediate microtubule-dependent retrograde transport of mast cell secretory granules via the RILP-dynein complex; Rab12 negatively regulates mast cell degranulation through this mechanism.","method":"Co-immunoprecipitation, siRNA knockdown, live-cell imaging, dominant-negative constructs, degranulation assays","journal":"Journal of Immunology","confidence":"Medium","confidence_rationale":"Tier 2 — direct interaction established, functional phenotype in loss-of-function, single lab","pmids":["26740112"],"is_preprint":false},{"year":2018,"finding":"Caspase-1 directly cleaves RILP at aspartic acid 75; alanine substitution at D75 blocks caspase-1-mediated cleavage; redistribution of cleaved RILP to the cytoplasm requires both cleavage and specific phosphorylation events near the caspase-1 site; combined cleavage + phosphorylation are required for release from dynein p150Glued and redistribution of CD63-positive vesicles.","method":"In vitro caspase-1 cleavage assay, site-directed mutagenesis (D75A), phosphorylation analysis, localization by fluorescence microscopy","journal":"Biochemical and Biophysical Research Communications","confidence":"Medium","confidence_rationale":"Tier 1–2 — direct in vitro enzymatic assay with mutagenesis, single lab","pmids":["30100068"],"is_preprint":false},{"year":2018,"finding":"Rab7 interacts with ORP1L via a non-canonical site (helix3 and 310-helix2 of Rab7), independently of GTP/GDP state; this leaves the canonical effector-interacting switch regions free for RILP binding, enabling simultaneous ORP1L-Rab7-RILP tripartite complex formation; mutational disruption of the ORP1L-Rab7 interface impairs late endosome positioning.","method":"Crystal structure of Rab7-ORP1L ARDN, biochemical binding assays, mutagenesis, late endosome positioning assay","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with mutagenesis and functional validation","pmids":["30012887"],"is_preprint":false},{"year":2019,"finding":"LRRK1 phosphorylates GTP-bound Rab7 at serine 72 at endosomal membranes; this phosphorylation promotes RILP interaction with Rab7, leading to dynein-dynactin recruitment and dynein-driven transport of EGFR-containing endosomes to the perinuclear region.","method":"In vitro kinase assay, phospho-specific antibody, co-immunoprecipitation, LRRK1 knockdown/overexpression, endosome transport assay","journal":"Journal of Cell Science","confidence":"High","confidence_rationale":"Tier 1–2 — direct kinase assay, site-specific phosphorylation, functional transport consequence","pmids":["31085713"],"is_preprint":false},{"year":2019,"finding":"RILP interacts with insulin granule-associated Rab26 and mediates lysosomal degradation of proinsulin; RILP overexpression induces insulin granule clustering and promotes Rab7-dependent, lysosomal inhibitor-sensitive proinsulin degradation, thereby restricting insulin secretion.","method":"Co-immunoprecipitation, overexpression, siRNA knockdown, lysosomal inhibitor treatment, insulin secretion assays in beta-cell lines and islets","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2 — direct interaction, loss-of-function, pharmacological inhibition, functional outcome","pmids":["31624142"],"is_preprint":false},{"year":2020,"finding":"RILP functions as a dynein adaptor for neuronal autophagosomes and controls autophagosome biogenesis: mTOR inhibition upregulates RILP expression and its localization to autophagosomes; RILP interacts with ATG5 on isolation membranes (preventing premature dynein recruitment) and with LC3 via LIR motifs; RILP depletion or LIR motif mutation strongly reduces autophagosome numbers and impairs autophagic turnover.","method":"siRNA knockdown, LIR motif mutagenesis, co-immunoprecipitation with ATG5 and LC3, live-cell imaging, autophagy flux assays","journal":"Developmental Cell","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods, mutagenesis, defined biogenesis and transport phenotypes","pmids":["32275887"],"is_preprint":false},{"year":2021,"finding":"Biochemical and in silico analysis reveals that Rab12 interacts with the RILP homology domain (RHD) of one RILP monomer and a C-terminal threonine of the other RILP monomer in a homodimeric RILP complex; lysine-71 of Rab12 is critical for binding RILP-L1 and RILP-L2 but dispensable for RILP binding; mutational analyses of RILP RHD demonstrate its involvement in mast cell secretory granule transport regulation.","method":"Molecular dynamics simulations, functional mutagenesis, peptide inhibition assays, biochemical binding assays","journal":"Scientific Reports","confidence":"Medium","confidence_rationale":"Tier 2 — mutagenesis and computational modeling with functional validation, single lab","pmids":["33986343"],"is_preprint":false},{"year":2024,"finding":"DENND6A acts as a GEF for Rab34 and as an effector of Arl8b; Arl8b recruits DENND6A to peripheral lysosomes, where it activates Rab34, which in turn recruits a RILP/dynein complex to drive lysosome retrograde transport and juxtanuclear repositioning; loss of DENND6A impairs autophagic flux.","method":"Cell-based GEF screen, co-immunoprecipitation, siRNA knockdown, lysosome positioning assay, autophagic flux assay","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 — epistasis established, direct interactions mapped, multiple functional readouts","pmids":["38296963"],"is_preprint":false},{"year":2024,"finding":"Rab7 phosphorylation at tyrosine 183 in diabetic cardiomyopathy promotes RILP recruitment to lipid droplets, enabling lysosomal degradation of lipid droplets via microlipophagy; Rab7 activator ML-098 enhances RILP levels and rescues cardiac dysfunction.","method":"RNA-seq, conditional knockout mice, phospho-specific analysis, in vivo pharmacological intervention, cardiac functional assays","journal":"Advanced Science","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo model with genetic and pharmacological evidence, single lab","pmids":["38837607"],"is_preprint":false},{"year":2024,"finding":"RILP induces late endosome/lysosome clustering that reduces ER-endolysosome contact sites; RILP interacts with ORP1L to competitively inhibit VAP-ORP1L contact site formation, blocking cholesterol flow from endolysosomes to ER and triggering RILP-dependent autophagy.","method":"Co-immunoprecipitation, immunofluorescence microscopy, cholesterol assays, autophagy assays, overexpression","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2–3 — direct interaction and functional consequence, single lab, moderate methods","pmids":["39195203"],"is_preprint":false},{"year":2024,"finding":"pH neutralization of late endosomes increases V1G1 (ATP6V1G1) subunit assembly on endosomal membranes; V1G1 stabilizes GTP-bound Rab7 via RILP interaction, leading to Rab7 hyperactivation, disrupted tubulation, and impaired CI-M6PR recycling, defining a V-ATPase–RILP–Rab7 feedback axis for endosomal pH control.","method":"LLOMe and NH4Cl treatments, dominant-active Rab7 mutants, co-immunoprecipitation, live-cell imaging, mannose-6-phosphate receptor trafficking assay","journal":"Journal of Cell Science","confidence":"Medium","confidence_rationale":"Tier 2 — multiple pharmacological and genetic tools, mechanistic pathway placement, single lab","pmids":["38578235"],"is_preprint":false},{"year":2025,"finding":"RILP functions as a RAB7A-dependent dynein adaptor for late endosome motility in neuronal dendrites, promotes endosome carrier formation, and is required for retrograde transport and clearance of degradative cargos from dendrites; importantly, RAB7A-RILP interaction is not required for lysosomal fusion or somatic degradation, but RAB7A/RILP-dependent late endosome transport is required for dendrite arborization.","method":"Separation-of-function RAB7A-L8A mutant (RILP-binding deficient) expressed in hippocampal neurons, live-cell imaging, cargo degradation assays, dendrite morphology analysis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — separation-of-function mutant with multiple functional readouts, preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.09.03.673267"],"is_preprint":true}],"current_model":"RILP is a coiled-coil effector protein that is recruited to late endosomal and lysosomal membranes by GTP-bound Rab7 (and also by active Rab34, Rab36, and Rab12), where it simultaneously binds the dynactin subunit p150Glued to recruit dynein-dynactin motors for minus-end microtubule transport, binds the HOPS tethering complex to couple transport with organelle fusion, binds ESCRT-II subunits (Vps22/Vps36) to regulate MVB biogenesis, and regulates V-ATPase function through interaction with V1G1; its activity is tuned by ORP1L as a cholesterol sensor that can disengage the dynein motor via ER-VAP contacts, by LRRK1-mediated phosphorylation of Rab7 at S72 to promote RILP interaction, and by caspase-1 or viral protease cleavage at D75 to re-route vesicular trafficking."},"narrative":{"teleology":[{"year":2001,"claim":"Identification of RILP as a Rab7-GTP-specific effector that recruits dynein-dynactin to late endosomes/lysosomes established the first molecular link between Rab7 signaling and minus-end-directed endosomal transport.","evidence":"Yeast two-hybrid, co-IP, GST pulldown, overexpression/dominant-negative constructs, degradation assays in mammalian cells","pmids":["11179213","11696325"],"confidence":"High","gaps":["Identity of the dynactin subunit directly contacted by RILP was not yet mapped","Whether RILP had functions beyond transport (e.g., fusion, MVB biogenesis) was unknown"]},{"year":2003,"claim":"Demonstrating that RILP is essential for phagosome maturation via dynein-dynactin-dependent tubule extension extended its function beyond canonical endosome transport to innate immunity, while domain mapping identified a 62-residue Rab-binding region also recognizing Rab34.","evidence":"RILP truncation mutants in phagosome maturation assays, electron microscopy, domain-swapping chimeras with RLP1","pmids":["12944476","14668488"],"confidence":"High","gaps":["Whether RILP-Rab34 interaction had independent physiological relevance was unclear","Structural basis for dual Rab recognition unknown"]},{"year":2004,"claim":"Discovery that Salmonella effector SifA disrupts the Rab7-RILP interaction to redirect vacuolar trafficking demonstrated that pathogens exploit the RILP-dynein axis as a vulnerability point in host defense.","evidence":"Immobilized RILP pulldown, immunofluorescence, SifA epistasis in infected cells","pmids":["15121880"],"confidence":"High","gaps":["Molecular mechanism by which SifA dissociates Rab7-RILP not resolved","Generalizability to other intracellular pathogens not yet established"]},{"year":2007,"claim":"Mapping RILP's direct contact to the p150Glued C-terminal domain and discovering the tripartite Rab7-RILP-ORP1L complex, together with RILP's interaction with ESCRT-II subunits Vps22/Vps36 for MVB biogenesis, revealed RILP as a multifunctional scaffold integrating transport, tethering, and cargo sorting.","evidence":"Co-IP, GST pulldown, siRNA, EM for intralumenal vesicles, EGFR degradation assays","pmids":["17283181","17959629","16857164"],"confidence":"High","gaps":["How RILP coordinates simultaneous binding to dynactin, ESCRT-II, and HOPS was structurally unresolved","Stoichiometry of the tripartite complex unknown"]},{"year":2009,"claim":"The finding that ORP1L senses late endosomal cholesterol levels and, under low cholesterol, triggers ER-LE contacts via VAP that strip dynein from RILP established a lipid-sensing regulatory switch controlling RILP-dependent transport direction.","evidence":"Cholesterol manipulation, co-IP, dominant-negative constructs, fluorescence microscopy","pmids":["19564404"],"confidence":"High","gaps":["Structural basis for VAP-mediated p150Glued displacement not determined","Whether cholesterol regulation of RILP occurs in all cell types unknown"]},{"year":2012,"claim":"Identification of Rab36 and melanoregulin as RILP partners for retrograde melanosome transport demonstrated that RILP functions as a shared dynein adaptor across multiple Rab GTPase pathways and organelle types beyond classical late endosomes.","evidence":"Yeast two-hybrid, site-directed mutagenesis of RHD, melanosome distribution assays in melanocytes, co-IP with p150Glued and melanoregulin","pmids":["22740695","22275436"],"confidence":"High","gaps":["Whether Rab36 and Rab7 compete for the same RILP dimer interface was not resolved","Physiological relevance of melanoregulin-RILP outside melanocytes unclear"]},{"year":2013,"claim":"Showing that RILP simultaneously binds HOPS tethering complex and p150Glued linked transport and fusion into a single module, explaining how late endosomes couple motility with homotypic tethering competence.","evidence":"Co-IP, siRNA, haploid cell genetic screen, Ebola infection assay, in vitro binding","pmids":["23729732"],"confidence":"High","gaps":["Which HOPS subunit(s) directly contact RILP was not mapped","Whether RILP-HOPS interaction is cholesterol-regulated like RILP-dynein was not fully dissected"]},{"year":2014,"claim":"The discovery that RILP binds and promotes proteasomal degradation of V-ATPase subunit V1G1 revealed an unexpected role in regulating endolysosomal acidification, extending RILP function beyond transport to organelle homeostasis.","evidence":"Co-IP, V-ATPase activity assay, ubiquitylation assay, siRNA knockdown","pmids":["24762812"],"confidence":"High","gaps":["E3 ligase mediating V1G1 ubiquitylation downstream of RILP was not identified","How V1G1-RILP and Rab7-RILP interactions are coordinated structurally unknown"]},{"year":2016,"claim":"Three discoveries — FLCN loading Rab34 onto RILP, Rab12-RILP controlling mast cell granule transport, and HCV NS3/4A protease cleaving RILP to redirect trafficking — established RILP as a convergence point for diverse upstream Rab signals and a target for pathogen-mediated subversion via proteolysis.","evidence":"In vitro reconstitution with purified FLCN-DENN/RILP, co-IP of Rab12, viral cleavage western blots, degranulation and virion secretion assays","pmids":["27113757","26740112","27791088"],"confidence":"High","gaps":["Whether FLCN-Rab34-RILP and Rab7-RILP complexes coexist or are mutually exclusive unknown","Precise cleavage site for NS3/4A on RILP not mapped at residue level"]},{"year":2018,"claim":"Crystal structure of Rab7-ORP1L revealed that ORP1L binds a non-canonical Rab7 surface, leaving switch regions free for RILP, structurally explaining simultaneous tripartite complex formation; caspase-1 cleavage at D75 and associated phosphorylation were shown to cooperatively release RILP from dynein.","evidence":"X-ray crystallography of Rab7-ORP1L, mutagenesis, in vitro caspase-1 cleavage assay with D75A mutant","pmids":["30012887","30100068"],"confidence":"High","gaps":["Full atomic structure of the Rab7-RILP-ORP1L ternary complex not yet solved","Kinase responsible for phosphorylation near D75 not identified"]},{"year":2019,"claim":"LRRK1 phosphorylation of Rab7 at S72 was shown to promote RILP binding and consequent dynein-mediated transport, establishing a kinase-dependent regulatory input upstream of the Rab7-RILP axis relevant to EGFR downregulation.","evidence":"In vitro kinase assay, phospho-specific antibody, co-IP, endosome transport assays with LRRK1 knockdown","pmids":["31085713"],"confidence":"High","gaps":["Phosphatase counteracting S72 phosphorylation not identified","Whether LRRK2 (Parkinson's-linked paralog) similarly regulates RILP binding unknown"]},{"year":2020,"claim":"Discovery that RILP interacts with ATG5 on isolation membranes and with LC3 via LIR motifs, controlling autophagosome biogenesis and subsequent dynein-mediated autophagosome transport, unified RILP's roles in degradative trafficking and autophagy.","evidence":"siRNA knockdown, LIR motif mutagenesis, co-IP with ATG5/LC3, autophagy flux assays in neurons","pmids":["32275887"],"confidence":"High","gaps":["Whether RILP-ATG5 interaction inhibits or scaffolds phagophore closure not distinguished","Regulation of RILP expression by mTOR pathway not mechanistically resolved"]},{"year":2024,"claim":"Multiple 2024 studies integrated RILP into broader regulatory circuits: DENND6A as an Arl8b effector activates Rab34 to recruit RILP/dynein for lysosome repositioning; a V-ATPase-RILP-Rab7 feedback loop controls endosomal pH; RILP-ORP1L competition with VAP regulates cholesterol transfer and autophagy; and Rab7 Y183 phosphorylation recruits RILP to lipid droplets for microlipophagy.","evidence":"GEF screen, epistasis, co-IP, lysosome/endosome positioning assays, pH manipulation, cholesterol assays, conditional knockout mice with pharmacological rescue","pmids":["38296963","38578235","39195203","38837607"],"confidence":"Medium","gaps":["Whether DENND6A-Rab34-RILP and Rab7-RILP represent parallel or sequential pathways on the same organelle unclear","Kinase mediating Rab7 Y183 phosphorylation not identified","In vivo validation of RILP's role in lipid droplet degradation limited to one disease model"]},{"year":null,"claim":"No high-resolution structure of the full-length RILP homodimer in complex with Rab7, dynactin p150Glued, and HOPS exists; how RILP coordinates its multiple binding partners simultaneously on the same membrane domain, and how cell-type-specific Rab inputs (Rab7, Rab34, Rab36, Rab12, Rab26) are prioritized, remain open questions.","evidence":"","pmids":[],"confidence":"Low","gaps":["No full-length RILP structure available","Stoichiometry and mutual exclusivity of RILP's simultaneous binding partners unresolved","Tissue-specific phenotypes of RILP loss in vivo not characterized in knockout animal models"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,5,13,23]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,5,12]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,1,5,6,10]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[0,1,14,25]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[2,17,22]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,1,5,10,13,17]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[23,25,27]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,4,8]}],"complexes":["Rab7-RILP-ORP1L tripartite complex","RILP-dynein-dynactin motor complex","RILP-HOPS tethering complex"],"partners":["RAB7A","DCTN1","ORP1L","VPS22","VPS36","ATP6V1G1","RAB34","FLCN"],"other_free_text":[]},"mechanistic_narrative":"RILP is a coiled-coil effector of Rab7 and related GTPases (Rab34, Rab36, Rab12) that serves as a central adaptor coupling late endosomal/lysosomal identity to dynein-dynactin-dependent minus-end microtubule transport, organelle tethering, multivesicular body biogenesis, and autophagy [PMID:11179213, PMID:11696325, PMID:23729732, PMID:32275887]. Recruited to endolysosomal membranes by GTP-bound Rab7, RILP directly binds the p150Glued subunit of dynactin and simultaneously engages the HOPS tethering complex, linking retrograde transport to homotypic fusion, while its interaction with ESCRT-II subunits Vps22/Vps36 regulates intralumenal vesicle formation and EGFR degradation [PMID:17283181, PMID:17959629, PMID:23729732]. RILP activity is tuned by cholesterol-sensing through ORP1L, which under low-cholesterol conditions promotes ER–late endosome contacts via VAP that strip dynein from the RILP complex, by LRRK1-mediated Rab7 S72 phosphorylation that enhances RILP recruitment, and by proteolytic cleavage at D75 by caspase-1 or viral proteases that redirect vesicular trafficking peripherally [PMID:19564404, PMID:31085713, PMID:27791088, PMID:30100068]. Beyond canonical endolysosomal trafficking, RILP controls phagosome maturation, autophagosome biogenesis through interaction with ATG5 and LC3, melanosome and mast cell granule positioning, and V-ATPase assembly via regulation of V1G1 subunit stability [PMID:12944476, PMID:32275887, PMID:22740695, PMID:26740112, PMID:24762812]."},"prefetch_data":{"uniprot":{"accession":"Q96NA2","full_name":"Rab-interacting lysosomal protein","aliases":[],"length_aa":401,"mass_kda":44.2,"function":"Rab effector playing a role in late endocytic transport to degradative compartments (PubMed:11179213, PubMed:11696325, PubMed:12944476, PubMed:14668488, PubMed:27113757). Involved in the regulation of lysosomal morphology and distribution (PubMed:14668488, PubMed:27113757). Induces recruitment of dynein-dynactin motor complexes to Rab7A-containing late endosome and lysosome compartments (PubMed:11179213, PubMed:11696325). Promotes centripetal migration of phagosomes and the fusion of phagosomes with the late endosomes and lysosomes (PubMed:12944476)","subcellular_location":"Late endosome membrane; Lysosome membrane; Cytoplasmic vesicle, phagosome membrane","url":"https://www.uniprot.org/uniprotkb/Q96NA2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RILP","classification":"Not Classified","n_dependent_lines":43,"n_total_lines":1208,"dependency_fraction":0.03559602649006623},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/RILP","total_profiled":1310},"omim":[{"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":"613215","title":"CHROMOSOME 17p13.3, CENTROMERIC, DUPLICATION SYNDROME","url":"https://www.omim.org/entry/613215"},{"mim_id":"613004","title":"HUNTINGTIN; HTT","url":"https://www.omim.org/entry/613004"},{"mim_id":"608552","title":"VPS33B LATE ENDOSOME AND LYSOSOME ASSOCIATED; VPS33B","url":"https://www.omim.org/entry/608552"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"heart muscle","ntpm":65.2},{"tissue":"skeletal muscle","ntpm":52.4}],"url":"https://www.proteinatlas.org/search/RILP"},"hgnc":{"alias_symbol":["FLJ31193"],"prev_symbol":[]},"alphafold":{"accession":"Q96MT3","domains":[{"cath_id":"2.10.110.10","chopping":"41-188","consensus_level":"high","plddt":92.6248,"start":41,"end":188},{"cath_id":"-","chopping":"217-246","consensus_level":"medium","plddt":92.8497,"start":217,"end":246}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96MT3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96MT3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96MT3-F1-predicted_aligned_error_v6.png","plddt_mean":55.66},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RILP","jax_strain_url":"https://www.jax.org/strain/search?query=RILP"},"sequence":{"accession":"Q96MT3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96MT3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96MT3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96MT3"}},"corpus_meta":[{"pmid":"11696325","id":"PMC_11696325","title":"The 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mice","date":"2024-09-17","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.12.612708","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":30818,"output_tokens":7072,"usd":0.099267},"stage2":{"model":"claude-opus-4-6","input_tokens":10770,"output_tokens":3939,"usd":0.228488},"total_usd":0.327755,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"RILP (Rab7-interacting lysosomal protein) specifically binds GTP-bound Rab7 and recruits functional dynein-dynactin motor complexes to late endosomes and lysosomes, causing their transport toward microtubule minus ends and inhibiting peripheral trafficking.\",\n      \"method\": \"Co-immunoprecipitation, overexpression in mammalian cells, fluorescence microscopy, dominant-negative constructs\",\n      \"journal\": \"Current Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal interaction demonstrated, replicated across two independent labs simultaneously\",\n      \"pmids\": [\"11696325\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"RILP is a 45 kDa protein containing two coiled-coil regions, found mainly in cytosol, that is recruited to late endosomal/lysosomal membranes by Rab7-GTP via its C-terminus; RILP-C33 (truncated C-terminal form lacking N-terminal half) acts as dominant negative, inhibiting EGF and LDL degradation and dispersing lysosomes similarly to dominant-negative Rab7.\",\n      \"method\": \"Yeast two-hybrid, GST pulldown, overexpression of truncation mutants, degradation assays\",\n      \"journal\": \"The EMBO Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods, foundational paper replicated by others\",\n      \"pmids\": [\"11179213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"RILP promotes extension of phagosomal tubules toward late endocytic compartments by recruiting dynein-dynactin; a truncated RILP lacking the dynein-dynactin-recruiting domain prevents tubule extension and phagosome-lysosome fusion, establishing RILP as essential for phagosome maturation.\",\n      \"method\": \"Fluorescence microscopy, electron microscopy, overexpression of RILP truncation mutants, functional phagosome maturation assays\",\n      \"journal\": \"Molecular and Cellular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods with defined phenotypic readout, high citation count\",\n      \"pmids\": [\"12944476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"A unique 62-residue region (amino acids 272–333) in RILP is necessary and sufficient for regulating lysosomal morphology and for interaction with GTP-bound Rab7 and Rab34; transferring this region into the related protein RLP1 confers lysosome-regulatory activity.\",\n      \"method\": \"Domain swapping/chimeric protein expression, GTPase interaction assays, lysosome morphology readout in mammalian cells\",\n      \"journal\": \"Molecular Biology of the Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — mutagenesis and domain transfer with functional validation\",\n      \"pmids\": [\"14668488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Salmonella effector SifA disrupts the Rab7–RILP interaction on Salmonella-containing vacuoles, preventing dynein recruitment; this uncoupling allows kinesin-dependent centrifugal extension of Salmonella-induced filaments, promoting bacterial replication in a protected compartment.\",\n      \"method\": \"Co-transfection, immunofluorescence, immobilized RILP pulldown of active Rab7, cell-free system with BCG supernatant\",\n      \"journal\": \"Molecular Biology of the Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vitro pulldown, cell-based imaging, epistasis with SifA\",\n      \"pmids\": [\"15121880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"GTP-bound Rab7 simultaneously binds RILP and ORP1L to form a tripartite RILP-Rab7-ORP1L complex; RILP directly contacts the C-terminal 25-kDa region of dynactin p150Glued; ORP1L and betaIII spectrin are additionally required for dynein motor activity, establishing a stepwise assembly cascade for minus-end endosomal transport.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown, siRNA knockdown, live-cell imaging, dominant-negative constructs\",\n      \"journal\": \"The Journal of Cell Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, direct binding mapped to specific domain, replicated\",\n      \"pmids\": [\"17283181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"RILP is required for biogenesis of multivesicular endosomes (MVEs): RILP depletion by siRNA reduces intralumenal vesicle content, impairs EGFR degradation (but not transferrin recycling), and causes elevated levels of late-endosomal markers. RILP interacts with ESCRT-II subunits Vps22 and Vps36.\",\n      \"method\": \"siRNA knockdown, electron microscopy, degradation assays for EGFR vs. transferrin, co-immunoprecipitation with ESCRT-II subunits\",\n      \"journal\": \"Journal of Cell Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with specific phenotype and direct interaction data, multiple orthogonal methods\",\n      \"pmids\": [\"17959629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"RILP interacts with VPS22 (EAP30/SNF8) of ESCRT-II via its N-terminal half, and with VPS36 (EAP45) via its C-terminal half; RILP overexpression causes enlarged, clustered MVBs and retards EGF sorting at sorting endosomes, suggesting a regulatory loop between early and late endocytic machinery.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, confocal immunofluorescence, RILP domain truncation analysis\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — co-IP and colocalization, single lab, moderate follow-up\",\n      \"pmids\": [\"17010938\", \"16857164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Mycobacterium bovis BCG inhibits phagosome maturation by preventing RILP recruitment to Rab7 on phagosomal membranes; BCG culture supernatant contains a factor that catalyzes GTP→GDP conversion on Rab7, maintaining Rab7 in inactive GDP-bound form and blocking RILP-mediated lysosomal fusion.\",\n      \"method\": \"Co-transfection, immobilized RILP pulldown of GTP-bound Rab7, cell-free GTPase activity assay\",\n      \"journal\": \"Journal of Leukocyte Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and cell-based assays, direct mechanistic link established\",\n      \"pmids\": [\"18040083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Huntingtin regulates REST/NRSF nuclear trafficking indirectly through a complex containing REST/NRSF, RILP, dynactin p150Glued, huntingtin, and HAP1; RILP directly binds p150Glued and REST/NRSF; mutant huntingtin weakens the dynactin p150Glued–RILP interaction; HAP1 prevents the complex from translocating REST/NRSF to the nucleus.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation of in vitro translated proteins, complex characterization\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — co-IP and two-hybrid, single lab, single paper\",\n      \"pmids\": [\"18922795\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Cholesterol levels in late endosomes are sensed by ORP1L; under low cholesterol, ORP1L conformation induces formation of ER-late endosome membrane contact sites where VAP (ER protein) interacts in trans with the Rab7-RILP complex to remove p150Glued and associated motors, causing plus-end directed movement. High cholesterol (as in Niemann-Pick C) prevents this, locking LEs at minus-end via dynein-RILP.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative constructs, fluorescence microscopy, fractionation, cholesterol manipulation\",\n      \"journal\": \"The Journal of Cell Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic epistasis with multiple orthogonal methods, high citation count, replicated by multiple labs\",\n      \"pmids\": [\"19564404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"RILP functions as an effector of Rab36 (in addition to Rab7) via its RILP homology domain (RHD, a coiled-coil domain); site-directed mutagenesis of RHD revealed differential amino acid contributions to Rab7 vs. Rab36 binding; Rab36-RILP interaction mediates retrograde melanosome transport in melanocytes, independent of Rab7.\",\n      \"method\": \"Yeast two-hybrid screen, GST pulldown, site-directed mutagenesis, knockdown in melanocytes, melanosome distribution assays\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — mutagenesis plus functional cellular assays with defined phenotype\",\n      \"pmids\": [\"22740695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Melanoregulin (Mreg) interacts with the C-terminal domain of RILP and forms a trimeric complex with RILP and p150Glued, mediating dynein-dynactin-dependent retrograde melanosome transport; Mreg knockdown or dynein-dynactin disruption restores peripheral melanosome distribution in Rab27A-deficient melanocytes.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, overexpression, melanosome distribution assays\",\n      \"journal\": \"Journal of Cell Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP and KD with defined phenotype, single lab\",\n      \"pmids\": [\"22275436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RILP simultaneously and directly binds both the HOPS tethering complex and p150Glued subunit of dynein-dynactin, coupling late endosomal transport and tethering into a single RAB7-RILP-ORP1L multiprotein complex; ORP1L acts as a cholesterol-sensing switch controlling RILP-HOPS-p150Glued interactions.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, genetic epistasis (haploid cell screen), Ebola infection assay, in vitro binding\",\n      \"journal\": \"Journal of Cell Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct binding, epistasis, functional assays with multiple methods\",\n      \"pmids\": [\"23729732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RILP interacts with the V1G1 subunit (ATP6V1G1) of vacuolar ATPase, controls V1G1 recruitment to late endosomal/lysosomal membranes, promotes proteasomal degradation of V1G1 (via ubiquitylation), and thereby regulates V-ATPase assembly and activity.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, V-ATPase activity assay, ubiquitylation assay, fluorescence microscopy\",\n      \"journal\": \"Journal of Cell Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, direct interaction with functional consequence on V-ATPase activity\",\n      \"pmids\": [\"24762812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RILP suppresses breast cancer cell invasion by interacting with RalGDS (Ral guanine nucleotide dissociation stimulator) via its N-terminal region; this interaction recruits RalGDS to late endosomes, inhibiting its GEF activity toward RalA and thereby suppressing invasion.\",\n      \"method\": \"Co-immunoprecipitation, truncation analysis, immunofluorescence, RalA activity assay, siRNA knockdown, migration/invasion assays\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct interaction mapped, GEF activity measured, functional phenotype demonstrated\",\n      \"pmids\": [\"26469971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Folliculin (FLCN) promotes perinuclear lysosome clustering by interacting directly via its C-terminal DENN domain with RILP; purified FLCN-DENN domain loads active Rab34 onto RILP (but does not act as a GEF for Rab34); this drives formation of Rab34-positive membrane contacts with lysosomes reducing their motility.\",\n      \"method\": \"Purified recombinant protein in vitro binding assay, siRNA knockdown, live-cell imaging, co-immunoprecipitation\",\n      \"journal\": \"EMBO Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with purified proteins plus cellular functional assays\",\n      \"pmids\": [\"27113757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"HCV (and Sendai virus) infection causes NS3/4A protease-dependent cleavage of RILP, generating a C-terminal fragment (cRILP) that lacks the N-terminus; cRILP redistributes to the cell periphery, releases from dynein p150Glued, and redirects Rab7 vesicles to kinesin-dependent trafficking, promoting virion secretion.\",\n      \"method\": \"Viral infection, western blot for RILP cleavage, siRNA knockdown, cRILP expression, kinesin inhibitor, trafficking assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple mechanistic orthogonal approaches, defined biochemical cleavage site, functional rescue\",\n      \"pmids\": [\"27791088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Rab12 is a novel binding partner and cargo of RILP; activated Rab12 interacts with RILP to mediate microtubule-dependent retrograde transport of mast cell secretory granules via the RILP-dynein complex; Rab12 negatively regulates mast cell degranulation through this mechanism.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, live-cell imaging, dominant-negative constructs, degranulation assays\",\n      \"journal\": \"Journal of Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct interaction established, functional phenotype in loss-of-function, single lab\",\n      \"pmids\": [\"26740112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Caspase-1 directly cleaves RILP at aspartic acid 75; alanine substitution at D75 blocks caspase-1-mediated cleavage; redistribution of cleaved RILP to the cytoplasm requires both cleavage and specific phosphorylation events near the caspase-1 site; combined cleavage + phosphorylation are required for release from dynein p150Glued and redistribution of CD63-positive vesicles.\",\n      \"method\": \"In vitro caspase-1 cleavage assay, site-directed mutagenesis (D75A), phosphorylation analysis, localization by fluorescence microscopy\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — direct in vitro enzymatic assay with mutagenesis, single lab\",\n      \"pmids\": [\"30100068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Rab7 interacts with ORP1L via a non-canonical site (helix3 and 310-helix2 of Rab7), independently of GTP/GDP state; this leaves the canonical effector-interacting switch regions free for RILP binding, enabling simultaneous ORP1L-Rab7-RILP tripartite complex formation; mutational disruption of the ORP1L-Rab7 interface impairs late endosome positioning.\",\n      \"method\": \"Crystal structure of Rab7-ORP1L ARDN, biochemical binding assays, mutagenesis, late endosome positioning assay\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with mutagenesis and functional validation\",\n      \"pmids\": [\"30012887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LRRK1 phosphorylates GTP-bound Rab7 at serine 72 at endosomal membranes; this phosphorylation promotes RILP interaction with Rab7, leading to dynein-dynactin recruitment and dynein-driven transport of EGFR-containing endosomes to the perinuclear region.\",\n      \"method\": \"In vitro kinase assay, phospho-specific antibody, co-immunoprecipitation, LRRK1 knockdown/overexpression, endosome transport assay\",\n      \"journal\": \"Journal of Cell Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct kinase assay, site-specific phosphorylation, functional transport consequence\",\n      \"pmids\": [\"31085713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RILP interacts with insulin granule-associated Rab26 and mediates lysosomal degradation of proinsulin; RILP overexpression induces insulin granule clustering and promotes Rab7-dependent, lysosomal inhibitor-sensitive proinsulin degradation, thereby restricting insulin secretion.\",\n      \"method\": \"Co-immunoprecipitation, overexpression, siRNA knockdown, lysosomal inhibitor treatment, insulin secretion assays in beta-cell lines and islets\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct interaction, loss-of-function, pharmacological inhibition, functional outcome\",\n      \"pmids\": [\"31624142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RILP functions as a dynein adaptor for neuronal autophagosomes and controls autophagosome biogenesis: mTOR inhibition upregulates RILP expression and its localization to autophagosomes; RILP interacts with ATG5 on isolation membranes (preventing premature dynein recruitment) and with LC3 via LIR motifs; RILP depletion or LIR motif mutation strongly reduces autophagosome numbers and impairs autophagic turnover.\",\n      \"method\": \"siRNA knockdown, LIR motif mutagenesis, co-immunoprecipitation with ATG5 and LC3, live-cell imaging, autophagy flux assays\",\n      \"journal\": \"Developmental Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, mutagenesis, defined biogenesis and transport phenotypes\",\n      \"pmids\": [\"32275887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Biochemical and in silico analysis reveals that Rab12 interacts with the RILP homology domain (RHD) of one RILP monomer and a C-terminal threonine of the other RILP monomer in a homodimeric RILP complex; lysine-71 of Rab12 is critical for binding RILP-L1 and RILP-L2 but dispensable for RILP binding; mutational analyses of RILP RHD demonstrate its involvement in mast cell secretory granule transport regulation.\",\n      \"method\": \"Molecular dynamics simulations, functional mutagenesis, peptide inhibition assays, biochemical binding assays\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mutagenesis and computational modeling with functional validation, single lab\",\n      \"pmids\": [\"33986343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DENND6A acts as a GEF for Rab34 and as an effector of Arl8b; Arl8b recruits DENND6A to peripheral lysosomes, where it activates Rab34, which in turn recruits a RILP/dynein complex to drive lysosome retrograde transport and juxtanuclear repositioning; loss of DENND6A impairs autophagic flux.\",\n      \"method\": \"Cell-based GEF screen, co-immunoprecipitation, siRNA knockdown, lysosome positioning assay, autophagic flux assay\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epistasis established, direct interactions mapped, multiple functional readouts\",\n      \"pmids\": [\"38296963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Rab7 phosphorylation at tyrosine 183 in diabetic cardiomyopathy promotes RILP recruitment to lipid droplets, enabling lysosomal degradation of lipid droplets via microlipophagy; Rab7 activator ML-098 enhances RILP levels and rescues cardiac dysfunction.\",\n      \"method\": \"RNA-seq, conditional knockout mice, phospho-specific analysis, in vivo pharmacological intervention, cardiac functional assays\",\n      \"journal\": \"Advanced Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo model with genetic and pharmacological evidence, single lab\",\n      \"pmids\": [\"38837607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RILP induces late endosome/lysosome clustering that reduces ER-endolysosome contact sites; RILP interacts with ORP1L to competitively inhibit VAP-ORP1L contact site formation, blocking cholesterol flow from endolysosomes to ER and triggering RILP-dependent autophagy.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence microscopy, cholesterol assays, autophagy assays, overexpression\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — direct interaction and functional consequence, single lab, moderate methods\",\n      \"pmids\": [\"39195203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"pH neutralization of late endosomes increases V1G1 (ATP6V1G1) subunit assembly on endosomal membranes; V1G1 stabilizes GTP-bound Rab7 via RILP interaction, leading to Rab7 hyperactivation, disrupted tubulation, and impaired CI-M6PR recycling, defining a V-ATPase–RILP–Rab7 feedback axis for endosomal pH control.\",\n      \"method\": \"LLOMe and NH4Cl treatments, dominant-active Rab7 mutants, co-immunoprecipitation, live-cell imaging, mannose-6-phosphate receptor trafficking assay\",\n      \"journal\": \"Journal of Cell Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple pharmacological and genetic tools, mechanistic pathway placement, single lab\",\n      \"pmids\": [\"38578235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RILP functions as a RAB7A-dependent dynein adaptor for late endosome motility in neuronal dendrites, promotes endosome carrier formation, and is required for retrograde transport and clearance of degradative cargos from dendrites; importantly, RAB7A-RILP interaction is not required for lysosomal fusion or somatic degradation, but RAB7A/RILP-dependent late endosome transport is required for dendrite arborization.\",\n      \"method\": \"Separation-of-function RAB7A-L8A mutant (RILP-binding deficient) expressed in hippocampal neurons, live-cell imaging, cargo degradation assays, dendrite morphology analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — separation-of-function mutant with multiple functional readouts, preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.09.03.673267\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"RILP is a coiled-coil effector protein that is recruited to late endosomal and lysosomal membranes by GTP-bound Rab7 (and also by active Rab34, Rab36, and Rab12), where it simultaneously binds the dynactin subunit p150Glued to recruit dynein-dynactin motors for minus-end microtubule transport, binds the HOPS tethering complex to couple transport with organelle fusion, binds ESCRT-II subunits (Vps22/Vps36) to regulate MVB biogenesis, and regulates V-ATPase function through interaction with V1G1; its activity is tuned by ORP1L as a cholesterol sensor that can disengage the dynein motor via ER-VAP contacts, by LRRK1-mediated phosphorylation of Rab7 at S72 to promote RILP interaction, and by caspase-1 or viral protease cleavage at D75 to re-route vesicular trafficking.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"RILP is a coiled-coil effector of Rab7 and related GTPases (Rab34, Rab36, Rab12) that serves as a central adaptor coupling late endosomal/lysosomal identity to dynein-dynactin-dependent minus-end microtubule transport, organelle tethering, multivesicular body biogenesis, and autophagy [PMID:11179213, PMID:11696325, PMID:23729732, PMID:32275887]. Recruited to endolysosomal membranes by GTP-bound Rab7, RILP directly binds the p150Glued subunit of dynactin and simultaneously engages the HOPS tethering complex, linking retrograde transport to homotypic fusion, while its interaction with ESCRT-II subunits Vps22/Vps36 regulates intralumenal vesicle formation and EGFR degradation [PMID:17283181, PMID:17959629, PMID:23729732]. RILP activity is tuned by cholesterol-sensing through ORP1L, which under low-cholesterol conditions promotes ER–late endosome contacts via VAP that strip dynein from the RILP complex, by LRRK1-mediated Rab7 S72 phosphorylation that enhances RILP recruitment, and by proteolytic cleavage at D75 by caspase-1 or viral proteases that redirect vesicular trafficking peripherally [PMID:19564404, PMID:31085713, PMID:27791088, PMID:30100068]. Beyond canonical endolysosomal trafficking, RILP controls phagosome maturation, autophagosome biogenesis through interaction with ATG5 and LC3, melanosome and mast cell granule positioning, and V-ATPase assembly via regulation of V1G1 subunit stability [PMID:12944476, PMID:32275887, PMID:22740695, PMID:26740112, PMID:24762812].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Identification of RILP as a Rab7-GTP-specific effector that recruits dynein-dynactin to late endosomes/lysosomes established the first molecular link between Rab7 signaling and minus-end-directed endosomal transport.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, GST pulldown, overexpression/dominant-negative constructs, degradation assays in mammalian cells\",\n      \"pmids\": [\"11179213\", \"11696325\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the dynactin subunit directly contacted by RILP was not yet mapped\", \"Whether RILP had functions beyond transport (e.g., fusion, MVB biogenesis) was unknown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstrating that RILP is essential for phagosome maturation via dynein-dynactin-dependent tubule extension extended its function beyond canonical endosome transport to innate immunity, while domain mapping identified a 62-residue Rab-binding region also recognizing Rab34.\",\n      \"evidence\": \"RILP truncation mutants in phagosome maturation assays, electron microscopy, domain-swapping chimeras with RLP1\",\n      \"pmids\": [\"12944476\", \"14668488\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether RILP-Rab34 interaction had independent physiological relevance was unclear\", \"Structural basis for dual Rab recognition unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Discovery that Salmonella effector SifA disrupts the Rab7-RILP interaction to redirect vacuolar trafficking demonstrated that pathogens exploit the RILP-dynein axis as a vulnerability point in host defense.\",\n      \"evidence\": \"Immobilized RILP pulldown, immunofluorescence, SifA epistasis in infected cells\",\n      \"pmids\": [\"15121880\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which SifA dissociates Rab7-RILP not resolved\", \"Generalizability to other intracellular pathogens not yet established\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Mapping RILP's direct contact to the p150Glued C-terminal domain and discovering the tripartite Rab7-RILP-ORP1L complex, together with RILP's interaction with ESCRT-II subunits Vps22/Vps36 for MVB biogenesis, revealed RILP as a multifunctional scaffold integrating transport, tethering, and cargo sorting.\",\n      \"evidence\": \"Co-IP, GST pulldown, siRNA, EM for intralumenal vesicles, EGFR degradation assays\",\n      \"pmids\": [\"17283181\", \"17959629\", \"16857164\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How RILP coordinates simultaneous binding to dynactin, ESCRT-II, and HOPS was structurally unresolved\", \"Stoichiometry of the tripartite complex unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"The finding that ORP1L senses late endosomal cholesterol levels and, under low cholesterol, triggers ER-LE contacts via VAP that strip dynein from RILP established a lipid-sensing regulatory switch controlling RILP-dependent transport direction.\",\n      \"evidence\": \"Cholesterol manipulation, co-IP, dominant-negative constructs, fluorescence microscopy\",\n      \"pmids\": [\"19564404\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for VAP-mediated p150Glued displacement not determined\", \"Whether cholesterol regulation of RILP occurs in all cell types unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification of Rab36 and melanoregulin as RILP partners for retrograde melanosome transport demonstrated that RILP functions as a shared dynein adaptor across multiple Rab GTPase pathways and organelle types beyond classical late endosomes.\",\n      \"evidence\": \"Yeast two-hybrid, site-directed mutagenesis of RHD, melanosome distribution assays in melanocytes, co-IP with p150Glued and melanoregulin\",\n      \"pmids\": [\"22740695\", \"22275436\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Rab36 and Rab7 compete for the same RILP dimer interface was not resolved\", \"Physiological relevance of melanoregulin-RILP outside melanocytes unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showing that RILP simultaneously binds HOPS tethering complex and p150Glued linked transport and fusion into a single module, explaining how late endosomes couple motility with homotypic tethering competence.\",\n      \"evidence\": \"Co-IP, siRNA, haploid cell genetic screen, Ebola infection assay, in vitro binding\",\n      \"pmids\": [\"23729732\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which HOPS subunit(s) directly contact RILP was not mapped\", \"Whether RILP-HOPS interaction is cholesterol-regulated like RILP-dynein was not fully dissected\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"The discovery that RILP binds and promotes proteasomal degradation of V-ATPase subunit V1G1 revealed an unexpected role in regulating endolysosomal acidification, extending RILP function beyond transport to organelle homeostasis.\",\n      \"evidence\": \"Co-IP, V-ATPase activity assay, ubiquitylation assay, siRNA knockdown\",\n      \"pmids\": [\"24762812\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase mediating V1G1 ubiquitylation downstream of RILP was not identified\", \"How V1G1-RILP and Rab7-RILP interactions are coordinated structurally unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Three discoveries — FLCN loading Rab34 onto RILP, Rab12-RILP controlling mast cell granule transport, and HCV NS3/4A protease cleaving RILP to redirect trafficking — established RILP as a convergence point for diverse upstream Rab signals and a target for pathogen-mediated subversion via proteolysis.\",\n      \"evidence\": \"In vitro reconstitution with purified FLCN-DENN/RILP, co-IP of Rab12, viral cleavage western blots, degranulation and virion secretion assays\",\n      \"pmids\": [\"27113757\", \"26740112\", \"27791088\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether FLCN-Rab34-RILP and Rab7-RILP complexes coexist or are mutually exclusive unknown\", \"Precise cleavage site for NS3/4A on RILP not mapped at residue level\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Crystal structure of Rab7-ORP1L revealed that ORP1L binds a non-canonical Rab7 surface, leaving switch regions free for RILP, structurally explaining simultaneous tripartite complex formation; caspase-1 cleavage at D75 and associated phosphorylation were shown to cooperatively release RILP from dynein.\",\n      \"evidence\": \"X-ray crystallography of Rab7-ORP1L, mutagenesis, in vitro caspase-1 cleavage assay with D75A mutant\",\n      \"pmids\": [\"30012887\", \"30100068\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full atomic structure of the Rab7-RILP-ORP1L ternary complex not yet solved\", \"Kinase responsible for phosphorylation near D75 not identified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"LRRK1 phosphorylation of Rab7 at S72 was shown to promote RILP binding and consequent dynein-mediated transport, establishing a kinase-dependent regulatory input upstream of the Rab7-RILP axis relevant to EGFR downregulation.\",\n      \"evidence\": \"In vitro kinase assay, phospho-specific antibody, co-IP, endosome transport assays with LRRK1 knockdown\",\n      \"pmids\": [\"31085713\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphatase counteracting S72 phosphorylation not identified\", \"Whether LRRK2 (Parkinson's-linked paralog) similarly regulates RILP binding unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Discovery that RILP interacts with ATG5 on isolation membranes and with LC3 via LIR motifs, controlling autophagosome biogenesis and subsequent dynein-mediated autophagosome transport, unified RILP's roles in degradative trafficking and autophagy.\",\n      \"evidence\": \"siRNA knockdown, LIR motif mutagenesis, co-IP with ATG5/LC3, autophagy flux assays in neurons\",\n      \"pmids\": [\"32275887\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether RILP-ATG5 interaction inhibits or scaffolds phagophore closure not distinguished\", \"Regulation of RILP expression by mTOR pathway not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Multiple 2024 studies integrated RILP into broader regulatory circuits: DENND6A as an Arl8b effector activates Rab34 to recruit RILP/dynein for lysosome repositioning; a V-ATPase-RILP-Rab7 feedback loop controls endosomal pH; RILP-ORP1L competition with VAP regulates cholesterol transfer and autophagy; and Rab7 Y183 phosphorylation recruits RILP to lipid droplets for microlipophagy.\",\n      \"evidence\": \"GEF screen, epistasis, co-IP, lysosome/endosome positioning assays, pH manipulation, cholesterol assays, conditional knockout mice with pharmacological rescue\",\n      \"pmids\": [\"38296963\", \"38578235\", \"39195203\", \"38837607\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether DENND6A-Rab34-RILP and Rab7-RILP represent parallel or sequential pathways on the same organelle unclear\", \"Kinase mediating Rab7 Y183 phosphorylation not identified\", \"In vivo validation of RILP's role in lipid droplet degradation limited to one disease model\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"No high-resolution structure of the full-length RILP homodimer in complex with Rab7, dynactin p150Glued, and HOPS exists; how RILP coordinates its multiple binding partners simultaneously on the same membrane domain, and how cell-type-specific Rab inputs (Rab7, Rab34, Rab36, Rab12, Rab26) are prioritized, remain open questions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No full-length RILP structure available\", \"Stoichiometry and mutual exclusivity of RILP's simultaneous binding partners unresolved\", \"Tissue-specific phenotypes of RILP loss in vivo not characterized in knockout animal models\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 5, 13, 23]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 5, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 1, 5, 6, 10]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [0, 1, 14, 25]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [2, 17, 22]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 1, 5, 10, 13, 17]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [23, 25, 27]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 4, 8]}\n    ],\n    \"complexes\": [\n      \"Rab7-RILP-ORP1L tripartite complex\",\n      \"RILP-dynein-dynactin motor complex\",\n      \"RILP-HOPS tethering complex\"\n    ],\n    \"partners\": [\n      \"RAB7A\",\n      \"DCTN1\",\n      \"ORP1L\",\n      \"VPS22\",\n      \"VPS36\",\n      \"ATP6V1G1\",\n      \"RAB34\",\n      \"FLCN\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}