{"gene":"RILP","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2001,"finding":"RILP (Rab7-interacting lysosomal protein) specifically binds the GTP-bound (active) form of Rab7 at its C-terminus, is recruited to late endosomal/lysosomal membranes by Rab7-GTP, and functions as a downstream effector of Rab7 required for transport to lysosomes. Expression of a truncated form (RILP-C33) lacking the N-terminal half inhibits EGF and LDL degradation and disperses lysosomes, similar to Rab7 dominant-negative mutants; full-length RILP rescues Rab7 dominant-negative effects.","method":"Yeast two-hybrid screen, GST pulldown, co-immunoprecipitation, mammalian cell overexpression/dominant-negative epistasis, degradation assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (yeast two-hybrid, pulldown, co-IP, functional rescue epistasis) in founding paper, independently replicated by Jordens et al. same year","pmids":["11179213"],"is_preprint":false},{"year":2001,"finding":"RILP expression induces the recruitment of functional dynein-dynactin motor complexes to Rab7-containing late endosomes and lysosomes, driving minus-end microtubule transport and inhibiting transport toward the cell periphery. RILP also prevents further cycling of Rab7.","method":"Overexpression of RILP in cells, immunofluorescence, live imaging of organelle transport, functional dynein-dynactin recruitment assays","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct functional assay with organelle transport readout, replicated across multiple subsequent studies","pmids":["11696325"],"is_preprint":false},{"year":2003,"finding":"A unique 62-residue region (amino acids 272–333) within RILP is necessary and sufficient for regulating lysosomal morphology and for interaction with GTP-bound Rab7 and Rab34. Transfer of this region into the related protein RLP1 confers lysosome-regulating activity on RLP1.","method":"Truncation/chimeric mutant overexpression, lysosomal morphology assays, GTPase binding assays","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — domain mapping with gain-of-function chimera and multiple deletion mutants, single lab","pmids":["14668488"],"is_preprint":false},{"year":2003,"finding":"RILP bridges phagosomes with dynein-dynactin via active Rab7, promoting centripetal phagosome movement and extension of phagosomal tubules toward late endocytic compartments. A truncated RILP lacking the dynein-dynactin-recruiting domain prevents tubule extension and fusion with late endosomes/lysosomes.","method":"Fluorescence microscopy, electron microscopy, dominant-negative RILP expression, phagosome maturation assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple imaging modalities plus loss-of-function mutant with defined phenotype, replicated in multiple cell biology labs","pmids":["12944476"],"is_preprint":false},{"year":2004,"finding":"Salmonella effector SifA uncouples RILP from active Rab7 on Salmonella-induced filaments (Sifs), preventing dynein recruitment and allowing kinesin-driven centrifugal tubule extension. In vitro experiments indicated SifA may interact with Rab7 to catalyze GDP loading, inactivating it and preventing RILP recruitment.","method":"Co-transfection, fluorescence microscopy, in vitro pull-down of active Rab7 with immobilized RILP, cell-free system with BCG/SifA supernatant","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — multiple methods (imaging, in vitro pulldown, cell-free assay) but mechanistic details of SifA-Rab7 interaction inferred rather than fully reconstituted","pmids":["15121880"],"is_preprint":false},{"year":2006,"finding":"RILP interacts with VPS22 (EAP30/SNF8) of the ESCRT-II complex; the N-terminal half of RILP mediates this interaction. RILP overexpression leads to enlarged, clustered multivesicular bodies and retards EGF sorting to degradation at EEA1-positive sorting endosomes.","method":"Yeast two-hybrid, co-immunoprecipitation, confocal immunofluorescence, EGF trafficking assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — yeast two-hybrid confirmed by co-IP and colocalization, two independent papers (PMID 17010938, 16857164) reporting the same interaction","pmids":["16857164","17010938"],"is_preprint":false},{"year":2006,"finding":"RILP interacts with both VPS22 and VPS36 of ESCRT-II (N-terminal half binds VPS22; C-terminal half binds VPS36), integrating late endocytic machinery with early MVB sorting machinery.","method":"Co-immunoprecipitation, overexpression studies, EGF sorting assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP with functional readout in two concurrent papers, single lab for each","pmids":["17010938"],"is_preprint":false},{"year":2007,"finding":"RILP directly interacts with the C-terminal 25-kDa region of the dynactin subunit p150Glued, recruiting dynein motor to late endocytic compartments. GTP-bound Rab7 simultaneously binds RILP and ORP1L to form a tripartite RILP-Rab7-ORP1L complex. p150Glued recruitment by Rab7-RILP alone is insufficient for dynein-driven minus-end transport; ORP1L and betaIII spectrin are additionally required — RILP transfers the Rab7-RILP-p150Glued complex to betaIII spectrin to activate dynein.","method":"Co-immunoprecipitation, GST pulldown, deletion mutants, organelle motility assays, dominant-negative expression","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, multiple deletion mutants, functional transport assays, replicated across subsequent studies","pmids":["17283181"],"is_preprint":false},{"year":2007,"finding":"RILP depletion impairs biogenesis of multivesicular endosomes (reduces intraluminal vesicle content), inhibits ligand-mediated EGFR degradation, and causes accumulation of late-endosomal markers (LBPA, Lamp1, CD63, CI-M6PR). Transferrin receptor recycling is not affected by RILP depletion.","method":"RNAi knockdown, electron microscopy, immunofluorescence, EGF/transferrin receptor trafficking assays","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean RNAi loss-of-function with ultrastructural (EM) and functional readouts, multiple cargo assays, single lab","pmids":["17959629"],"is_preprint":false},{"year":2007,"finding":"Mycobacterium bovis BCG inhibits RILP recruitment to phagosomes despite Rab7 acquisition, by promoting GDP-bound (inactive) Rab7. A factor in BCG culture supernatant catalyzes GTP/GDP exchange on Rab7, preventing RILP-mediated lysosomal fusion. This was demonstrated using immobilized RILP to pull down active (GTP-bound) Rab7 from macrophage lysates.","method":"Co-transfection, RILP pulldown assay for active Rab7, cell-free system with BCG supernatant, fluorescence microscopy","journal":"Journal of leukocyte biology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — novel pulldown assay for active Rab7, cell-free reconstitution, functional imaging, single lab","pmids":["18040083"],"is_preprint":false},{"year":2008,"finding":"RILP forms a complex with dynactin p150Glued and REST/NRSF (via its LIM domain), facilitating nuclear translocation of REST/NRSF. Mutant huntingtin weakens the RILP-p150Glued interaction, impairing the complex. HAP1 prevents the complex from translocating REST/NRSF to the nucleus. Huntingtin interacts with p150Glued but not directly with RILP.","method":"Yeast two-hybrid, co-immunoprecipitation of in vitro translated proteins, cell-based co-IP","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid plus co-IP, two orthogonal methods, single lab; no direct structural validation","pmids":["18922795"],"is_preprint":false},{"year":2009,"finding":"ORP1L senses cholesterol levels in late endosomes (LEs): under low cholesterol conditions, ORP1L conformation induces ER-LE membrane contact sites where the ER protein VAP interacts in trans with the Rab7-RILP complex to remove p150Glued and associated dynein motors, causing LEs to move to microtubule plus ends. Under high cholesterol (e.g., Niemann-Pick type C), this contact is prevented and dynein activity clusters LEs at the minus end.","method":"Co-immunoprecipitation, fluorescence microscopy, organelle motility assays, NPC disease cell model, cholesterol manipulation","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods, replicated in disease model, mechanistic dissection with functional readouts, independently replicated in subsequent work","pmids":["19564404"],"is_preprint":false},{"year":2012,"finding":"RILP interacts with the Rab7-binding RILP homology domain (RHD), and this domain also mediates interaction with Rab36. RILP expression in melanocytes induces perinuclear melanosome aggregation dependent on Rab36 (not Rab7); Rab36 knockdown disperses melanosomes in Rab27A-deficient melanocytes. Site-directed mutagenesis of the RHD identified distinct amino acid contributions to Rab7 vs. Rab36 binding.","method":"Yeast two-hybrid screen, GST pulldown, site-directed mutagenesis, RNAi knockdown, melanosome distribution assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro binding assays, mutagenesis, and functional cell-based readout with multiple genetic manipulations, single lab","pmids":["22740695"],"is_preprint":false},{"year":2012,"finding":"Melanoregulin (Mreg) interacts with the C-terminal domain of RILP and forms a complex with RILP and p150Glued in cells. Mreg overexpression or RILP overexpression induces perinuclear melanosome aggregation; Mreg knockdown or functional disruption of dynein-dynactin restores peripheral distribution in Rab27A-deficient melanocytes, identifying Mreg as a regulator of RILP-p150Glued-dynein-dependent retrograde melanosome transport.","method":"Co-immunoprecipitation, overexpression, RNAi knockdown, melanosome distribution assays","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — co-IP plus functional knockdown/overexpression with defined organelle transport readout, single lab","pmids":["22275436"],"is_preprint":false},{"year":2013,"finding":"RILP directly and concomitantly binds the tethering HOPS complex and the p150Glued dynactin subunit, linking late endosomal transport and fusion into a single multiprotein complex (RAB7-RILP-ORP1L). ORP1L acts as a cholesterol-sensing switch controlling RILP-HOPS-p150Glued interactions. RILP and ORP1L also control Ebola virus infection, which depends on late endosomal fusion.","method":"Co-immunoprecipitation, direct binding assays, overexpression/knockdown, viral infection assay","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods, mechanistic dissection of transport-fusion coupling, replicated with disease-relevant readout (Ebola), single lab","pmids":["23729732"],"is_preprint":false},{"year":2014,"finding":"RILP interacts with V1G1 (ATP6V1G1), a subunit of the peripheral stalk of vacuolar ATPase (V-ATPase). RILP regulates V1G1 recruitment to late endosomal/lysosomal membranes and controls V1G1 stability by promoting its ubiquitylation and proteasomal degradation. Alterations in V1G1 expression impair V-ATPase activity.","method":"Yeast two-hybrid, co-immunoprecipitation, overexpression/knockdown, ubiquitylation assays, V-ATPase activity assays","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — multiple orthogonal methods including enzymatic activity measurement and ubiquitylation assay with direct functional readout, single lab","pmids":["24762812"],"is_preprint":false},{"year":2015,"finding":"RILP interacts with RalGDS (Ral guanine nucleotide dissociation stimulator) via its N-terminal region binding the GEF domain of RalGDS, recruiting RalGDS to late endosomal compartments. RILP overexpression inhibits RalA activity (a downstream target of RalGDS), suppressing breast cancer cell migration and invasion.","method":"Co-immunoprecipitation, truncation mapping, immunofluorescence microscopy, RalA activity assay, migration/invasion assays, RNAi knockdown","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — co-IP with domain mapping, GEF activity readout, functional invasion assay, single lab","pmids":["26469971"],"is_preprint":false},{"year":2016,"finding":"RILP is a direct effector of Rab34: FLCN (folliculin) interacts with RILP via its C-terminal DENN domain and loads active Rab34 onto RILP using purified recombinant proteins. This Rab34-RILP complex mediates starvation-induced peri-nuclear lysosome clustering. FLCN-DENN does not act as a GEF for Rab34 but rather promotes Rab34-RILP complex formation.","method":"Purified recombinant protein binding assays, co-immunoprecipitation, knockdown, live-cell imaging of lysosome distribution","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstitution with purified recombinant proteins plus cell-based functional assay, single lab but strong biochemical evidence","pmids":["27113757"],"is_preprint":false},{"year":2016,"finding":"HCV (and Sendai virus) infection causes cleavage of RILP, generating a cleaved fragment (cRILP) missing the N-terminus that re-localizes to the cell periphery. Both RILP knockdown and cRILP expression reproduce HCV-induced inhibition of Rab7-dependent endosome-lysosome fusion. cRILP promotes virion secretion via kinesin-dependent trafficking; restoring full-length RILP reverses the trafficking defect.","method":"Viral infection, RILP knockdown, cRILP overexpression, kinesin inhibitor treatment, vesicular trafficking assays, fluorescence microscopy","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple complementary functional approaches (knockdown, overexpression, inhibitor, rescue), defined molecular mechanism, single lab","pmids":["27091088"],"is_preprint":false},{"year":2016,"finding":"Rab12 is a novel effector of RILP: GTP-bound Rab12 interacts with RILP and mediates minus-end retrograde transport of mast cell secretory granules via the RILP-dynein complex in a stimulus-dependent manner.","method":"Co-immunoprecipitation, GTPase pulldown, RNAi knockdown, overexpression, granule transport assays","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — co-IP, pulldown, and functional transport assay with defined phenotypic readout, single lab","pmids":["26740112"],"is_preprint":false},{"year":2017,"finding":"RILP (and Rab7, Rab11) regulates intracellular trafficking of the CMA receptor LAMP2A. The truncated RILP-C33 form cannot rescue defective LAMP2A trafficking in cystinosis, while full-length RILP restores LAMP2A localization at lysosomes. Dominant-negative Rab7 or Rab11 impairs LAMP2A trafficking.","method":"Overexpression of wild-type and mutant RILP, dominant-negative constructs, immunofluorescence, knockdown studies in cystinotic cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — overexpression/dominant-negative with functional trafficking readout, single lab","pmids":["28465352"],"is_preprint":false},{"year":2018,"finding":"Caspase-1 directly cleaves RILP at aspartic acid 75; alanine substitution at D75 blocks caspase-1-mediated cleavage. Cleavage alone is insufficient to re-localize RILP; combined cleavage and phosphorylation near the recognition site are required for redistribution of RILP from perinuclear vesicles throughout the cytoplasm and release from dynactin p150Glued, leading to redistribution of CD63+ intracellular vesicles.","method":"Caspase-1 cleavage assay, site-directed mutagenesis (D75A), phosphorylation analysis, immunofluorescence of RILP and CD63 vesicles","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro cleavage assay with mutagenesis to define recognition site, combined with functional cell localization readout, single lab","pmids":["30100068"],"is_preprint":false},{"year":2018,"finding":"Structural and biochemical analysis revealed that Rab7 interacts with ORP1L's N-terminal ankyrin repeat domain (ARDN) independently of Rab7's GTP/GDP binding state, via a unique helix3/310-helix2 region. This leaves Rab7's canonical effector-binding switch regions free to bind RILP simultaneously, enabling formation of the ORP1L-Rab7-RILP tripartite complex. Mutational disruption of the ORP1L-Rab7 interface impairs late endosome positioning.","method":"Crystal structure determination, biochemical binding assays, site-directed mutagenesis, late endosome positioning assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus mutagenesis and functional cell assay, single lab, structural validation","pmids":["30012887"],"is_preprint":false},{"year":2019,"finding":"LRRK1 phosphorylates GTP-bound Rab7 on serine 72 at the endosomal membrane, and this phosphorylation promotes the interaction of Rab7 with RILP, thereby recruiting dynein-dynactin to Rab7-positive vesicles and facilitating dynein-driven transport of EGFR-containing endosomes toward the perinuclear region.","method":"Kinase assay, phospho-specific antibodies, co-immunoprecipitation, endosomal transport assays, LRRK1 knockdown","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vitro kinase assay defining phosphorylation site, co-IP showing phosphorylation-dependent interaction with RILP, functional transport readout, single lab","pmids":["31085713"],"is_preprint":false},{"year":2019,"finding":"RILP promotes lysosomal degradation of proinsulin by clustering insulin granules and reducing proinsulin-containing granules in pancreatic beta cells. RILP interacts with insulin granule-associated Rab26, restricting insulin secretion. RILP-induced proinsulin degradation is inhibited by lysosomal inhibitors and is Rab7-dependent; RILP depletion sustains proinsulin and increases insulin secretion.","method":"Overexpression, RNAi knockdown, lysosomal inhibitor treatment, co-immunoprecipitation with Rab26, insulin secretion assays, islet transplantation","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — co-IP identifying Rab26 as binding partner, functional assays with inhibitors and genetic knockdown, single lab","pmids":["31624142"],"is_preprint":false},{"year":2020,"finding":"RILP is essential for retrograde transport of neuronal autophagosomes and, unexpectedly, for their biogenesis. mTOR inhibition upregulates RILP expression and its localization to autophagosomes. RILP depletion or mutations in LC3-binding LIR motifs strongly decrease autophagosome numbers. RILP also interacts with ATG5 on isolation membranes, precluding premature dynein recruitment. RILP inhibition impedes autophagic turnover and causes p62/sequestosome-1 aggregation.","method":"RNAi knockdown, LIR motif mutagenesis, co-immunoprecipitation with ATG5 and LC3, autophagosome counting, mTOR inhibitor treatment, p62 aggregation assay","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (knockdown, mutagenesis, co-IP with multiple partners, functional flux assays) in neuronal context, single lab","pmids":["32275887"],"is_preprint":false},{"year":2021,"finding":"Rab12 interacts with RILP via its switch I and switch II regions at the RILP homology domain (RHD) of one RILP monomer and a C-terminal threonine of the other monomer in a RILP homodimer. Lysine-71 in Rab12 is critical for interaction with RILP-L1 and RILP-L2 but dispensable for RILP binding. Mutational analyses of RILP RHD confirmed its involvement in regulating secretory granule transport.","method":"Molecular dynamics simulations, functional mutational analyses, peptide inhibition assays, biochemical binding assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — computational modeling with functional mutational validation, single lab","pmids":["33986343"],"is_preprint":false},{"year":2023,"finding":"RILP interacts with Grb10 (growth factor receptor binding protein-10) as identified by co-immunoprecipitation, and through this interaction restrains PI3K/AKT/mTOR signaling. RILP overexpression promotes autophagy in osteosarcoma cells in a PI3K/AKT/mTOR-dependent manner; partial attenuation by autophagy inhibitor 3-MA implicates autophagy in EMT regulation.","method":"Co-immunoprecipitation, RNA-seq pathway analysis, PI3K activator rescue, 3-MA autophagy inhibition, xenograft mouse model","journal":"Molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2-3 / Weak — co-IP identifying Grb10 as binding partner, functional pathway assays, single lab","pmids":["37789274"],"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 then recruits RILP and dynein to lysosomes for retrograde transport. Loss of DENND6A impairs autophagic flux.","method":"Cell-based GEF assay screening all Rabs, co-immunoprecipitation, lysosome positioning assays, RNAi knockdown, autophagic flux assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — cell-based GEF screen with functional validation, co-IP, and autophagic flux readout; RILP role inferred from Rab34 interaction rather than directly assayed, single lab","pmids":["38296963"],"is_preprint":false},{"year":2024,"finding":"RILP interacts with ORP1L to competitively inhibit formation of the VAP-ORP1L contact site between the ER and endolysosomes. RILP overexpression causes late endosome/lysosome clustering, reduces ER-endolysosome contact, and leads to cholesterol accumulation in clustered endolysosomes, triggering RILP-dependent cellular autophagy.","method":"Co-immunoprecipitation, immunofluorescence microscopy, cholesterol staining, autophagy assays, overexpression studies","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — co-IP and functional cell imaging with cholesterol and autophagy readouts, single lab","pmids":["39195203"],"is_preprint":false},{"year":2024,"finding":"pH neutralization of late endosomes increases assembly of the V1G1 subunit of V-ATPase on endosomal membranes, which stabilizes GTP-bound Rab7 via RILP (a known interactor of both Rab7 and V1G1), causing Rab7 hyperactivation and disrupting late endosomal tubulation and CI-M6PR recycling.","method":"LLOMe treatment, NH4Cl pH neutralization, Rab7 hyperactive mutants, immunofluorescence, CI-M6PR trafficking assay","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — pharmacological and genetic perturbation with functional readouts, single lab; RILP role inferred from known interactions rather than directly mutagenized in this study","pmids":["38578235"],"is_preprint":false},{"year":2024,"finding":"Rab7 phosphorylation at Tyrosine 183 in diabetic cardiomyocytes allows recruitment of RILP to promote lysosomal degradation of lipid droplets via microlipophagy. Rab7 activator ML-098 enhanced RILP levels and rescued cardiac dysfunction in diabetic mice.","method":"Rab7-CKO mice, RNA-seq, phospho-specific analysis, in vivo Rab7 activator treatment, cardiac function assays","journal":"Advanced science","confidence":"Low","confidence_rationale":"Tier 3 / Weak — phosphorylation site and RILP recruitment inferred from in vivo model; direct biochemical validation of pY183-Rab7 binding to RILP not shown in abstract, single lab","pmids":["38837607"],"is_preprint":false},{"year":2024,"finding":"HDAC1 (stabilized by deubiquitinase USP5) deacetylates RILP in DDP-resistant NSCLC cells, reducing RILP acetylation levels and contributing to cisplatin resistance. RILP upregulation counteracts the effects of HDAC1 overexpression on cisplatin resistance.","method":"Co-immunoprecipitation for USP5-HDAC1 interaction, RILP acetylation co-IP assay, HDAC1/USP5 silencing, MG132 assay, xenograft model","journal":"Thoracic cancer","confidence":"Low","confidence_rationale":"Tier 3 / Weak — co-IP identifying RILP acetylation regulated by HDAC1, limited mechanistic depth in abstract, single lab","pmids":["39582290"],"is_preprint":false},{"year":2025,"finding":"RILP functions as a dynein adaptor for late endosome motility in dendrites, dependent on RAB7A binding: expression of RAB7A-L8A (RILP-binding-deficient mutant) impairs retrograde late endosome transport in dendrites and inhibits dendrite arborization. Surprisingly, lysosomal fusion and somatic degradation do not require RAB7A-RILP interaction, separating transport from degradation functions. RILP also promotes endosome carrier formation in dendrites.","method":"Separation-of-function RAB7A mutant (L8A) expression in rat/mouse hippocampal neurons, live imaging, dendrite arborization assays, cargo degradation assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean separation-of-function mutant with defined transport and morphology readouts in primary neurons; preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.09.03.673267"],"is_preprint":true},{"year":2025,"finding":"RILP cleavage (induced by inflammatory mediators LPS/ATP via caspase-1) impairs tau degradation in microglia, increases intracellular tau accumulation, and enhances cell-cell tau propagation. RILP cleavage status influences extracellular vesicle secretion in microglia. Expression of a noncleavable RILP mitigates inflammation-enhanced tau propagation.","method":"LPS/ATP treatment, caspase-1 activation, noncleavable RILP mutant expression, tau propagation assay, EV secretion assay, AD brain tissue analysis","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — functional rescue with noncleavable mutant, EV assay, correlation with AD brain cleavage, single lab","pmids":["40137558"],"is_preprint":false}],"current_model":"RILP is a multifunctional effector protein that is recruited to late endosomal and lysosomal membranes by GTP-bound Rab7 (and also Rab34, Rab36, Rab12, and Rab26), where it acts as a dynein adaptor by directly binding the p150Glued dynactin subunit to drive minus-end microtubule transport of late endosomes, lysosomes, phagosomes, and autophagosomes; it coordinates transport with fusion by simultaneously engaging the HOPS tethering complex, interacts with ESCRT-II subunits VPS22/VPS36 to regulate MVB biogenesis, controls V-ATPase activity through V1G1 interaction, and can be inactivated by viral- or inflammatory-state-induced caspase-1 cleavage (at D75) that redirects vesicle trafficking toward the cell periphery."},"narrative":{"mechanistic_narrative":"RILP is a Rab effector that converts the GTP-loaded state of late endosomal/lysosomal small GTPases into directed minus-end microtubule transport, coupling organelle motility with tethering, fusion, and maturation [PMID:11179213, PMID:11696325, PMID:17283181]. It is recruited to late endosomal and lysosomal membranes by GTP-bound Rab7 through a defined Rab-homology region (residues ~272–333) and acts as a dynein adaptor by directly binding the C-terminal 25-kDa region of the dynactin subunit p150Glued, thereby recruiting the dynein-dynactin motor to drive centripetal transport of late endosomes, lysosomes, and phagosomes [PMID:11179213, PMID:14668488, PMID:12944476, PMID:17283181]. Productive dynein activation requires assembly of a tripartite Rab7-RILP-ORP1L complex, with ORP1L acting as a cholesterol-sensing switch: under low cholesterol ORP1L promotes ER-endosome VAP contacts that strip p150Glued from the Rab7-RILP complex, while RILP can competitively inhibit VAP-ORP1L contact formation, integrating organelle positioning with sterol status [PMID:17283181, PMID:19564404, PMID:23729732, PMID:30012887, PMID:39195203]. RILP simultaneously engages the HOPS tethering complex to couple transport with endolysosomal fusion, interacts with ESCRT-II subunits VPS22 and VPS36 to support multivesicular body biogenesis and EGFR degradation, and binds the V-ATPase peripheral-stalk subunit V1G1 (ATP6V1G1) to control its membrane recruitment, ubiquitylation-dependent turnover, and V-ATPase activity [PMID:16857164, PMID:17010938, PMID:17959629, PMID:23729732, PMID:24762812]. The same adaptor module is used by additional Rab GTPases — Rab34, Rab36, Rab12, and Rab26 — to position lysosomes, melanosomes, secretory granules, and insulin granules, and RILP is required for retrograde transport and biogenesis of autophagosomes via LIR-dependent LC3 binding and ATG5 interaction [PMID:22740695, PMID:27113757, PMID:26740112, PMID:31624142, PMID:32275887]. RILP activity is controlled post-translationally: LRRK1 phosphorylation of Rab7 on Ser72 enhances Rab7-RILP binding, while caspase-1 cleavage at Asp75, together with nearby phosphorylation, releases RILP from p150Glued and redistributes vesicles to the cell periphery, a mechanism exploited by HCV and inflammatory states to redirect trafficking [PMID:27091088, PMID:30100068, PMID:31085713, PMID:40137558].","teleology":[{"year":2001,"claim":"Established that RILP is the downstream effector translating Rab7 activation into lysosomal transport, answering how the Rab7 GTPase switch is read out functionally.","evidence":"Yeast two-hybrid, GST pulldown, co-IP, and dominant-negative epistasis with degradation assays in mammalian cells","pmids":["11179213","11696325"],"confidence":"High","gaps":["Did not identify the motor-recruiting partner directly","Structural basis of Rab7-GTP recognition not resolved"]},{"year":2003,"claim":"Mapped a unique ~62-residue region sufficient for Rab7/Rab34 binding and lysosomal morphology control, defining the modular Rab-homology element that confers effector activity.","evidence":"Truncation/chimeric mutants transferred into RLP1 with lysosomal morphology and GTPase-binding assays; phagosome maturation imaging","pmids":["14668488","12944476"],"confidence":"High","gaps":["Did not define the dynein-recruiting interface at residue level","Mechanism of tubule extension during phagosome maturation incomplete"]},{"year":2007,"claim":"Identified p150Glued as the direct RILP partner and showed dynein activation needs additional ORP1L/betaIII-spectrin factors, refining RILP from a simple motor bridge to part of a multi-component activation module.","evidence":"Reciprocal co-IP, GST pulldown, deletion mutants, and organelle motility assays; RNAi loss-of-function with EM and cargo trafficking","pmids":["17283181","17959629"],"confidence":"High","gaps":["How betaIII-spectrin triggers dynein activation mechanistically unresolved","Stoichiometry of the Rab7-RILP-p150Glued-ORP1L complex unknown"]},{"year":2006,"claim":"Connected RILP to ESCRT-II via VPS22 and VPS36 binding, linking late endosomal transport to MVB sorting machinery.","evidence":"Yeast two-hybrid, co-IP, colocalization, and EGF sorting assays across two concurrent papers","pmids":["16857164","17010938"],"confidence":"Medium","gaps":["Functional consequence of ESCRT-II binding for ILV formation not mechanistically dissected","Single-lab observations without structural validation"]},{"year":2009,"claim":"Revealed cholesterol sensing through ORP1L as the switch governing RILP-dependent endosome positioning, explaining how lipid status controls motor recruitment.","evidence":"Co-IP, organelle motility assays, and NPC disease cell model with cholesterol manipulation","pmids":["19564404"],"confidence":"High","gaps":["How VAP trans-interaction physically removes p150Glued not resolved at structural level"]},{"year":2013,"claim":"Showed RILP concomitantly binds HOPS and p150Glued, coupling transport and fusion into one complex and explaining its role in viral entry requiring endolysosomal fusion.","evidence":"Co-IP, direct binding assays, knockdown, and Ebola virus infection assay","pmids":["23729732"],"confidence":"High","gaps":["Temporal ordering of HOPS vs dynein engagement on a single organelle unknown"]},{"year":2012,"claim":"Demonstrated that the RILP Rab-homology domain reads multiple Rab GTPases (Rab36 for melanosomes), generalizing RILP as a shared adaptor for different organelle transport systems.","evidence":"Yeast two-hybrid, GST pulldown, site-directed mutagenesis, and melanosome distribution assays; Mreg interaction with melanosome readout","pmids":["22740695","22275436"],"confidence":"High","gaps":["Determinants of Rab selectivity in vivo incompletely defined","Mreg's regulatory mechanism on dynein not resolved"]},{"year":2014,"claim":"Identified V1G1 as a RILP target whose stability and membrane recruitment RILP controls, extending RILP function to regulation of V-ATPase-dependent acidification.","evidence":"Yeast two-hybrid, co-IP, ubiquitylation assays, and V-ATPase activity measurements","pmids":["24762812"],"confidence":"High","gaps":["Identity of the ubiquitin ligase acting on V1G1 not established","Link between acidification control and transport not integrated"]},{"year":2016,"claim":"Expanded the RILP Rab repertoire to Rab34 (via FLCN), Rab12, and other GTPases and connected RILP-loss to viral exploitation through HCV-induced cleavage redirecting trafficking peripherally.","evidence":"Purified recombinant binding assays, co-IP, knockdown, live imaging; viral infection with cRILP overexpression and kinesin inhibition","pmids":["27113757","26740112","27091088"],"confidence":"High","gaps":["Identity of the protease producing cRILP in HCV infection not defined here","How FLCN-DENN promotes complex formation without GEF activity unclear"]},{"year":2018,"claim":"Defined caspase-1 cleavage at Asp75 plus adjacent phosphorylation as the inactivating switch that releases RILP from p150Glued, providing a regulated mechanism to redistribute vesicles to the periphery.","evidence":"In vitro caspase-1 cleavage with D75A mutagenesis, phosphorylation analysis, and CD63 vesicle imaging; crystal structure of ORP1L-Rab7 interface with positioning assays","pmids":["30100068","30012887"],"confidence":"High","gaps":["Kinase responsible for the priming phosphorylation not identified","Physiological triggers of caspase-1-mediated RILP cleavage beyond viral context unclear"]},{"year":2019,"claim":"Showed Rab7 phosphorylation (LRRK1 on Ser72) enhances Rab7-RILP binding, establishing kinase-regulated control of motor recruitment.","evidence":"In vitro kinase assay, phospho-specific antibodies, co-IP, and endosomal transport assays with LRRK1 knockdown","pmids":["31085713"],"confidence":"High","gaps":["Whether other Rab kinases similarly tune RILP affinity not addressed"]},{"year":2020,"claim":"Established RILP as essential not only for autophagosome retrograde transport but unexpectedly for their biogenesis, via LIR-dependent LC3 binding and ATG5 interaction that delays premature dynein recruitment.","evidence":"RNAi knockdown, LIR motif mutagenesis, co-IP with ATG5/LC3, autophagosome counting, and p62 flux assays in neurons","pmids":["32275887"],"confidence":"High","gaps":["How RILP contributes mechanistically to isolation membrane formation unresolved","Relationship between biogenesis and transport roles not separated"]},{"year":2024,"claim":"Integrated RILP into broader physiology — insulin granule degradation via Rab26, lysosome positioning via the Arl8b-DENND6A-Rab34 axis, V-ATPase/pH-coupled Rab7 hyperactivation, ER-contact competition with ORP1L, and inflammation/tau and cancer roles.","evidence":"Co-IP, knockdown/overexpression, GEF screens, cholesterol/autophagy assays, and disease models (diabetes, osteosarcoma, NSCLC, AD-related tau)","pmids":["31624142","38296963","38578235","39195203","37789274","31624142"],"confidence":"Medium","gaps":["Many disease links rely on single-lab overexpression/knockdown","Direct biochemical role of RILP in several inferred axes not always assayed"]},{"year":2025,"claim":"Separated RILP transport from degradation functions using a RILP-binding-deficient Rab7 mutant, showing dendritic late endosome motility and arborization require RILP but somatic degradation does not.","evidence":"Separation-of-function RAB7A-L8A mutant in hippocampal neurons with live imaging and dendrite/cargo assays (preprint); caspase-1-cleaved RILP impairs microglial tau degradation and propagation","pmids":["bio_10.1101_2025.09.03.673267","40137558"],"confidence":"Medium","gaps":["Preprint not yet peer-reviewed","How transport and degradation roles diverge mechanistically remains open"]},{"year":null,"claim":"How the multiple RILP partner interactions (Rab GTPases, p150Glued, HOPS, ORP1L, ESCRT-II, V1G1) are spatially and temporally ordered on a single maturing organelle, and the structure of the assembled motor-tethering supercomplex, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No high-resolution structure of the full RILP-containing transport/fusion supercomplex","Quantitative interplay among competing RILP interactions during organelle maturation undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,7,14]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[7,1]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[15,16]}],"localization":[{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[0,2,17]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[3,19,24]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[1,3,7,14]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[25,29,28]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[11,17,33]}],"complexes":["Rab7-RILP-ORP1L tripartite complex","HOPS tethering complex","dynein-dynactin (p150Glued) motor complex","ESCRT-II (VPS22/VPS36)"],"partners":["RAB7A","DCTN1/P150GLUED","ORP1L","VPS22","VPS36","ATP6V1G1","RAB34","RAB36"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96MT3","full_name":"Prickle-like protein 1","aliases":["REST/NRSF-interacting LIM domain protein 1"],"length_aa":831,"mass_kda":94.3,"function":"Involved in the planar cell polarity pathway that controls convergent extension during gastrulation and neural tube closure. Convergent extension is a complex morphogenetic process during which cells elongate, move mediolaterally, and intercalate between neighboring cells, leading to convergence toward the mediolateral axis and extension along the anteroposterior axis. Necessary for nuclear localization of REST. 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pathology","url":"https://pubmed.ncbi.nlm.nih.gov/36801641","citation_count":4,"is_preprint":false},{"pmid":"39582290","id":"PMC_39582290","title":"USP5-dependent HDAC1 promotes cisplatin resistance and the malignant progression of non-small cell lung cancer by regulating RILP acetylation levels.","date":"2024","source":"Thoracic cancer","url":"https://pubmed.ncbi.nlm.nih.gov/39582290","citation_count":4,"is_preprint":false},{"pmid":"31059814","id":"PMC_31059814","title":"Molecular cloning of the Rab7 effector RILP (Rab-interacting lysosomal protein) in Litopenaeus vannamei and preliminary analysis of its role in white spot syndrome virus infection.","date":"2019","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31059814","citation_count":4,"is_preprint":false},{"pmid":"40137558","id":"PMC_40137558","title":"RILP cleavage links an inflammatory state to enhanced tau propagation in a cell culture model of Alzheimer's disease.","date":"2025","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/40137558","citation_count":4,"is_preprint":false},{"pmid":"35981451","id":"PMC_35981451","title":"RILP inhibits proliferation, migration, and invasion of PC3 prostate cancer cells.","date":"2022","source":"Acta histochemica","url":"https://pubmed.ncbi.nlm.nih.gov/35981451","citation_count":3,"is_preprint":false},{"pmid":"37534141","id":"PMC_37534141","title":"Evolutional insights into the interaction between Rab7 and RILP in lysosome motility.","date":"2023","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/37534141","citation_count":3,"is_preprint":false},{"pmid":"39958873","id":"PMC_39958873","title":"Mechanism of mTOR/RILP-regulated autophagic flux in increased susceptibility to myocardial ischemia-reperfusion in diabetic mice.","date":"2025","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39958873","citation_count":3,"is_preprint":false},{"pmid":"39195203","id":"PMC_39195203","title":"RILP Induces Cholesterol Accumulation in Lysosomes by Inhibiting Endoplasmic Reticulum-Endolysosome Interactions.","date":"2024","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/39195203","citation_count":2,"is_preprint":false},{"pmid":"37961579","id":"PMC_37961579","title":"Collapse of late endosomal pH elicits a rapid Rab7 response via V-ATPase and RILP.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/37961579","citation_count":1,"is_preprint":false},{"pmid":"21199191","id":"PMC_21199191","title":"RE1-silencing transcription factor (REST) and REST-interacting LIM domain protein (RILP) affect P19CL6 differentiation.","date":"2011","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/21199191","citation_count":1,"is_preprint":false},{"pmid":"37851568","id":"PMC_37851568","title":"Functional assessment of lysosomal Rab7 and RILP with RNA interference and overexpression in Spodoptera frugiperda Sf9 cell lines.","date":"2023","source":"STAR protocols","url":"https://pubmed.ncbi.nlm.nih.gov/37851568","citation_count":0,"is_preprint":false},{"pmid":"36945482","id":"PMC_36945482","title":"\"Disruption of Golgi markers by two RILP-directed shRNAs in neurons: a new role for RILP or a neuron-specific off-target phenotype?\".","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/36945482","citation_count":0,"is_preprint":false},{"pmid":"42191265","id":"PMC_42191265","title":"Cepharanthine-mediated PD-L1 autophagic degradation via regulation of TSPO and RILP boosts anti-lung cancer chemo-immunotherapy efficacy.","date":"2026","source":"Biochimica et biophysica acta. Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/42191265","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.03.673267","title":"Late endosome transport by RILP-RAB7A promotes dendrite arborization","date":"2025-09-03","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.03.673267","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.08.19.670962","title":"Structural basis for binding of RILPL1 to TMEM55B reveals a lysosomal platform for adaptor assembly through a conserved TBM motif","date":"2025-08-24","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.19.670962","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.09.12.612708","title":"Loss of PRICKLE1 in the myometrium leads to reduced fertility, abnormal myometrial architecture, and aberrant extracellular matrix deposition in 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":32111,"output_tokens":9118,"usd":0.116552,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":18778,"output_tokens":4983,"usd":0.109232,"stage2_stop_reason":"end_turn"},"total_usd":0.225784,"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\": 2001,\n      \"finding\": \"RILP (Rab7-interacting lysosomal protein) specifically binds the GTP-bound (active) form of Rab7 at its C-terminus, is recruited to late endosomal/lysosomal membranes by Rab7-GTP, and functions as a downstream effector of Rab7 required for transport to lysosomes. Expression of a truncated form (RILP-C33) lacking the N-terminal half inhibits EGF and LDL degradation and disperses lysosomes, similar to Rab7 dominant-negative mutants; full-length RILP rescues Rab7 dominant-negative effects.\",\n      \"method\": \"Yeast two-hybrid screen, GST pulldown, co-immunoprecipitation, mammalian cell overexpression/dominant-negative epistasis, degradation assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (yeast two-hybrid, pulldown, co-IP, functional rescue epistasis) in founding paper, independently replicated by Jordens et al. same year\",\n      \"pmids\": [\"11179213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"RILP expression induces the recruitment of functional dynein-dynactin motor complexes to Rab7-containing late endosomes and lysosomes, driving minus-end microtubule transport and inhibiting transport toward the cell periphery. RILP also prevents further cycling of Rab7.\",\n      \"method\": \"Overexpression of RILP in cells, immunofluorescence, live imaging of organelle transport, functional dynein-dynactin recruitment assays\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct functional assay with organelle transport readout, replicated across multiple subsequent studies\",\n      \"pmids\": [\"11696325\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"A unique 62-residue region (amino acids 272–333) within RILP is necessary and sufficient for regulating lysosomal morphology and for interaction with GTP-bound Rab7 and Rab34. Transfer of this region into the related protein RLP1 confers lysosome-regulating activity on RLP1.\",\n      \"method\": \"Truncation/chimeric mutant overexpression, lysosomal morphology assays, GTPase binding assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — domain mapping with gain-of-function chimera and multiple deletion mutants, single lab\",\n      \"pmids\": [\"14668488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"RILP bridges phagosomes with dynein-dynactin via active Rab7, promoting centripetal phagosome movement and extension of phagosomal tubules toward late endocytic compartments. A truncated RILP lacking the dynein-dynactin-recruiting domain prevents tubule extension and fusion with late endosomes/lysosomes.\",\n      \"method\": \"Fluorescence microscopy, electron microscopy, dominant-negative RILP expression, phagosome maturation assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple imaging modalities plus loss-of-function mutant with defined phenotype, replicated in multiple cell biology labs\",\n      \"pmids\": [\"12944476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Salmonella effector SifA uncouples RILP from active Rab7 on Salmonella-induced filaments (Sifs), preventing dynein recruitment and allowing kinesin-driven centrifugal tubule extension. In vitro experiments indicated SifA may interact with Rab7 to catalyze GDP loading, inactivating it and preventing RILP recruitment.\",\n      \"method\": \"Co-transfection, fluorescence microscopy, in vitro pull-down of active Rab7 with immobilized RILP, cell-free system with BCG/SifA supernatant\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — multiple methods (imaging, in vitro pulldown, cell-free assay) but mechanistic details of SifA-Rab7 interaction inferred rather than fully reconstituted\",\n      \"pmids\": [\"15121880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"RILP interacts with VPS22 (EAP30/SNF8) of the ESCRT-II complex; the N-terminal half of RILP mediates this interaction. RILP overexpression leads to enlarged, clustered multivesicular bodies and retards EGF sorting to degradation at EEA1-positive sorting endosomes.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, confocal immunofluorescence, EGF trafficking assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — yeast two-hybrid confirmed by co-IP and colocalization, two independent papers (PMID 17010938, 16857164) reporting the same interaction\",\n      \"pmids\": [\"16857164\", \"17010938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"RILP interacts with both VPS22 and VPS36 of ESCRT-II (N-terminal half binds VPS22; C-terminal half binds VPS36), integrating late endocytic machinery with early MVB sorting machinery.\",\n      \"method\": \"Co-immunoprecipitation, overexpression studies, EGF sorting assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP with functional readout in two concurrent papers, single lab for each\",\n      \"pmids\": [\"17010938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"RILP directly interacts with the C-terminal 25-kDa region of the dynactin subunit p150Glued, recruiting dynein motor to late endocytic compartments. GTP-bound Rab7 simultaneously binds RILP and ORP1L to form a tripartite RILP-Rab7-ORP1L complex. p150Glued recruitment by Rab7-RILP alone is insufficient for dynein-driven minus-end transport; ORP1L and betaIII spectrin are additionally required — RILP transfers the Rab7-RILP-p150Glued complex to betaIII spectrin to activate dynein.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown, deletion mutants, organelle motility assays, dominant-negative expression\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, multiple deletion mutants, functional transport assays, replicated across subsequent studies\",\n      \"pmids\": [\"17283181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"RILP depletion impairs biogenesis of multivesicular endosomes (reduces intraluminal vesicle content), inhibits ligand-mediated EGFR degradation, and causes accumulation of late-endosomal markers (LBPA, Lamp1, CD63, CI-M6PR). Transferrin receptor recycling is not affected by RILP depletion.\",\n      \"method\": \"RNAi knockdown, electron microscopy, immunofluorescence, EGF/transferrin receptor trafficking assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean RNAi loss-of-function with ultrastructural (EM) and functional readouts, multiple cargo assays, single lab\",\n      \"pmids\": [\"17959629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Mycobacterium bovis BCG inhibits RILP recruitment to phagosomes despite Rab7 acquisition, by promoting GDP-bound (inactive) Rab7. A factor in BCG culture supernatant catalyzes GTP/GDP exchange on Rab7, preventing RILP-mediated lysosomal fusion. This was demonstrated using immobilized RILP to pull down active (GTP-bound) Rab7 from macrophage lysates.\",\n      \"method\": \"Co-transfection, RILP pulldown assay for active Rab7, cell-free system with BCG supernatant, fluorescence microscopy\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — novel pulldown assay for active Rab7, cell-free reconstitution, functional imaging, single lab\",\n      \"pmids\": [\"18040083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"RILP forms a complex with dynactin p150Glued and REST/NRSF (via its LIM domain), facilitating nuclear translocation of REST/NRSF. Mutant huntingtin weakens the RILP-p150Glued interaction, impairing the complex. HAP1 prevents the complex from translocating REST/NRSF to the nucleus. Huntingtin interacts with p150Glued but not directly with RILP.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation of in vitro translated proteins, cell-based co-IP\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid plus co-IP, two orthogonal methods, single lab; no direct structural validation\",\n      \"pmids\": [\"18922795\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ORP1L senses cholesterol levels in late endosomes (LEs): under low cholesterol conditions, ORP1L conformation induces ER-LE membrane contact sites where the ER protein VAP interacts in trans with the Rab7-RILP complex to remove p150Glued and associated dynein motors, causing LEs to move to microtubule plus ends. Under high cholesterol (e.g., Niemann-Pick type C), this contact is prevented and dynein activity clusters LEs at the minus end.\",\n      \"method\": \"Co-immunoprecipitation, fluorescence microscopy, organelle motility assays, NPC disease cell model, cholesterol manipulation\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods, replicated in disease model, mechanistic dissection with functional readouts, independently replicated in subsequent work\",\n      \"pmids\": [\"19564404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"RILP interacts with the Rab7-binding RILP homology domain (RHD), and this domain also mediates interaction with Rab36. RILP expression in melanocytes induces perinuclear melanosome aggregation dependent on Rab36 (not Rab7); Rab36 knockdown disperses melanosomes in Rab27A-deficient melanocytes. Site-directed mutagenesis of the RHD identified distinct amino acid contributions to Rab7 vs. Rab36 binding.\",\n      \"method\": \"Yeast two-hybrid screen, GST pulldown, site-directed mutagenesis, RNAi knockdown, melanosome distribution assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro binding assays, mutagenesis, and functional cell-based readout with multiple genetic manipulations, single lab\",\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 complex with RILP and p150Glued in cells. Mreg overexpression or RILP overexpression induces perinuclear melanosome aggregation; Mreg knockdown or functional disruption of dynein-dynactin restores peripheral distribution in Rab27A-deficient melanocytes, identifying Mreg as a regulator of RILP-p150Glued-dynein-dependent retrograde melanosome transport.\",\n      \"method\": \"Co-immunoprecipitation, overexpression, RNAi knockdown, melanosome distribution assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — co-IP plus functional knockdown/overexpression with defined organelle transport readout, single lab\",\n      \"pmids\": [\"22275436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RILP directly and concomitantly binds the tethering HOPS complex and the p150Glued dynactin subunit, linking late endosomal transport and fusion into a single multiprotein complex (RAB7-RILP-ORP1L). ORP1L acts as a cholesterol-sensing switch controlling RILP-HOPS-p150Glued interactions. RILP and ORP1L also control Ebola virus infection, which depends on late endosomal fusion.\",\n      \"method\": \"Co-immunoprecipitation, direct binding assays, overexpression/knockdown, viral infection assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods, mechanistic dissection of transport-fusion coupling, replicated with disease-relevant readout (Ebola), single lab\",\n      \"pmids\": [\"23729732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RILP interacts with V1G1 (ATP6V1G1), a subunit of the peripheral stalk of vacuolar ATPase (V-ATPase). RILP regulates V1G1 recruitment to late endosomal/lysosomal membranes and controls V1G1 stability by promoting its ubiquitylation and proteasomal degradation. Alterations in V1G1 expression impair V-ATPase activity.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, overexpression/knockdown, ubiquitylation assays, V-ATPase activity assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple orthogonal methods including enzymatic activity measurement and ubiquitylation assay with direct functional readout, single lab\",\n      \"pmids\": [\"24762812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RILP interacts with RalGDS (Ral guanine nucleotide dissociation stimulator) via its N-terminal region binding the GEF domain of RalGDS, recruiting RalGDS to late endosomal compartments. RILP overexpression inhibits RalA activity (a downstream target of RalGDS), suppressing breast cancer cell migration and invasion.\",\n      \"method\": \"Co-immunoprecipitation, truncation mapping, immunofluorescence microscopy, RalA activity assay, migration/invasion assays, RNAi knockdown\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — co-IP with domain mapping, GEF activity readout, functional invasion assay, single lab\",\n      \"pmids\": [\"26469971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"RILP is a direct effector of Rab34: FLCN (folliculin) interacts with RILP via its C-terminal DENN domain and loads active Rab34 onto RILP using purified recombinant proteins. This Rab34-RILP complex mediates starvation-induced peri-nuclear lysosome clustering. FLCN-DENN does not act as a GEF for Rab34 but rather promotes Rab34-RILP complex formation.\",\n      \"method\": \"Purified recombinant protein binding assays, co-immunoprecipitation, knockdown, live-cell imaging of lysosome distribution\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution with purified recombinant proteins plus cell-based functional assay, single lab but strong biochemical evidence\",\n      \"pmids\": [\"27113757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"HCV (and Sendai virus) infection causes cleavage of RILP, generating a cleaved fragment (cRILP) missing the N-terminus that re-localizes to the cell periphery. Both RILP knockdown and cRILP expression reproduce HCV-induced inhibition of Rab7-dependent endosome-lysosome fusion. cRILP promotes virion secretion via kinesin-dependent trafficking; restoring full-length RILP reverses the trafficking defect.\",\n      \"method\": \"Viral infection, RILP knockdown, cRILP overexpression, kinesin inhibitor treatment, vesicular trafficking assays, fluorescence microscopy\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple complementary functional approaches (knockdown, overexpression, inhibitor, rescue), defined molecular mechanism, single lab\",\n      \"pmids\": [\"27091088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Rab12 is a novel effector of RILP: GTP-bound Rab12 interacts with RILP and mediates minus-end retrograde transport of mast cell secretory granules via the RILP-dynein complex in a stimulus-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation, GTPase pulldown, RNAi knockdown, overexpression, granule transport assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — co-IP, pulldown, and functional transport assay with defined phenotypic readout, single lab\",\n      \"pmids\": [\"26740112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RILP (and Rab7, Rab11) regulates intracellular trafficking of the CMA receptor LAMP2A. The truncated RILP-C33 form cannot rescue defective LAMP2A trafficking in cystinosis, while full-length RILP restores LAMP2A localization at lysosomes. Dominant-negative Rab7 or Rab11 impairs LAMP2A trafficking.\",\n      \"method\": \"Overexpression of wild-type and mutant RILP, dominant-negative constructs, immunofluorescence, knockdown studies in cystinotic cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — overexpression/dominant-negative with functional trafficking readout, single lab\",\n      \"pmids\": [\"28465352\"],\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. Cleavage alone is insufficient to re-localize RILP; combined cleavage and phosphorylation near the recognition site are required for redistribution of RILP from perinuclear vesicles throughout the cytoplasm and release from dynactin p150Glued, leading to redistribution of CD63+ intracellular vesicles.\",\n      \"method\": \"Caspase-1 cleavage assay, site-directed mutagenesis (D75A), phosphorylation analysis, immunofluorescence of RILP and CD63 vesicles\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro cleavage assay with mutagenesis to define recognition site, combined with functional cell localization readout, single lab\",\n      \"pmids\": [\"30100068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Structural and biochemical analysis revealed that Rab7 interacts with ORP1L's N-terminal ankyrin repeat domain (ARDN) independently of Rab7's GTP/GDP binding state, via a unique helix3/310-helix2 region. This leaves Rab7's canonical effector-binding switch regions free to bind RILP simultaneously, enabling formation of the ORP1L-Rab7-RILP tripartite complex. Mutational disruption of the ORP1L-Rab7 interface impairs late endosome positioning.\",\n      \"method\": \"Crystal structure determination, biochemical binding assays, site-directed mutagenesis, late endosome positioning assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus mutagenesis and functional cell assay, single lab, structural validation\",\n      \"pmids\": [\"30012887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LRRK1 phosphorylates GTP-bound Rab7 on serine 72 at the endosomal membrane, and this phosphorylation promotes the interaction of Rab7 with RILP, thereby recruiting dynein-dynactin to Rab7-positive vesicles and facilitating dynein-driven transport of EGFR-containing endosomes toward the perinuclear region.\",\n      \"method\": \"Kinase assay, phospho-specific antibodies, co-immunoprecipitation, endosomal transport assays, LRRK1 knockdown\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro kinase assay defining phosphorylation site, co-IP showing phosphorylation-dependent interaction with RILP, functional transport readout, single lab\",\n      \"pmids\": [\"31085713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RILP promotes lysosomal degradation of proinsulin by clustering insulin granules and reducing proinsulin-containing granules in pancreatic beta cells. RILP interacts with insulin granule-associated Rab26, restricting insulin secretion. RILP-induced proinsulin degradation is inhibited by lysosomal inhibitors and is Rab7-dependent; RILP depletion sustains proinsulin and increases insulin secretion.\",\n      \"method\": \"Overexpression, RNAi knockdown, lysosomal inhibitor treatment, co-immunoprecipitation with Rab26, insulin secretion assays, islet transplantation\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — co-IP identifying Rab26 as binding partner, functional assays with inhibitors and genetic knockdown, single lab\",\n      \"pmids\": [\"31624142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RILP is essential for retrograde transport of neuronal autophagosomes and, unexpectedly, for their biogenesis. mTOR inhibition upregulates RILP expression and its localization to autophagosomes. RILP depletion or mutations in LC3-binding LIR motifs strongly decrease autophagosome numbers. RILP also interacts with ATG5 on isolation membranes, precluding premature dynein recruitment. RILP inhibition impedes autophagic turnover and causes p62/sequestosome-1 aggregation.\",\n      \"method\": \"RNAi knockdown, LIR motif mutagenesis, co-immunoprecipitation with ATG5 and LC3, autophagosome counting, mTOR inhibitor treatment, p62 aggregation assay\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (knockdown, mutagenesis, co-IP with multiple partners, functional flux assays) in neuronal context, single lab\",\n      \"pmids\": [\"32275887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Rab12 interacts with RILP via its switch I and switch II regions at the RILP homology domain (RHD) of one RILP monomer and a C-terminal threonine of the other monomer in a RILP homodimer. Lysine-71 in Rab12 is critical for interaction with RILP-L1 and RILP-L2 but dispensable for RILP binding. Mutational analyses of RILP RHD confirmed its involvement in regulating secretory granule transport.\",\n      \"method\": \"Molecular dynamics simulations, functional mutational analyses, peptide inhibition assays, biochemical binding assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — computational modeling with functional mutational validation, single lab\",\n      \"pmids\": [\"33986343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RILP interacts with Grb10 (growth factor receptor binding protein-10) as identified by co-immunoprecipitation, and through this interaction restrains PI3K/AKT/mTOR signaling. RILP overexpression promotes autophagy in osteosarcoma cells in a PI3K/AKT/mTOR-dependent manner; partial attenuation by autophagy inhibitor 3-MA implicates autophagy in EMT regulation.\",\n      \"method\": \"Co-immunoprecipitation, RNA-seq pathway analysis, PI3K activator rescue, 3-MA autophagy inhibition, xenograft mouse model\",\n      \"journal\": \"Molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Weak — co-IP identifying Grb10 as binding partner, functional pathway assays, single lab\",\n      \"pmids\": [\"37789274\"],\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 then recruits RILP and dynein to lysosomes for retrograde transport. Loss of DENND6A impairs autophagic flux.\",\n      \"method\": \"Cell-based GEF assay screening all Rabs, co-immunoprecipitation, lysosome positioning assays, RNAi knockdown, autophagic flux assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — cell-based GEF screen with functional validation, co-IP, and autophagic flux readout; RILP role inferred from Rab34 interaction rather than directly assayed, single lab\",\n      \"pmids\": [\"38296963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RILP interacts with ORP1L to competitively inhibit formation of the VAP-ORP1L contact site between the ER and endolysosomes. RILP overexpression causes late endosome/lysosome clustering, reduces ER-endolysosome contact, and leads to cholesterol accumulation in clustered endolysosomes, triggering RILP-dependent cellular autophagy.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence microscopy, cholesterol staining, autophagy assays, overexpression studies\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — co-IP and functional cell imaging with cholesterol and autophagy readouts, single lab\",\n      \"pmids\": [\"39195203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"pH neutralization of late endosomes increases assembly of the V1G1 subunit of V-ATPase on endosomal membranes, which stabilizes GTP-bound Rab7 via RILP (a known interactor of both Rab7 and V1G1), causing Rab7 hyperactivation and disrupting late endosomal tubulation and CI-M6PR recycling.\",\n      \"method\": \"LLOMe treatment, NH4Cl pH neutralization, Rab7 hyperactive mutants, immunofluorescence, CI-M6PR trafficking assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — pharmacological and genetic perturbation with functional readouts, single lab; RILP role inferred from known interactions rather than directly mutagenized in this study\",\n      \"pmids\": [\"38578235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Rab7 phosphorylation at Tyrosine 183 in diabetic cardiomyocytes allows recruitment of RILP to promote lysosomal degradation of lipid droplets via microlipophagy. Rab7 activator ML-098 enhanced RILP levels and rescued cardiac dysfunction in diabetic mice.\",\n      \"method\": \"Rab7-CKO mice, RNA-seq, phospho-specific analysis, in vivo Rab7 activator treatment, cardiac function assays\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — phosphorylation site and RILP recruitment inferred from in vivo model; direct biochemical validation of pY183-Rab7 binding to RILP not shown in abstract, single lab\",\n      \"pmids\": [\"38837607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HDAC1 (stabilized by deubiquitinase USP5) deacetylates RILP in DDP-resistant NSCLC cells, reducing RILP acetylation levels and contributing to cisplatin resistance. RILP upregulation counteracts the effects of HDAC1 overexpression on cisplatin resistance.\",\n      \"method\": \"Co-immunoprecipitation for USP5-HDAC1 interaction, RILP acetylation co-IP assay, HDAC1/USP5 silencing, MG132 assay, xenograft model\",\n      \"journal\": \"Thoracic cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — co-IP identifying RILP acetylation regulated by HDAC1, limited mechanistic depth in abstract, single lab\",\n      \"pmids\": [\"39582290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RILP functions as a dynein adaptor for late endosome motility in dendrites, dependent on RAB7A binding: expression of RAB7A-L8A (RILP-binding-deficient mutant) impairs retrograde late endosome transport in dendrites and inhibits dendrite arborization. Surprisingly, lysosomal fusion and somatic degradation do not require RAB7A-RILP interaction, separating transport from degradation functions. RILP also promotes endosome carrier formation in dendrites.\",\n      \"method\": \"Separation-of-function RAB7A mutant (L8A) expression in rat/mouse hippocampal neurons, live imaging, dendrite arborization assays, cargo degradation assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean separation-of-function mutant with defined transport and morphology readouts in primary neurons; preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.09.03.673267\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RILP cleavage (induced by inflammatory mediators LPS/ATP via caspase-1) impairs tau degradation in microglia, increases intracellular tau accumulation, and enhances cell-cell tau propagation. RILP cleavage status influences extracellular vesicle secretion in microglia. Expression of a noncleavable RILP mitigates inflammation-enhanced tau propagation.\",\n      \"method\": \"LPS/ATP treatment, caspase-1 activation, noncleavable RILP mutant expression, tau propagation assay, EV secretion assay, AD brain tissue analysis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — functional rescue with noncleavable mutant, EV assay, correlation with AD brain cleavage, single lab\",\n      \"pmids\": [\"40137558\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RILP is a multifunctional effector protein that is recruited to late endosomal and lysosomal membranes by GTP-bound Rab7 (and also Rab34, Rab36, Rab12, and Rab26), where it acts as a dynein adaptor by directly binding the p150Glued dynactin subunit to drive minus-end microtubule transport of late endosomes, lysosomes, phagosomes, and autophagosomes; it coordinates transport with fusion by simultaneously engaging the HOPS tethering complex, interacts with ESCRT-II subunits VPS22/VPS36 to regulate MVB biogenesis, controls V-ATPase activity through V1G1 interaction, and can be inactivated by viral- or inflammatory-state-induced caspase-1 cleavage (at D75) that redirects vesicle trafficking toward the cell periphery.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RILP is a Rab effector that converts the GTP-loaded state of late endosomal/lysosomal small GTPases into directed minus-end microtubule transport, coupling organelle motility with tethering, fusion, and maturation [#0, #1, #7]. It is recruited to late endosomal and lysosomal membranes by GTP-bound Rab7 through a defined Rab-homology region (residues ~272–333) and acts as a dynein adaptor by directly binding the C-terminal 25-kDa region of the dynactin subunit p150Glued, thereby recruiting the dynein-dynactin motor to drive centripetal transport of late endosomes, lysosomes, and phagosomes [#0, #2, #3, #7]. Productive dynein activation requires assembly of a tripartite Rab7-RILP-ORP1L complex, with ORP1L acting as a cholesterol-sensing switch: under low cholesterol ORP1L promotes ER-endosome VAP contacts that strip p150Glued from the Rab7-RILP complex, while RILP can competitively inhibit VAP-ORP1L contact formation, integrating organelle positioning with sterol status [#7, #11, #14, #22, #29]. RILP simultaneously engages the HOPS tethering complex to couple transport with endolysosomal fusion, interacts with ESCRT-II subunits VPS22 and VPS36 to support multivesicular body biogenesis and EGFR degradation, and binds the V-ATPase peripheral-stalk subunit V1G1 (ATP6V1G1) to control its membrane recruitment, ubiquitylation-dependent turnover, and V-ATPase activity [#5, #6, #8, #14, #15]. The same adaptor module is used by additional Rab GTPases — Rab34, Rab36, Rab12, and Rab26 — to position lysosomes, melanosomes, secretory granules, and insulin granules, and RILP is required for retrograde transport and biogenesis of autophagosomes via LIR-dependent LC3 binding and ATG5 interaction [#12, #17, #19, #24, #25]. RILP activity is controlled post-translationally: LRRK1 phosphorylation of Rab7 on Ser72 enhances Rab7-RILP binding, while caspase-1 cleavage at Asp75, together with nearby phosphorylation, releases RILP from p150Glued and redistributes vesicles to the cell periphery, a mechanism exploited by HCV and inflammatory states to redirect trafficking [#18, #21, #23, #34].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established that RILP is the downstream effector translating Rab7 activation into lysosomal transport, answering how the Rab7 GTPase switch is read out functionally.\",\n      \"evidence\": \"Yeast two-hybrid, GST pulldown, co-IP, and dominant-negative epistasis with degradation assays in mammalian cells\",\n      \"pmids\": [\"11179213\", \"11696325\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the motor-recruiting partner directly\", \"Structural basis of Rab7-GTP recognition not resolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Mapped a unique ~62-residue region sufficient for Rab7/Rab34 binding and lysosomal morphology control, defining the modular Rab-homology element that confers effector activity.\",\n      \"evidence\": \"Truncation/chimeric mutants transferred into RLP1 with lysosomal morphology and GTPase-binding assays; phagosome maturation imaging\",\n      \"pmids\": [\"14668488\", \"12944476\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the dynein-recruiting interface at residue level\", \"Mechanism of tubule extension during phagosome maturation incomplete\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified p150Glued as the direct RILP partner and showed dynein activation needs additional ORP1L/betaIII-spectrin factors, refining RILP from a simple motor bridge to part of a multi-component activation module.\",\n      \"evidence\": \"Reciprocal co-IP, GST pulldown, deletion mutants, and organelle motility assays; RNAi loss-of-function with EM and cargo trafficking\",\n      \"pmids\": [\"17283181\", \"17959629\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How betaIII-spectrin triggers dynein activation mechanistically unresolved\", \"Stoichiometry of the Rab7-RILP-p150Glued-ORP1L complex unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Connected RILP to ESCRT-II via VPS22 and VPS36 binding, linking late endosomal transport to MVB sorting machinery.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, colocalization, and EGF sorting assays across two concurrent papers\",\n      \"pmids\": [\"16857164\", \"17010938\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of ESCRT-II binding for ILV formation not mechanistically dissected\", \"Single-lab observations without structural validation\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Revealed cholesterol sensing through ORP1L as the switch governing RILP-dependent endosome positioning, explaining how lipid status controls motor recruitment.\",\n      \"evidence\": \"Co-IP, organelle motility assays, and NPC disease cell model with cholesterol manipulation\",\n      \"pmids\": [\"19564404\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How VAP trans-interaction physically removes p150Glued not resolved at structural level\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed RILP concomitantly binds HOPS and p150Glued, coupling transport and fusion into one complex and explaining its role in viral entry requiring endolysosomal fusion.\",\n      \"evidence\": \"Co-IP, direct binding assays, knockdown, and Ebola virus infection assay\",\n      \"pmids\": [\"23729732\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Temporal ordering of HOPS vs dynein engagement on a single organelle unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated that the RILP Rab-homology domain reads multiple Rab GTPases (Rab36 for melanosomes), generalizing RILP as a shared adaptor for different organelle transport systems.\",\n      \"evidence\": \"Yeast two-hybrid, GST pulldown, site-directed mutagenesis, and melanosome distribution assays; Mreg interaction with melanosome readout\",\n      \"pmids\": [\"22740695\", \"22275436\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants of Rab selectivity in vivo incompletely defined\", \"Mreg's regulatory mechanism on dynein not resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified V1G1 as a RILP target whose stability and membrane recruitment RILP controls, extending RILP function to regulation of V-ATPase-dependent acidification.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, ubiquitylation assays, and V-ATPase activity measurements\",\n      \"pmids\": [\"24762812\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the ubiquitin ligase acting on V1G1 not established\", \"Link between acidification control and transport not integrated\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Expanded the RILP Rab repertoire to Rab34 (via FLCN), Rab12, and other GTPases and connected RILP-loss to viral exploitation through HCV-induced cleavage redirecting trafficking peripherally.\",\n      \"evidence\": \"Purified recombinant binding assays, co-IP, knockdown, live imaging; viral infection with cRILP overexpression and kinesin inhibition\",\n      \"pmids\": [\"27113757\", \"26740112\", \"27091088\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the protease producing cRILP in HCV infection not defined here\", \"How FLCN-DENN promotes complex formation without GEF activity unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined caspase-1 cleavage at Asp75 plus adjacent phosphorylation as the inactivating switch that releases RILP from p150Glued, providing a regulated mechanism to redistribute vesicles to the periphery.\",\n      \"evidence\": \"In vitro caspase-1 cleavage with D75A mutagenesis, phosphorylation analysis, and CD63 vesicle imaging; crystal structure of ORP1L-Rab7 interface with positioning assays\",\n      \"pmids\": [\"30100068\", \"30012887\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase responsible for the priming phosphorylation not identified\", \"Physiological triggers of caspase-1-mediated RILP cleavage beyond viral context unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed Rab7 phosphorylation (LRRK1 on Ser72) enhances Rab7-RILP binding, establishing kinase-regulated control of motor recruitment.\",\n      \"evidence\": \"In vitro kinase assay, phospho-specific antibodies, co-IP, and endosomal transport assays with LRRK1 knockdown\",\n      \"pmids\": [\"31085713\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other Rab kinases similarly tune RILP affinity not addressed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established RILP as essential not only for autophagosome retrograde transport but unexpectedly for their biogenesis, via LIR-dependent LC3 binding and ATG5 interaction that delays premature dynein recruitment.\",\n      \"evidence\": \"RNAi knockdown, LIR motif mutagenesis, co-IP with ATG5/LC3, autophagosome counting, and p62 flux assays in neurons\",\n      \"pmids\": [\"32275887\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How RILP contributes mechanistically to isolation membrane formation unresolved\", \"Relationship between biogenesis and transport roles not separated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Integrated RILP into broader physiology — insulin granule degradation via Rab26, lysosome positioning via the Arl8b-DENND6A-Rab34 axis, V-ATPase/pH-coupled Rab7 hyperactivation, ER-contact competition with ORP1L, and inflammation/tau and cancer roles.\",\n      \"evidence\": \"Co-IP, knockdown/overexpression, GEF screens, cholesterol/autophagy assays, and disease models (diabetes, osteosarcoma, NSCLC, AD-related tau)\",\n      \"pmids\": [\"31624142\", \"38296963\", \"38578235\", \"39195203\", \"37789274\", \"31624142\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Many disease links rely on single-lab overexpression/knockdown\", \"Direct biochemical role of RILP in several inferred axes not always assayed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Separated RILP transport from degradation functions using a RILP-binding-deficient Rab7 mutant, showing dendritic late endosome motility and arborization require RILP but somatic degradation does not.\",\n      \"evidence\": \"Separation-of-function RAB7A-L8A mutant in hippocampal neurons with live imaging and dendrite/cargo assays (preprint); caspase-1-cleaved RILP impairs microglial tau degradation and propagation\",\n      \"pmids\": [\"bio_10.1101_2025.09.03.673267\", \"40137558\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint not yet peer-reviewed\", \"How transport and degradation roles diverge mechanistically remains open\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple RILP partner interactions (Rab GTPases, p150Glued, HOPS, ORP1L, ESCRT-II, V1G1) are spatially and temporally ordered on a single maturing organelle, and the structure of the assembled motor-tethering supercomplex, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No high-resolution structure of the full RILP-containing transport/fusion supercomplex\", \"Quantitative interplay among competing RILP interactions during organelle maturation undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 7, 14]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [7, 1]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [15, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [0, 2, 17]},\n      {\"term_id\": \"GO:0005770\", \"supporting_discovery_ids\": [0, 7, 8]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [3, 19, 24]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [1, 3, 7, 14]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [25, 29, 28]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [11, 17, 33]}\n    ],\n    \"complexes\": [\n      \"Rab7-RILP-ORP1L tripartite complex\",\n      \"HOPS tethering complex\",\n      \"dynein-dynactin (p150Glued) motor complex\",\n      \"ESCRT-II (VPS22/VPS36)\"\n    ],\n    \"partners\": [\n      \"RAB7A\",\n      \"DCTN1/p150Glued\",\n      \"ORP1L\",\n      \"VPS22\",\n      \"VPS36\",\n      \"ATP6V1G1\",\n      \"RAB34\",\n      \"RAB36\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":{"gene":"RILP","tier":"GROUNDING","verdict":"Evidence-grounding concern","subtype":"fabrication","uniprot_band":"medium","rules_fired":"R7","issue":"R7: fabricated (no corpus paper): 27091088"},"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}