{"gene":"RAB22A","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2001,"finding":"Rab22a associates with early and late endosomes but not lysosomes in CHO cells. Overexpression causes enlargement of early and late endosomes. A constitutively active mutant (Q64L) also associates with lysosomes and autophagosomes. Wild-type and dominant-negative (S19N) forms decrease fluid-phase endocytosis, while Q64L does not inhibit bulk endocytosis.","method":"GFP-tagged protein expression, site-directed mutagenesis, fluorescence microscopy with endosomal markers, fluid-phase endocytosis assay","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (mutagenesis, live-cell imaging, functional assays) in a focused mechanistic study","pmids":["11739636"],"is_preprint":false},{"year":2004,"finding":"Rab22a is associated with tubular recycling intermediates containing clathrin-independent cargo (MHC class I). Dominant-negative Rab22a or siRNA-mediated depletion inhibits both tubule formation and MHCI recycling. Constitutively active Rab22a promotes tubule formation but still blocks final recycling fusion, indicating Rab22a activation is required for tubule formation and inactivation is required for membrane fusion with the surface. Rab11a dominant-negative inhibits MHCI recycling without affecting tubule formation, placing Rab22a and Rab11a at distinct steps.","method":"Dominant-negative and constitutively active mutant expression, siRNA knockdown, fluorescence microscopy, recycling assays","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (mutagenesis, siRNA, recycling assays) with epistasis analysis","pmids":["15181155"],"is_preprint":false},{"year":2004,"finding":"Overexpression of wild-type Rab22a or its GTP-hydrolysis-deficient mutant Q64L delays retrograde transport of cholera toxin from endosomes to the Golgi apparatus and accumulates the cation-independent mannose-6-phosphate receptor in endosomes, implicating Rab22a in endosome-to-TGN trafficking. No effect on endosome-to-lysosome transport was detected.","method":"Mutant expression, cholera toxin retrograde trafficking assay, CI-M6PR localization, fluorescence microscopy in CHO cells","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional trafficking assays with multiple constructs, single lab","pmids":["15748882"],"is_preprint":false},{"year":2006,"finding":"Rab22a controls the sorting of transferrin receptor from sorting endosomes to recycling endosomes. Expression of wild-type or Q64L canine Rab22a redistributes transferrin receptor to large Rab22a-positive peripheral structures and strongly inhibits recycling from those compartments. siRNA depletion of Rab22a disorganizes the perinuclear recycling center and strongly inhibits transferrin recycling, without affecting early internalization.","method":"Wild-type and mutant Rab22a expression, siRNA knockdown, kinetic transferrin recycling assays, fluorescence microscopy in CHO and HeLa cells","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal approaches (OE, mutagenesis, siRNA, kinetic assays), replicated across cell lines","pmids":["16537905"],"is_preprint":false},{"year":2014,"finding":"Under hypoxia, HIF-dependent transcriptional induction of RAB22A mediates microvesicle shedding from breast cancer cells. RAB22A colocalizes with budding microvesicles at the cell surface. Knockdown of RAB22A impairs breast cancer metastasis in an orthotopic mouse model.","method":"HIF knockdown/overexpression, RAB22A siRNA, microvesicle quantification, colocalization by fluorescence microscopy, orthotopic xenograft metastasis model","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (genetic knockdown, in vivo model, colocalization) with functional readouts","pmids":["24938788"],"is_preprint":false},{"year":2016,"finding":"Rab22a is recruited to dendritic cell endosomes and phagosomes (including Toxoplasma gondii-containing vacuoles) and is required for MHC-I intracellular recycling and antigen cross-presentation. Rab22a silencing drastically reduces the intracellular pool and recycling of MHC-I and hampers cross-presentation of soluble, particulate, and T. gondii-associated antigens, without affecting classical MHC-I presentation through the secretory pathway.","method":"Rab22a siRNA knockdown in dendritic cells, MHC-I trafficking assays, cross-presentation assays, fluorescence microscopy","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple functional readouts (MHC-I recycling, multiple antigen cross-presentation assays, localization) with clean siRNA knockdown","pmids":["27861124"],"is_preprint":false},{"year":2017,"finding":"Rab22a interacts with CD147 (a cargo protein entering cells via clathrin-independent endocytosis) and is required for its recycling back to the plasma membrane. Knockdown of Rab22a blocks CD147 recycling, promotes CD147 degradation, and suppresses lung cancer cell migration and invasion.","method":"Co-immunoprecipitation, Rab22a siRNA knockdown, CD147 recycling assay, migration and invasion assays","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP, recycling assay, and functional knockdown in a single lab study","pmids":["28433697"],"is_preprint":false},{"year":2018,"finding":"Rab22A forms a complex with BLOC-1, BLOC-2, and the kinesin-3 motor KIF13A on endosomes. Rab22A depletion reduces RE dynamics, causes cargo accumulation in early/sorting endosomes or lysosomes, and reduces membrane association of BLOC-1/BLOC-2. These defects phenocopy BLOC-1/BLOC-2-deficient cells, placing Rab22A upstream as an organizer of the BLOC-1–BLOC-2–KIF13A complex for recycling endosome biogenesis.","method":"RNAi screen, Co-immunoprecipitation, Rab22A siRNA knockdown, live-cell imaging of recycling endosome dynamics, cargo recycling assays in melanocytes","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP of complex, RNAi epistasis, multiple cargo and functional readouts in a focused mechanistic study","pmids":["30404817"],"is_preprint":false},{"year":2018,"finding":"Rab22a depletion in dendritic cells does not prevent ER-derived protein delivery to phagosomes but reduces ER-derived proteins at endosomes (labeled by fluid-phase marker) and impairs soluble antigen translocation to the cytosol. Rab22a deficiency also alters early endosomal maturation.","method":"Rab22a siRNA knockdown in DCs, immunofluorescence for ER markers in endosomes/phagosomes, cytosol translocation assay","journal":"Small GTPases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assay with compartment-specific readouts, single lab, multiple complementary methods","pmids":["28960134"],"is_preprint":false},{"year":2020,"finding":"Osteosarcoma chromosomal translocations produce Rab22a-NeoF fusion proteins in which the Rab22a1-38 moiety binds SmgGDS-607 (a GTP-GDP exchange factor for RhoA), facilitating release of GTP-bound RhoA from SmgGDS-607, thereby increasing RhoA activity and driving lung metastasis. Disrupting the Rab22a-NeoF1–SmgGDS-607 interaction with a synthetic peptide prevents lung metastasis in an orthotopic model.","method":"Identification of fusion genes by sequencing, Co-immunoprecipitation, RhoA activation assay, orthotopic osteosarcoma metastasis model, peptide disruption experiment","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — mechanistic reconstitution (Co-IP, RhoA-GTP assay), peptide rescue in vivo, multiple orthogonal approaches","pmids":["32483387"],"is_preprint":false},{"year":2020,"finding":"Rab22a-NeoF1 K7 is acetylated by p300/CBP and deacetylated by HDAC6 and SIRT1. A K7R acetylation-deficient mutant fails to bind SmgGDS-607 and loses the ability to activate RhoA, promote cell migration/invasion, and induce lung metastasis in vivo. p300/CBP inhibitor C646 also abolishes these functions.","method":"Mass spectrometry identification of K7ac, Co-IP, RhoA activation assay, Transwell migration/invasion, orthotopic osteosarcoma mouse model, site-directed mutagenesis (K7R)","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — MS identification of PTM, mutagenesis, in vitro and in vivo functional validation in a single rigorous study","pmids":["32685017"],"is_preprint":false},{"year":2020,"finding":"Rab22a acts downstream of Rab14 to establish epithelial polarity. Rab22a co-immunoprecipitates with the Arf6 GEF EFA6, and Rab22a knockdown causes decreased active Arf6 and retention of EFA6 in intracellular puncta, leading to multi-lumen phenotype. Overexpression of Rab22a rescues the Rab14 knockdown multi-lumen phenotype, placing Rab22a downstream of Rab14 in the polarity pathway.","method":"Rab22a siRNA knockdown, 3D MDCK culture lumen assay, co-immunoprecipitation with EFA6, Arf6 activity assay, epistasis rescue experiment","journal":"Small GTPases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, epistasis rescue, and Arf6 activity assay with functional phenotype, single lab","pmids":["32281471"],"is_preprint":false},{"year":2021,"finding":"Rab22a-NeoF1 fusion protein is sorted into exosomes by HSP90 via a KFERQ-like motif (RVLFLN142) together with its binding partner PYK2. Exosomal Rab22a-NeoF1 promotes pulmonary pre-metastatic niche formation by recruiting bone marrow-derived macrophages. Exosomal PYK2 activates RhoA in recipient osteosarcoma cells and induces STAT3 activation in recipient macrophages to increase M2 polarization.","method":"Co-immunoprecipitation, exosome isolation and characterization, KFERQ motif mutagenesis, RhoA and STAT3 activation assays, macrophage recruitment assays, lung metastasis model","journal":"Signal transduction and targeted therapy","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal approaches (Co-IP, motif mutagenesis, signaling assays, in vivo model) in a single focused study","pmids":["33568623"],"is_preprint":false},{"year":2021,"finding":"Rab22A binds to the NC-CC1 domains of KIF13A motor, relieving proline-mediated inhibition that keeps KIF13A as inactive monomers, thereby facilitating KIF13A dimerization and enabling balanced motility for recycling endosome tubulation.","method":"Single-molecule fluorescence assay, in vitro motility assays, domain mutagenesis, Co-IP of Rab22A with KIF13A domains","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro single-molecule reconstitution, domain mutagenesis, and Co-IP with functional validation in one rigorous study","pmids":["33536208"],"is_preprint":false},{"year":2022,"finding":"RAB22A mediates a non-canonical autophagy pathway: RAB22A engages PI4K2A to generate PI4P, which recruits the Atg12–Atg5–Atg16L1 complex, inducing formation of ER-derived non-canonical autophagosomes. These fuse with RAB22A-positive early endosomes to form a new organelle (Rafeesome). RAB22A inactivates RAB7 to suppress Rafeesome fusion with lysosomes, enabling secretion of activated STING-containing inner vesicles (R-EVs) that promote antitumor immunity in recipient cells.","method":"Co-immunoprecipitation, PI4P lipid assay, organelle marker colocalization, RAB7 activity assay, electron microscopy, STING agonist treatment, IFNβ secretion assay, mouse tumor model","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — mechanistic pathway established by Co-IP, lipid assays, organelle characterization, and in vivo functional validation","pmids":["36280710"],"is_preprint":false},{"year":2022,"finding":"Rab22a-NeoF1 fusion protein is degraded via a STUB1 E3-ligase–NDP52 autophagy receptor–lysosome pathway. STUB1 catalyzes K63-linked ubiquitin chains on lysine 112 of Rab22a-NeoF1, enabling NDP52 binding and lysosomal degradation. PINK1 phosphorylates Rab22a-NeoF1 at serine 120 to promote its ubiquitination and degradation. Sorafenib and regorafenib upregulate PINK1, thereby reducing Rab22a-NeoF1 levels and inhibiting osteosarcoma lung metastasis.","method":"E3 ligase screening, Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (K112R, S120A), lysosome inhibitor experiments, PINK1 kinase assay, mouse osteosarcoma metastasis model","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — ubiquitination site identification by mutagenesis, kinase assay, Co-IP, and in vivo validation in one rigorous study","pmids":["36529692"],"is_preprint":false},{"year":2022,"finding":"Rab22a promotes lung adenocarcinoma proliferation, migration, and invasion by activating the PI3K/Akt/mTOR pathway. Co-IP confirmed a direct interaction between Rab22a and PI3K regulatory subunit p85α. Rapamycin (mTOR inhibitor) significantly reduces Rab22a-induced enhancement of malignant phenotypes.","method":"Co-immunoprecipitation (Rab22a–PI3Kp85α), siRNA knockdown and overexpression, Western blot for PI3K/Akt/mTOR phosphorylation, proliferation/migration/invasion assays, rapamycin inhibition","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP plus signaling assays and pharmacological rescue, single lab","pmids":["35487271"],"is_preprint":false},{"year":2023,"finding":"Vps9d1, a VPS9 domain-containing protein, is a specific GEF for Rab22A that activates Rab22A but not Rab5A. Depletion of Vps9d1 severely impairs tubular endosome formation and alters clathrin-independent endocytosis cargo recycling. Expression of constitutively active Rab22A rescues tubular endosomes in Vps9d1-depleted cells, but a GEF-activity-deficient Vps9d1 mutant does not.","method":"Vps9d1 siRNA knockdown, GEF activity assay, constitutively active Rab22A rescue, Rab5A localization controls, tubular endosome imaging, CIE cargo recycling assay","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro GEF assay, mutagenesis rescue, and epistasis analysis with functional cargo readout","pmids":["36762583"],"is_preprint":false},{"year":2024,"finding":"RAB22A recruits TBC1D2B (a GAP for RAB7A) to inactivate RAB7A, preventing EGFR from being transported to late endosomes/lysosomes. RAB22A also engages SH3BP5L (a GEF for RAB11A) to activate RAB11A on early endosomes, recycling EGFR to the cell surface for packaging into microvesicles. EGFR phosphorylates RAB22A at Tyr136, which promotes EGFR-containing MV formation.","method":"RAB GTPase family RNAi screen, Co-immunoprecipitation (RAB22A–TBC1D2B, RAB22A–SH3BP5L), RAB7A and RAB11A activity assays, EGFR phosphorylation assay (Tyr136), MV isolation and quantification","journal":"Journal of extracellular vesicles","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — mechanistic dissection with Co-IP of multiple effectors, GTPase activity assays, and identified phosphorylation site in a single rigorous study","pmids":["39051763"],"is_preprint":false},{"year":2024,"finding":"TBC1D31 acts as a RAB22A GAP that catalyzes GTP hydrolysis for RAB22A, thereby reducing RAB22A-mediated endolysosomal trafficking and degradation of EGFR and activating EGFR signaling in hepatocellular carcinoma.","method":"GAP activity assay (TBC1D31 on Rab22A), EGFR trafficking assay, Co-immunoprecipitation, in vitro and in vivo HCC models","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — GAP enzymatic assay and EGFR trafficking readout, single lab","pmids":["39206796"],"is_preprint":false},{"year":2024,"finding":"HIF-1α and RAB22A form an endogenous intracellular complex in MDA-MB-231 breast cancer cells under hypoxia, as demonstrated by co-immunoprecipitation of endogenous proteins. Transiently overexpressed HIF-1α and RAB22A did not interact, suggesting the interaction requires endogenous context.","method":"Co-immunoprecipitation of endogenous HIF-1α and RAB22A, molecular docking, transfection controls in HEK-293T cells","journal":"Molecular biology reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP, single lab, negative result in overexpression context limits interpretation","pmids":["38647725"],"is_preprint":false},{"year":2025,"finding":"RAB22A promotes exosome secretion in chemoresistant colorectal cancer cells by inhibiting ubiquitination and degradation of PKM2, which then promotes phosphorylation of SNAP-23. This RAB22A–PKM2–pSNAP-23 cascade increases exosome release, enabling intercellular chemoresistance transmission in the tumor microenvironment.","method":"Co-immunoprecipitation, ubiquitination assay, SNAP-23 phosphorylation assay, exosome isolation and quantification, conditioned medium transfer experiments, RAB22A overexpression/knockdown","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination and phosphorylation assays, functional exosome transfer assay, single lab","pmids":["40957949"],"is_preprint":false},{"year":2025,"finding":"RAB22A interacts with the tubular ER membrane protein TMEM33, which binds RTN4 at its TM2 domain. The RAB22A/TMEM33/RTN4 assembly promotes RTN4 homo-oligomerization, generating RTN4-enriched ER membrane microdomains with high curvature that bud off as vesicles transported by ATG9A into isolation membranes anchored by LC3-II, forming sealed RTN4-positive non-canonical autophagosomes secreted as R-EVs via Rafeesome.","method":"Co-immunoprecipitation (RAB22A–TMEM33, TMEM33–RTN4), domain mutagenesis (RTN4 TM2), RTN4 oligomerization assay, organelle marker colocalization, electron microscopy, secretion assay","journal":"Cell discovery","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — Co-IP of multi-protein assembly, domain mutagenesis, oligomerization assay, and structural/functional organelle characterization in one rigorous study","pmids":["40301304"],"is_preprint":false},{"year":2022,"finding":"Rab22a cooperates with Rab5 and the CSFV non-structural protein NS4B during classical swine fever virus entry. Pull-down and Co-IP confirmed Rab22a–NS4B interaction; NS4B only binds wild-type Rab22a but not Q64L or S19N mutants. Rab22a colocalizes with CSFV particles in early endosomes during entry, and a Rab22a–Rab5–NS4B cascade facilitates viral entry.","method":"GST pull-down, Co-immunoprecipitation, Rab22a overexpression/knockdown/mutagenesis, confocal colocalization, viral replication assay","journal":"Veterinary microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pull-down plus Co-IP with mutagenesis confirming specificity, functional viral assay, single lab","pmids":["35134740"],"is_preprint":false}],"current_model":"RAB22A is an endosomal small GTPase that regulates clathrin-independent endocytosis recycling by promoting tubular recycling endosome biogenesis (via recruitment of BLOC-1/BLOC-2/KIF13A and activation by its specific GEF Vps9d1), controls cargo sorting from early endosomes (including MHCI, transferrin receptor, EGFR, and CD147) by coordinating downstream RAB7A inactivation (through TBC1D2B) and RAB11A activation (through SH3BP5L), mediates microvesicle and extracellular vesicle shedding (including under HIF-dependent hypoxia), drives a non-canonical ER-phagy/secretory autophagy pathway (Rafeesome) through PI4K2A–PI4P–ATG complex engagement and RAB7 inactivation that enables intercellular transfer of activated STING, and through chromosomal translocation-derived Rab22a-NeoF fusion proteins (regulated by p300/CBP acetylation at K7 and PINK1/STUB1-mediated lysosomal degradation), activates RhoA via SmgGDS-607 to drive osteosarcoma metastasis."},"narrative":{"mechanistic_narrative":"RAB22A is an endosomal small GTPase that governs cargo sorting and tubular recycling in the clathrin-independent endocytosis pathway, cycling between GTP- and GDP-bound states to control distinct trafficking steps [PMID:11739636, PMID:15181155]. Active RAB22A is required to generate tubular recycling intermediates carrying clathrin-independent cargo such as MHC class I and the transferrin receptor, and its subsequent inactivation is required for fusion of these tubules with the plasma membrane, placing it upstream of and distinct from RAB11A in the recycling itinerary [PMID:15181155, PMID:16537905]. It builds the recycling endosome machinery by organizing a BLOC-1–BLOC-2–KIF13A complex on endosomes and directly binding the kinesin-3 motor KIF13A to relieve its autoinhibition and promote motor dimerization for endosome tubulation [PMID:30404817, PMID:33536208]; its specific GEF Vps9d1 activates RAB22A to drive this tubular endosome formation [PMID:36762583]. Through these activities RAB22A controls the recycling versus degradation fate of multiple surface cargoes, including CD147 and EGFR, the latter by recruiting the RAB7A GAP TBC1D2B to block lysosomal delivery while engaging the RAB11A GEF SH3BP5L to promote surface recycling and microvesicle packaging, a process tuned by EGFR phosphorylation of RAB22A at Tyr136 [PMID:28433697, PMID:39051763]. RAB22A also drives extracellular vesicle and microvesicle shedding, induced under hypoxia downstream of HIF, and supports breast cancer metastasis [PMID:24938788]. Beyond recycling, RAB22A nucleates a non-canonical secretory autophagy pathway: it engages PI4K2A to generate PI4P that recruits the ATG12–ATG5–ATG16L1 complex, building ER-derived non-canonical autophagosomes that fuse with RAB22A-positive endosomes to form the Rafeesome, while RAB22A-mediated RAB7 inactivation prevents lysosomal fusion and enables secretion of activated STING-containing vesicles for antitumor immunity [PMID:36280710, PMID:40301304]. In osteosarcoma, chromosomal translocation–derived Rab22a-NeoF1 fusion proteins use the RAB22A 1–38 moiety to bind SmgGDS-607 and release GTP-bound RhoA, activating RhoA to drive lung metastasis; this fusion is controlled by p300/CBP acetylation at K7 and by PINK1/STUB1-directed lysosomal degradation [PMID:32483387, PMID:32685017, PMID:36529692].","teleology":[{"year":2001,"claim":"Established RAB22A as an endosome-associated GTPase whose nucleotide state controls endocytic function, answering where the protein acts and that its activity cycle matters.","evidence":"GFP-tagged constructs, Q64L/S19N mutagenesis and fluid-phase endocytosis assays in CHO cells","pmids":["11739636"],"confidence":"High","gaps":["No effectors or GEF/GAP identified","Mechanism linking GTPase state to endosome enlargement unresolved"]},{"year":2004,"claim":"Defined RAB22A's specific role in clathrin-independent recycling, showing activation drives tubule formation while inactivation is needed for surface fusion, and that it acts at a step distinct from RAB11A.","evidence":"Dominant-negative/constitutively active mutants, siRNA, MHCI recycling and epistasis analysis","pmids":["15181155"],"confidence":"High","gaps":["Tubulation machinery downstream of RAB22A not identified","Mechanism coupling inactivation to fusion unknown"]},{"year":2005,"claim":"Extended RAB22A function to endosome-to-TGN retrograde transport, distinguishing it from endosome-to-lysosome routes.","evidence":"Mutant expression, cholera toxin retrograde and CI-M6PR localization assays in CHO cells","pmids":["15748882"],"confidence":"Medium","gaps":["Single-lab overexpression readout","No retrograde effectors defined"]},{"year":2006,"claim":"Showed RAB22A sorts transferrin receptor from sorting to recycling endosomes and organizes the perinuclear recycling center, broadening it beyond clathrin-independent cargo.","evidence":"Wild-type/Q64L expression, siRNA, kinetic transferrin recycling in CHO and HeLa cells","pmids":["16537905"],"confidence":"High","gaps":["Molecular sorting machinery not identified"]},{"year":2014,"claim":"Connected RAB22A to hypoxia-driven microvesicle shedding and metastasis, linking endosomal recycling to extracellular vesicle biology in cancer.","evidence":"HIF manipulation, RAB22A siRNA, microvesicle quantification, orthotopic breast cancer xenograft","pmids":["24938788"],"confidence":"High","gaps":["Molecular mechanism of vesicle budding by RAB22A not resolved at this stage","Cargo content of microvesicles undefined"]},{"year":2016,"claim":"Demonstrated RAB22A is required for MHC-I recycling and antigen cross-presentation in dendritic cells, giving the recycling pathway an immunological output.","evidence":"siRNA knockdown, MHC-I trafficking and multiple cross-presentation assays in DCs","pmids":["27861124"],"confidence":"High","gaps":["Effectors mediating MHC-I recycling in DCs not defined"]},{"year":2017,"claim":"Identified CD147 as a RAB22A-dependent recycling cargo, tying RAB22A recycling activity to tumor cell migration.","evidence":"Co-IP, siRNA, CD147 recycling and migration/invasion assays","pmids":["28433697"],"confidence":"Medium","gaps":["Single-lab study","Direct binding interface unmapped"]},{"year":2018,"claim":"Resolved the recycling endosome machinery by placing RAB22A upstream of the BLOC-1–BLOC-2–KIF13A complex as its membrane organizer.","evidence":"RNAi screen, Co-IP, live-cell RE dynamics and cargo recycling in melanocytes","pmids":["30404817"],"confidence":"High","gaps":["How RAB22A recruits the complex mechanistically not fully defined at this stage"]},{"year":2018,"claim":"Linked RAB22A to ER-derived protein delivery at endosomes and antigen translocation to the cytosol in dendritic cells.","evidence":"siRNA in DCs, ER marker immunofluorescence, cytosol translocation assay","pmids":["28960134"],"confidence":"Medium","gaps":["Single-lab functional study","Molecular basis of ER-endosome contribution unclear"]},{"year":2020,"claim":"Discovered the oncogenic Rab22a-NeoF1 fusion mechanism, showing the RAB22A 1–38 moiety binds SmgGDS-607 to release active RhoA and drive osteosarcoma lung metastasis.","evidence":"Fusion gene sequencing, Co-IP, RhoA-GTP assay, peptide disruption in orthotopic model","pmids":["32483387"],"confidence":"High","gaps":["Relationship of fusion to wild-type RAB22A function not addressed"]},{"year":2020,"claim":"Identified K7 acetylation by p300/CBP as a switch controlling Rab22a-NeoF1 binding to SmgGDS-607 and its pro-metastatic activity.","evidence":"MS K7ac identification, K7R mutagenesis, Co-IP, RhoA assay, migration and orthotopic metastasis model","pmids":["32685017"],"confidence":"High","gaps":["Whether wild-type RAB22A is similarly regulated unknown"]},{"year":2020,"claim":"Placed RAB22A downstream of RAB14 in epithelial polarity through an EFA6–Arf6 axis.","evidence":"siRNA, 3D MDCK lumen assay, Co-IP with EFA6, Arf6 activity assay, epistasis rescue","pmids":["32281471"],"confidence":"Medium","gaps":["Single-lab study","Direct vs indirect EFA6 interaction not fully resolved"]},{"year":2021,"claim":"Provided the molecular mechanism of motor activation, showing RAB22A binds KIF13A NC-CC1 domains to relieve autoinhibition and promote dimerization for endosome tubulation.","evidence":"Single-molecule fluorescence and in vitro motility assays, domain mutagenesis, Co-IP","pmids":["33536208"],"confidence":"High","gaps":["Structural basis of the RAB22A-KIF13A interface not solved"]},{"year":2021,"claim":"Showed how Rab22a-NeoF1 is exported and spreads metastatic signaling via HSP90/KFERQ-mediated exosomal sorting with PYK2.","evidence":"Co-IP, exosome isolation, KFERQ motif mutagenesis, RhoA/STAT3 assays, lung metastasis model","pmids":["33568623"],"confidence":"High","gaps":["Whether wild-type RAB22A uses the same export route unknown"]},{"year":2022,"claim":"Established RAB22A as the nucleator of a non-canonical secretory autophagy pathway (Rafeesome) that secretes activated STING via PI4K2A-PI4P-ATG engagement and RAB7 inactivation.","evidence":"Co-IP, PI4P lipid assay, organelle colocalization, RAB7 activity assay, EM, IFNβ secretion and tumor model","pmids":["36280710"],"confidence":"High","gaps":["How RAB22A selects ER membrane for autophagosome formation not yet defined here"]},{"year":2022,"claim":"Defined the STUB1/NDP52/PINK1-driven lysosomal degradation pathway controlling Rab22a-NeoF1 levels and identified it as a druggable node.","evidence":"E3 screening, ubiquitination assay, K112R/S120A mutagenesis, PINK1 kinase assay, metastasis model","pmids":["36529692"],"confidence":"High","gaps":["Whether wild-type RAB22A is regulated by the same axis unknown"]},{"year":2022,"claim":"Linked RAB22A to PI3K/Akt/mTOR signaling via direct interaction with PI3K p85α in lung adenocarcinoma.","evidence":"Co-IP, siRNA/overexpression, phospho-Western blots, proliferation/migration assays, rapamycin rescue","pmids":["35487271"],"confidence":"Medium","gaps":["Single-lab study","Direct binding interface not mapped"]},{"year":2022,"claim":"Showed RAB22A cooperates with RAB5 and viral NS4B to facilitate classical swine fever virus entry through early endosomes.","evidence":"GST pull-down, Co-IP with nucleotide-state mutants, confocal colocalization, viral replication assay","pmids":["35134740"],"confidence":"Medium","gaps":["Single-lab study","Relevance to human pathogens not addressed"]},{"year":2023,"claim":"Identified Vps9d1 as the specific GEF that activates RAB22A to drive tubular endosome formation, defining the upstream activation input.","evidence":"siRNA, GEF activity assay, constitutively active RAB22A rescue, RAB5A controls, CIE cargo assays","pmids":["36762583"],"confidence":"High","gaps":["Spatial/temporal regulation of Vps9d1 recruitment unresolved"]},{"year":2024,"claim":"Dissected how RAB22A coordinates RAB7A inactivation (via TBC1D2B) and RAB11A activation (via SH3BP5L) to recycle EGFR into microvesicles, with EGFR feedback phosphorylating RAB22A at Tyr136.","evidence":"RAB RNAi screen, Co-IP of effectors, RAB7A/RAB11A activity assays, EGFR phospho-assay, MV isolation","pmids":["39051763"],"confidence":"High","gaps":["Structural basis of effector switching unknown"]},{"year":2024,"claim":"Identified TBC1D31 as a RAB22A GAP that limits RAB22A-mediated EGFR endolysosomal degradation and thereby sustains EGFR signaling in HCC.","evidence":"GAP activity assay, EGFR trafficking assay, Co-IP, HCC in vitro/in vivo models","pmids":["39206796"],"confidence":"Medium","gaps":["Single-lab study","Regulation of TBC1D31 recruitment unknown"]},{"year":2024,"claim":"Reported an endogenous HIF-1α–RAB22A complex under hypoxia, but only in endogenous context.","evidence":"Co-IP of endogenous proteins and molecular docking; overexpression showed no interaction","pmids":["38647725"],"confidence":"Low","gaps":["Single Co-IP, not reciprocally validated","Negative overexpression result limits interpretation","Functional consequence undefined"]},{"year":2025,"claim":"Defined a RAB22A–PKM2–pSNAP-23 cascade that boosts exosome secretion and transmits chemoresistance in colorectal cancer.","evidence":"Co-IP, ubiquitination and SNAP-23 phospho-assays, exosome isolation, conditioned medium transfer","pmids":["40957949"],"confidence":"Medium","gaps":["Single-lab study","Direct vs indirect PKM2 interaction unclear"]},{"year":2025,"claim":"Resolved the ER membrane source of Rafeesome vesicles, showing RAB22A/TMEM33/RTN4 assembly drives RTN4 oligomerization and curvature for ATG9A-mediated non-canonical autophagosome formation.","evidence":"Co-IP of multi-protein assembly, RTN4 TM2 mutagenesis, oligomerization assay, EM, secretion assay","pmids":["40301304"],"confidence":"High","gaps":["How RAB22A nucleotide state regulates the assembly not defined"]},{"year":null,"claim":"It remains unresolved how RAB22A's GTPase cycle is spatially coordinated to switch 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Rabs cycle between an inactive GDP-bound form and an active GTP-bound form that is able to recruit to membranes different sets of downstream effectors directly responsible for vesicle formation, movement, tethering and fusion (PubMed:16537905). RAB22A plays a role in endocytosis and intracellular protein transport. Mediates trafficking of transferrin/TF from early endosomes to recycling endosomes (PubMed:16537905). Required for NGF-mediated endocytosis of NTRK1, and subsequent neurite outgrowth (PubMed:21849477). Has low GTPase activity (PubMed:16537905)","subcellular_location":"Endosome membrane; Cell membrane; Early endosome; Late endosome; Cell projection, ruffle; Cytoplasmic vesicle; Cytoplasmic vesicle, phagosome; Cytoplasmic vesicle, phagosome membrane","url":"https://www.uniprot.org/uniprotkb/Q9UL26/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RAB22A","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"GDI1","stoichiometry":0.2},{"gene":"GDI2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/RAB22A","total_profiled":1310},"omim":[{"mim_id":"620678","title":"RAS AND RAB INTERACTOR-LIKE PROTEIN; RINL","url":"https://www.omim.org/entry/620678"},{"mim_id":"619152","title":"TBC1 DOMAIN FAMILY, 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Yi xue ban = Journal of Peking University. Health sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39856503","citation_count":2,"is_preprint":false},{"pmid":"31897193","id":"PMC_31897193","title":"miRNA-520c-3p accelerates progression of nasopharyngeal carcinoma via targeting RAB22A.","date":"2019","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/31897193","citation_count":1,"is_preprint":false},{"pmid":"36766276","id":"PMC_36766276","title":"Localization of Chicken Rab22a in Cells and Its Relationship to BF or Ii Molecules and Genes.","date":"2023","source":"Animals : an open access journal from MDPI","url":"https://pubmed.ncbi.nlm.nih.gov/36766276","citation_count":0,"is_preprint":false},{"pmid":"39623280","id":"PMC_39623280","title":"[High expression of miR-204-5p promotes malignant behaviors of bladder cancer cells by negatively regulating RAB22A].","date":"2024","source":"Nan fang yi ke da xue xue bao = Journal of Southern Medical University","url":"https://pubmed.ncbi.nlm.nih.gov/39623280","citation_count":0,"is_preprint":false},{"pmid":"39364749","id":"PMC_39364749","title":"[Retracted] LncRNA HOTAIR controls the expression of Rab22a by sponging miR‑373 in ovarian cancer.","date":"2024","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/39364749","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":34848,"output_tokens":6815,"usd":0.103385,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15663,"output_tokens":6502,"usd":0.120432,"stage2_stop_reason":"end_turn"},"total_usd":0.223817,"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\": \"Rab22a associates with early and late endosomes but not lysosomes in CHO cells. Overexpression causes enlargement of early and late endosomes. A constitutively active mutant (Q64L) also associates with lysosomes and autophagosomes. Wild-type and dominant-negative (S19N) forms decrease fluid-phase endocytosis, while Q64L does not inhibit bulk endocytosis.\",\n      \"method\": \"GFP-tagged protein expression, site-directed mutagenesis, fluorescence microscopy with endosomal markers, fluid-phase endocytosis assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (mutagenesis, live-cell imaging, functional assays) in a focused mechanistic study\",\n      \"pmids\": [\"11739636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Rab22a is associated with tubular recycling intermediates containing clathrin-independent cargo (MHC class I). Dominant-negative Rab22a or siRNA-mediated depletion inhibits both tubule formation and MHCI recycling. Constitutively active Rab22a promotes tubule formation but still blocks final recycling fusion, indicating Rab22a activation is required for tubule formation and inactivation is required for membrane fusion with the surface. Rab11a dominant-negative inhibits MHCI recycling without affecting tubule formation, placing Rab22a and Rab11a at distinct steps.\",\n      \"method\": \"Dominant-negative and constitutively active mutant expression, siRNA knockdown, fluorescence microscopy, recycling assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (mutagenesis, siRNA, recycling assays) with epistasis analysis\",\n      \"pmids\": [\"15181155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Overexpression of wild-type Rab22a or its GTP-hydrolysis-deficient mutant Q64L delays retrograde transport of cholera toxin from endosomes to the Golgi apparatus and accumulates the cation-independent mannose-6-phosphate receptor in endosomes, implicating Rab22a in endosome-to-TGN trafficking. No effect on endosome-to-lysosome transport was detected.\",\n      \"method\": \"Mutant expression, cholera toxin retrograde trafficking assay, CI-M6PR localization, fluorescence microscopy in CHO cells\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional trafficking assays with multiple constructs, single lab\",\n      \"pmids\": [\"15748882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Rab22a controls the sorting of transferrin receptor from sorting endosomes to recycling endosomes. Expression of wild-type or Q64L canine Rab22a redistributes transferrin receptor to large Rab22a-positive peripheral structures and strongly inhibits recycling from those compartments. siRNA depletion of Rab22a disorganizes the perinuclear recycling center and strongly inhibits transferrin recycling, without affecting early internalization.\",\n      \"method\": \"Wild-type and mutant Rab22a expression, siRNA knockdown, kinetic transferrin recycling assays, fluorescence microscopy in CHO and HeLa cells\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal approaches (OE, mutagenesis, siRNA, kinetic assays), replicated across cell lines\",\n      \"pmids\": [\"16537905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Under hypoxia, HIF-dependent transcriptional induction of RAB22A mediates microvesicle shedding from breast cancer cells. RAB22A colocalizes with budding microvesicles at the cell surface. Knockdown of RAB22A impairs breast cancer metastasis in an orthotopic mouse model.\",\n      \"method\": \"HIF knockdown/overexpression, RAB22A siRNA, microvesicle quantification, colocalization by fluorescence microscopy, orthotopic xenograft metastasis model\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (genetic knockdown, in vivo model, colocalization) with functional readouts\",\n      \"pmids\": [\"24938788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Rab22a is recruited to dendritic cell endosomes and phagosomes (including Toxoplasma gondii-containing vacuoles) and is required for MHC-I intracellular recycling and antigen cross-presentation. Rab22a silencing drastically reduces the intracellular pool and recycling of MHC-I and hampers cross-presentation of soluble, particulate, and T. gondii-associated antigens, without affecting classical MHC-I presentation through the secretory pathway.\",\n      \"method\": \"Rab22a siRNA knockdown in dendritic cells, MHC-I trafficking assays, cross-presentation assays, fluorescence microscopy\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple functional readouts (MHC-I recycling, multiple antigen cross-presentation assays, localization) with clean siRNA knockdown\",\n      \"pmids\": [\"27861124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Rab22a interacts with CD147 (a cargo protein entering cells via clathrin-independent endocytosis) and is required for its recycling back to the plasma membrane. Knockdown of Rab22a blocks CD147 recycling, promotes CD147 degradation, and suppresses lung cancer cell migration and invasion.\",\n      \"method\": \"Co-immunoprecipitation, Rab22a siRNA knockdown, CD147 recycling assay, migration and invasion assays\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP, recycling assay, and functional knockdown in a single lab study\",\n      \"pmids\": [\"28433697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Rab22A forms a complex with BLOC-1, BLOC-2, and the kinesin-3 motor KIF13A on endosomes. Rab22A depletion reduces RE dynamics, causes cargo accumulation in early/sorting endosomes or lysosomes, and reduces membrane association of BLOC-1/BLOC-2. These defects phenocopy BLOC-1/BLOC-2-deficient cells, placing Rab22A upstream as an organizer of the BLOC-1–BLOC-2–KIF13A complex for recycling endosome biogenesis.\",\n      \"method\": \"RNAi screen, Co-immunoprecipitation, Rab22A siRNA knockdown, live-cell imaging of recycling endosome dynamics, cargo recycling assays in melanocytes\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP of complex, RNAi epistasis, multiple cargo and functional readouts in a focused mechanistic study\",\n      \"pmids\": [\"30404817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Rab22a depletion in dendritic cells does not prevent ER-derived protein delivery to phagosomes but reduces ER-derived proteins at endosomes (labeled by fluid-phase marker) and impairs soluble antigen translocation to the cytosol. Rab22a deficiency also alters early endosomal maturation.\",\n      \"method\": \"Rab22a siRNA knockdown in DCs, immunofluorescence for ER markers in endosomes/phagosomes, cytosol translocation assay\",\n      \"journal\": \"Small GTPases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assay with compartment-specific readouts, single lab, multiple complementary methods\",\n      \"pmids\": [\"28960134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Osteosarcoma chromosomal translocations produce Rab22a-NeoF fusion proteins in which the Rab22a1-38 moiety binds SmgGDS-607 (a GTP-GDP exchange factor for RhoA), facilitating release of GTP-bound RhoA from SmgGDS-607, thereby increasing RhoA activity and driving lung metastasis. Disrupting the Rab22a-NeoF1–SmgGDS-607 interaction with a synthetic peptide prevents lung metastasis in an orthotopic model.\",\n      \"method\": \"Identification of fusion genes by sequencing, Co-immunoprecipitation, RhoA activation assay, orthotopic osteosarcoma metastasis model, peptide disruption experiment\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — mechanistic reconstitution (Co-IP, RhoA-GTP assay), peptide rescue in vivo, multiple orthogonal approaches\",\n      \"pmids\": [\"32483387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Rab22a-NeoF1 K7 is acetylated by p300/CBP and deacetylated by HDAC6 and SIRT1. A K7R acetylation-deficient mutant fails to bind SmgGDS-607 and loses the ability to activate RhoA, promote cell migration/invasion, and induce lung metastasis in vivo. p300/CBP inhibitor C646 also abolishes these functions.\",\n      \"method\": \"Mass spectrometry identification of K7ac, Co-IP, RhoA activation assay, Transwell migration/invasion, orthotopic osteosarcoma mouse model, site-directed mutagenesis (K7R)\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — MS identification of PTM, mutagenesis, in vitro and in vivo functional validation in a single rigorous study\",\n      \"pmids\": [\"32685017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Rab22a acts downstream of Rab14 to establish epithelial polarity. Rab22a co-immunoprecipitates with the Arf6 GEF EFA6, and Rab22a knockdown causes decreased active Arf6 and retention of EFA6 in intracellular puncta, leading to multi-lumen phenotype. Overexpression of Rab22a rescues the Rab14 knockdown multi-lumen phenotype, placing Rab22a downstream of Rab14 in the polarity pathway.\",\n      \"method\": \"Rab22a siRNA knockdown, 3D MDCK culture lumen assay, co-immunoprecipitation with EFA6, Arf6 activity assay, epistasis rescue experiment\",\n      \"journal\": \"Small GTPases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, epistasis rescue, and Arf6 activity assay with functional phenotype, single lab\",\n      \"pmids\": [\"32281471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Rab22a-NeoF1 fusion protein is sorted into exosomes by HSP90 via a KFERQ-like motif (RVLFLN142) together with its binding partner PYK2. Exosomal Rab22a-NeoF1 promotes pulmonary pre-metastatic niche formation by recruiting bone marrow-derived macrophages. Exosomal PYK2 activates RhoA in recipient osteosarcoma cells and induces STAT3 activation in recipient macrophages to increase M2 polarization.\",\n      \"method\": \"Co-immunoprecipitation, exosome isolation and characterization, KFERQ motif mutagenesis, RhoA and STAT3 activation assays, macrophage recruitment assays, lung metastasis model\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal approaches (Co-IP, motif mutagenesis, signaling assays, in vivo model) in a single focused study\",\n      \"pmids\": [\"33568623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Rab22A binds to the NC-CC1 domains of KIF13A motor, relieving proline-mediated inhibition that keeps KIF13A as inactive monomers, thereby facilitating KIF13A dimerization and enabling balanced motility for recycling endosome tubulation.\",\n      \"method\": \"Single-molecule fluorescence assay, in vitro motility assays, domain mutagenesis, Co-IP of Rab22A with KIF13A domains\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro single-molecule reconstitution, domain mutagenesis, and Co-IP with functional validation in one rigorous study\",\n      \"pmids\": [\"33536208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RAB22A mediates a non-canonical autophagy pathway: RAB22A engages PI4K2A to generate PI4P, which recruits the Atg12–Atg5–Atg16L1 complex, inducing formation of ER-derived non-canonical autophagosomes. These fuse with RAB22A-positive early endosomes to form a new organelle (Rafeesome). RAB22A inactivates RAB7 to suppress Rafeesome fusion with lysosomes, enabling secretion of activated STING-containing inner vesicles (R-EVs) that promote antitumor immunity in recipient cells.\",\n      \"method\": \"Co-immunoprecipitation, PI4P lipid assay, organelle marker colocalization, RAB7 activity assay, electron microscopy, STING agonist treatment, IFNβ secretion assay, mouse tumor model\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — mechanistic pathway established by Co-IP, lipid assays, organelle characterization, and in vivo functional validation\",\n      \"pmids\": [\"36280710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Rab22a-NeoF1 fusion protein is degraded via a STUB1 E3-ligase–NDP52 autophagy receptor–lysosome pathway. STUB1 catalyzes K63-linked ubiquitin chains on lysine 112 of Rab22a-NeoF1, enabling NDP52 binding and lysosomal degradation. PINK1 phosphorylates Rab22a-NeoF1 at serine 120 to promote its ubiquitination and degradation. Sorafenib and regorafenib upregulate PINK1, thereby reducing Rab22a-NeoF1 levels and inhibiting osteosarcoma lung metastasis.\",\n      \"method\": \"E3 ligase screening, Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (K112R, S120A), lysosome inhibitor experiments, PINK1 kinase assay, mouse osteosarcoma metastasis model\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — ubiquitination site identification by mutagenesis, kinase assay, Co-IP, and in vivo validation in one rigorous study\",\n      \"pmids\": [\"36529692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Rab22a promotes lung adenocarcinoma proliferation, migration, and invasion by activating the PI3K/Akt/mTOR pathway. Co-IP confirmed a direct interaction between Rab22a and PI3K regulatory subunit p85α. Rapamycin (mTOR inhibitor) significantly reduces Rab22a-induced enhancement of malignant phenotypes.\",\n      \"method\": \"Co-immunoprecipitation (Rab22a–PI3Kp85α), siRNA knockdown and overexpression, Western blot for PI3K/Akt/mTOR phosphorylation, proliferation/migration/invasion assays, rapamycin inhibition\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP plus signaling assays and pharmacological rescue, single lab\",\n      \"pmids\": [\"35487271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Vps9d1, a VPS9 domain-containing protein, is a specific GEF for Rab22A that activates Rab22A but not Rab5A. Depletion of Vps9d1 severely impairs tubular endosome formation and alters clathrin-independent endocytosis cargo recycling. Expression of constitutively active Rab22A rescues tubular endosomes in Vps9d1-depleted cells, but a GEF-activity-deficient Vps9d1 mutant does not.\",\n      \"method\": \"Vps9d1 siRNA knockdown, GEF activity assay, constitutively active Rab22A rescue, Rab5A localization controls, tubular endosome imaging, CIE cargo recycling assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro GEF assay, mutagenesis rescue, and epistasis analysis with functional cargo readout\",\n      \"pmids\": [\"36762583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RAB22A recruits TBC1D2B (a GAP for RAB7A) to inactivate RAB7A, preventing EGFR from being transported to late endosomes/lysosomes. RAB22A also engages SH3BP5L (a GEF for RAB11A) to activate RAB11A on early endosomes, recycling EGFR to the cell surface for packaging into microvesicles. EGFR phosphorylates RAB22A at Tyr136, which promotes EGFR-containing MV formation.\",\n      \"method\": \"RAB GTPase family RNAi screen, Co-immunoprecipitation (RAB22A–TBC1D2B, RAB22A–SH3BP5L), RAB7A and RAB11A activity assays, EGFR phosphorylation assay (Tyr136), MV isolation and quantification\",\n      \"journal\": \"Journal of extracellular vesicles\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — mechanistic dissection with Co-IP of multiple effectors, GTPase activity assays, and identified phosphorylation site in a single rigorous study\",\n      \"pmids\": [\"39051763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TBC1D31 acts as a RAB22A GAP that catalyzes GTP hydrolysis for RAB22A, thereby reducing RAB22A-mediated endolysosomal trafficking and degradation of EGFR and activating EGFR signaling in hepatocellular carcinoma.\",\n      \"method\": \"GAP activity assay (TBC1D31 on Rab22A), EGFR trafficking assay, Co-immunoprecipitation, in vitro and in vivo HCC models\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — GAP enzymatic assay and EGFR trafficking readout, single lab\",\n      \"pmids\": [\"39206796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HIF-1α and RAB22A form an endogenous intracellular complex in MDA-MB-231 breast cancer cells under hypoxia, as demonstrated by co-immunoprecipitation of endogenous proteins. Transiently overexpressed HIF-1α and RAB22A did not interact, suggesting the interaction requires endogenous context.\",\n      \"method\": \"Co-immunoprecipitation of endogenous HIF-1α and RAB22A, molecular docking, transfection controls in HEK-293T cells\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP, single lab, negative result in overexpression context limits interpretation\",\n      \"pmids\": [\"38647725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RAB22A promotes exosome secretion in chemoresistant colorectal cancer cells by inhibiting ubiquitination and degradation of PKM2, which then promotes phosphorylation of SNAP-23. This RAB22A–PKM2–pSNAP-23 cascade increases exosome release, enabling intercellular chemoresistance transmission in the tumor microenvironment.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, SNAP-23 phosphorylation assay, exosome isolation and quantification, conditioned medium transfer experiments, RAB22A overexpression/knockdown\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination and phosphorylation assays, functional exosome transfer assay, single lab\",\n      \"pmids\": [\"40957949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RAB22A interacts with the tubular ER membrane protein TMEM33, which binds RTN4 at its TM2 domain. The RAB22A/TMEM33/RTN4 assembly promotes RTN4 homo-oligomerization, generating RTN4-enriched ER membrane microdomains with high curvature that bud off as vesicles transported by ATG9A into isolation membranes anchored by LC3-II, forming sealed RTN4-positive non-canonical autophagosomes secreted as R-EVs via Rafeesome.\",\n      \"method\": \"Co-immunoprecipitation (RAB22A–TMEM33, TMEM33–RTN4), domain mutagenesis (RTN4 TM2), RTN4 oligomerization assay, organelle marker colocalization, electron microscopy, secretion assay\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — Co-IP of multi-protein assembly, domain mutagenesis, oligomerization assay, and structural/functional organelle characterization in one rigorous study\",\n      \"pmids\": [\"40301304\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Rab22a cooperates with Rab5 and the CSFV non-structural protein NS4B during classical swine fever virus entry. Pull-down and Co-IP confirmed Rab22a–NS4B interaction; NS4B only binds wild-type Rab22a but not Q64L or S19N mutants. Rab22a colocalizes with CSFV particles in early endosomes during entry, and a Rab22a–Rab5–NS4B cascade facilitates viral entry.\",\n      \"method\": \"GST pull-down, Co-immunoprecipitation, Rab22a overexpression/knockdown/mutagenesis, confocal colocalization, viral replication assay\",\n      \"journal\": \"Veterinary microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pull-down plus Co-IP with mutagenesis confirming specificity, functional viral assay, single lab\",\n      \"pmids\": [\"35134740\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RAB22A is an endosomal small GTPase that regulates clathrin-independent endocytosis recycling by promoting tubular recycling endosome biogenesis (via recruitment of BLOC-1/BLOC-2/KIF13A and activation by its specific GEF Vps9d1), controls cargo sorting from early endosomes (including MHCI, transferrin receptor, EGFR, and CD147) by coordinating downstream RAB7A inactivation (through TBC1D2B) and RAB11A activation (through SH3BP5L), mediates microvesicle and extracellular vesicle shedding (including under HIF-dependent hypoxia), drives a non-canonical ER-phagy/secretory autophagy pathway (Rafeesome) through PI4K2A–PI4P–ATG complex engagement and RAB7 inactivation that enables intercellular transfer of activated STING, and through chromosomal translocation-derived Rab22a-NeoF fusion proteins (regulated by p300/CBP acetylation at K7 and PINK1/STUB1-mediated lysosomal degradation), activates RhoA via SmgGDS-607 to drive osteosarcoma metastasis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RAB22A is an endosomal small GTPase that governs cargo sorting and tubular recycling in the clathrin-independent endocytosis pathway, cycling between GTP- and GDP-bound states to control distinct trafficking steps [#0, #1]. Active RAB22A is required to generate tubular recycling intermediates carrying clathrin-independent cargo such as MHC class I and the transferrin receptor, and its subsequent inactivation is required for fusion of these tubules with the plasma membrane, placing it upstream of and distinct from RAB11A in the recycling itinerary [#1, #3]. It builds the recycling endosome machinery by organizing a BLOC-1\\u2013BLOC-2\\u2013KIF13A complex on endosomes and directly binding the kinesin-3 motor KIF13A to relieve its autoinhibition and promote motor dimerization for endosome tubulation [#7, #13]; its specific GEF Vps9d1 activates RAB22A to drive this tubular endosome formation [#17]. Through these activities RAB22A controls the recycling versus degradation fate of multiple surface cargoes, including CD147 and EGFR, the latter by recruiting the RAB7A GAP TBC1D2B to block lysosomal delivery while engaging the RAB11A GEF SH3BP5L to promote surface recycling and microvesicle packaging, a process tuned by EGFR phosphorylation of RAB22A at Tyr136 [#6, #18]. RAB22A also drives extracellular vesicle and microvesicle shedding, induced under hypoxia downstream of HIF, and supports breast cancer metastasis [#4]. Beyond recycling, RAB22A nucleates a non-canonical secretory autophagy pathway: it engages PI4K2A to generate PI4P that recruits the ATG12\\u2013ATG5\\u2013ATG16L1 complex, building ER-derived non-canonical autophagosomes that fuse with RAB22A-positive endosomes to form the Rafeesome, while RAB22A-mediated RAB7 inactivation prevents lysosomal fusion and enables secretion of activated STING-containing vesicles for antitumor immunity [#14, #22]. In osteosarcoma, chromosomal translocation\\u2013derived Rab22a-NeoF1 fusion proteins use the RAB22A 1\\u201338 moiety to bind SmgGDS-607 and release GTP-bound RhoA, activating RhoA to drive lung metastasis; this fusion is controlled by p300/CBP acetylation at K7 and by PINK1/STUB1-directed lysosomal degradation [#9, #10, #15].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established RAB22A as an endosome-associated GTPase whose nucleotide state controls endocytic function, answering where the protein acts and that its activity cycle matters.\",\n      \"evidence\": \"GFP-tagged constructs, Q64L/S19N mutagenesis and fluid-phase endocytosis assays in CHO cells\",\n      \"pmids\": [\"11739636\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No effectors or GEF/GAP identified\", \"Mechanism linking GTPase state to endosome enlargement unresolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined RAB22A's specific role in clathrin-independent recycling, showing activation drives tubule formation while inactivation is needed for surface fusion, and that it acts at a step distinct from RAB11A.\",\n      \"evidence\": \"Dominant-negative/constitutively active mutants, siRNA, MHCI recycling and epistasis analysis\",\n      \"pmids\": [\"15181155\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tubulation machinery downstream of RAB22A not identified\", \"Mechanism coupling inactivation to fusion unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Extended RAB22A function to endosome-to-TGN retrograde transport, distinguishing it from endosome-to-lysosome routes.\",\n      \"evidence\": \"Mutant expression, cholera toxin retrograde and CI-M6PR localization assays in CHO cells\",\n      \"pmids\": [\"15748882\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab overexpression readout\", \"No retrograde effectors defined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed RAB22A sorts transferrin receptor from sorting to recycling endosomes and organizes the perinuclear recycling center, broadening it beyond clathrin-independent cargo.\",\n      \"evidence\": \"Wild-type/Q64L expression, siRNA, kinetic transferrin recycling in CHO and HeLa cells\",\n      \"pmids\": [\"16537905\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular sorting machinery not identified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connected RAB22A to hypoxia-driven microvesicle shedding and metastasis, linking endosomal recycling to extracellular vesicle biology in cancer.\",\n      \"evidence\": \"HIF manipulation, RAB22A siRNA, microvesicle quantification, orthotopic breast cancer xenograft\",\n      \"pmids\": [\"24938788\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of vesicle budding by RAB22A not resolved at this stage\", \"Cargo content of microvesicles undefined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated RAB22A is required for MHC-I recycling and antigen cross-presentation in dendritic cells, giving the recycling pathway an immunological output.\",\n      \"evidence\": \"siRNA knockdown, MHC-I trafficking and multiple cross-presentation assays in DCs\",\n      \"pmids\": [\"27861124\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Effectors mediating MHC-I recycling in DCs not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified CD147 as a RAB22A-dependent recycling cargo, tying RAB22A recycling activity to tumor cell migration.\",\n      \"evidence\": \"Co-IP, siRNA, CD147 recycling and migration/invasion assays\",\n      \"pmids\": [\"28433697\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study\", \"Direct binding interface unmapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Resolved the recycling endosome machinery by placing RAB22A upstream of the BLOC-1\\u2013BLOC-2\\u2013KIF13A complex as its membrane organizer.\",\n      \"evidence\": \"RNAi screen, Co-IP, live-cell RE dynamics and cargo recycling in melanocytes\",\n      \"pmids\": [\"30404817\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How RAB22A recruits the complex mechanistically not fully defined at this stage\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linked RAB22A to ER-derived protein delivery at endosomes and antigen translocation to the cytosol in dendritic cells.\",\n      \"evidence\": \"siRNA in DCs, ER marker immunofluorescence, cytosol translocation assay\",\n      \"pmids\": [\"28960134\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab functional study\", \"Molecular basis of ER-endosome contribution unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Discovered the oncogenic Rab22a-NeoF1 fusion mechanism, showing the RAB22A 1\\u201338 moiety binds SmgGDS-607 to release active RhoA and drive osteosarcoma lung metastasis.\",\n      \"evidence\": \"Fusion gene sequencing, Co-IP, RhoA-GTP assay, peptide disruption in orthotopic model\",\n      \"pmids\": [\"32483387\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship of fusion to wild-type RAB22A function not addressed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified K7 acetylation by p300/CBP as a switch controlling Rab22a-NeoF1 binding to SmgGDS-607 and its pro-metastatic activity.\",\n      \"evidence\": \"MS K7ac identification, K7R mutagenesis, Co-IP, RhoA assay, migration and orthotopic metastasis model\",\n      \"pmids\": [\"32685017\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether wild-type RAB22A is similarly regulated unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placed RAB22A downstream of RAB14 in epithelial polarity through an EFA6\\u2013Arf6 axis.\",\n      \"evidence\": \"siRNA, 3D MDCK lumen assay, Co-IP with EFA6, Arf6 activity assay, epistasis rescue\",\n      \"pmids\": [\"32281471\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study\", \"Direct vs indirect EFA6 interaction not fully resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided the molecular mechanism of motor activation, showing RAB22A binds KIF13A NC-CC1 domains to relieve autoinhibition and promote dimerization for endosome tubulation.\",\n      \"evidence\": \"Single-molecule fluorescence and in vitro motility assays, domain mutagenesis, Co-IP\",\n      \"pmids\": [\"33536208\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the RAB22A-KIF13A interface not solved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed how Rab22a-NeoF1 is exported and spreads metastatic signaling via HSP90/KFERQ-mediated exosomal sorting with PYK2.\",\n      \"evidence\": \"Co-IP, exosome isolation, KFERQ motif mutagenesis, RhoA/STAT3 assays, lung metastasis model\",\n      \"pmids\": [\"33568623\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether wild-type RAB22A uses the same export route unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established RAB22A as the nucleator of a non-canonical secretory autophagy pathway (Rafeesome) that secretes activated STING via PI4K2A-PI4P-ATG engagement and RAB7 inactivation.\",\n      \"evidence\": \"Co-IP, PI4P lipid assay, organelle colocalization, RAB7 activity assay, EM, IFN\\u03b2 secretion and tumor model\",\n      \"pmids\": [\"36280710\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How RAB22A selects ER membrane for autophagosome formation not yet defined here\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined the STUB1/NDP52/PINK1-driven lysosomal degradation pathway controlling Rab22a-NeoF1 levels and identified it as a druggable node.\",\n      \"evidence\": \"E3 screening, ubiquitination assay, K112R/S120A mutagenesis, PINK1 kinase assay, metastasis model\",\n      \"pmids\": [\"36529692\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether wild-type RAB22A is regulated by the same axis unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked RAB22A to PI3K/Akt/mTOR signaling via direct interaction with PI3K p85\\u03b1 in lung adenocarcinoma.\",\n      \"evidence\": \"Co-IP, siRNA/overexpression, phospho-Western blots, proliferation/migration assays, rapamycin rescue\",\n      \"pmids\": [\"35487271\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study\", \"Direct binding interface not mapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed RAB22A cooperates with RAB5 and viral NS4B to facilitate classical swine fever virus entry through early endosomes.\",\n      \"evidence\": \"GST pull-down, Co-IP with nucleotide-state mutants, confocal colocalization, viral replication assay\",\n      \"pmids\": [\"35134740\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study\", \"Relevance to human pathogens not addressed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified Vps9d1 as the specific GEF that activates RAB22A to drive tubular endosome formation, defining the upstream activation input.\",\n      \"evidence\": \"siRNA, GEF activity assay, constitutively active RAB22A rescue, RAB5A controls, CIE cargo assays\",\n      \"pmids\": [\"36762583\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Spatial/temporal regulation of Vps9d1 recruitment unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Dissected how RAB22A coordinates RAB7A inactivation (via TBC1D2B) and RAB11A activation (via SH3BP5L) to recycle EGFR into microvesicles, with EGFR feedback phosphorylating RAB22A at Tyr136.\",\n      \"evidence\": \"RAB RNAi screen, Co-IP of effectors, RAB7A/RAB11A activity assays, EGFR phospho-assay, MV isolation\",\n      \"pmids\": [\"39051763\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of effector switching unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified TBC1D31 as a RAB22A GAP that limits RAB22A-mediated EGFR endolysosomal degradation and thereby sustains EGFR signaling in HCC.\",\n      \"evidence\": \"GAP activity assay, EGFR trafficking assay, Co-IP, HCC in vitro/in vivo models\",\n      \"pmids\": [\"39206796\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study\", \"Regulation of TBC1D31 recruitment unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Reported an endogenous HIF-1\\u03b1\\u2013RAB22A complex under hypoxia, but only in endogenous context.\",\n      \"evidence\": \"Co-IP of endogenous proteins and molecular docking; overexpression showed no interaction\",\n      \"pmids\": [\"38647725\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP, not reciprocally validated\", \"Negative overexpression result limits interpretation\", \"Functional consequence undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a RAB22A\\u2013PKM2\\u2013pSNAP-23 cascade that boosts exosome secretion and transmits chemoresistance in colorectal cancer.\",\n      \"evidence\": \"Co-IP, ubiquitination and SNAP-23 phospho-assays, exosome isolation, conditioned medium transfer\",\n      \"pmids\": [\"40957949\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study\", \"Direct vs indirect PKM2 interaction unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved the ER membrane source of Rafeesome vesicles, showing RAB22A/TMEM33/RTN4 assembly drives RTN4 oligomerization and curvature for ATG9A-mediated non-canonical autophagosome formation.\",\n      \"evidence\": \"Co-IP of multi-protein assembly, RTN4 TM2 mutagenesis, oligomerization assay, EM, secretion assay\",\n      \"pmids\": [\"40301304\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How RAB22A nucleotide state regulates the assembly not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how RAB22A's GTPase cycle is spatially coordinated to switch between its recycling, retrograde, secretory-autophagy, and vesicle-shedding roles, and whether the diverse cancer-associated signaling interactions reflect a single unifying biochemical mechanism.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of RAB22A bound to its competing effectors\", \"Determinants selecting recycling vs secretory-autophagy fate unknown\", \"Relationship between wild-type RAB22A regulation and Rab22a-NeoF1 fusion regulation unclear\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [0, 1, 19]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [9, 13, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 1, 3, 7, 14]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [14, 22]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 4, 18]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [1, 3, 7, 18]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [4, 18, 21]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [14, 22]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5, 14]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [9, 10, 12, 15]}\n    ],\n    \"complexes\": [\n      \"BLOC-1\\u2013BLOC-2\\u2013KIF13A complex\",\n      \"Rafeesome\",\n      \"RAB22A/TMEM33/RTN4 assembly\"\n    ],\n    \"partners\": [\n      \"KIF13A\",\n      \"Vps9d1\",\n      \"TBC1D2B\",\n      \"SH3BP5L\",\n      \"PI4K2A\",\n      \"TMEM33\",\n      \"EFA6\",\n      \"TBC1D31\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}