{"gene":"SIDT2","run_date":"2026-06-10T07:46:32","timeline":{"discoveries":[{"year":2016,"finding":"SIDT2 is a transmembrane lysosomal integral membrane protein that mediates direct RNA translocation across the lysosomal membrane during RNautophagy; gain- and loss-of-function studies with isolated lysosomes showed SIDT2 knockdown inhibited ~50% of total cellular RNA degradation independently of macroautophagy.","method":"Gain- and loss-of-function studies with isolated lysosomes; subcellular fractionation; immunofluorescence with lysosomal markers","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain/loss-of-function in isolated lysosomes, replicated across multiple papers from independent groups","pmids":["27046251"],"is_preprint":false},{"year":2010,"finding":"SIDT2 is a highly glycosylated lysosomal integral membrane protein; its lysosomal localization was determined by immunofluorescence with lysosomal markers and subcellular fractionation, and its apparent molecular weight (~120–130 kDa) decreases to ~95 kDa after PNGase F digestion, confirming extensive N-glycosylation.","method":"Immunofluorescence, subcellular fractionation, PNGase F digestion, Western blot","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (fractionation, immunofluorescence, enzymatic deglycosylation), replicated in subsequent studies","pmids":["20965152"],"is_preprint":false},{"year":2016,"finding":"SIDT2 also mediates DNA translocation during DNautophagy, the direct uptake of DNA by lysosomes in an ATP-dependent manner.","method":"Gain- and loss-of-function studies with isolated lysosomes","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isolated lysosome assay, single lab, consistent with prior RNA transport findings","pmids":["27846365"],"is_preprint":false},{"year":2017,"finding":"SIDT2 is required for transport of internalized extracellular dsRNA from endocytic compartments into the cytoplasm for innate immune activation; Sidt2-deficient mice show impaired antiviral cytokine production and reduced survival upon EMCV and HSV-1 infection.","method":"Sidt2 knockout mouse model; virus challenge (EMCV, HSV-1); cytokine production assays; extracellular dsRNA treatment","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockout with defined survival and cytokine phenotypes, multiple viral challenges, replicated across pathogens","pmids":["28916264"],"is_preprint":false},{"year":2017,"finding":"Three cytosolic YxxΦ motifs in SIDT2 are required for its lysosomal localization; SIDT2 interacts with adaptor protein complexes AP-1 and AP-2, and this lysosomal targeting is necessary for its function in RNautophagy. Overexpression of SIDT2 substantially increases endogenous RNA degradation at the cellular level.","method":"Mutagenesis of YxxΦ motifs; co-immunoprecipitation with AP-1 and AP-2; live-cell imaging; RNA degradation assays","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — mutagenesis with functional readout, Co-IP with adaptor complexes, multiple orthogonal methods in one study","pmids":["28724756"],"is_preprint":false},{"year":2017,"finding":"SIDT2 mediates gymnosis — the uptake of naked single-stranded oligonucleotides (ssOligos) into living cells; SIDT2 knockdown significantly reduced ssOligo uptake, overexpression enhanced it, and a single amino acid mutation in SIDT2 abolished the enhancing effect.","method":"siRNA knockdown; overexpression; single amino acid mutagenesis; fluorescent ssOligo uptake assay","journal":"RNA biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function, gain-of-function, and mutagenesis with quantitative uptake readout, single lab","pmids":["28277980"],"is_preprint":false},{"year":2020,"finding":"SIDT2 directly binds RNA and DNA through an arginine-rich motif (ARM) in its main cytosolic domain; disruption of this ARM dramatically impairs SIDT2-mediated RNautophagic activity. SIDT2 ARM also mediates interaction with the CAG repeat-containing HTT exon 1 transcript, and overexpression of SIDT2 promoted HTT mRNA degradation and reduced polyQ-expanded HTT aggregates. SIDT2 and LAMP2C ARM motifs act synergistically in RNautophagy.","method":"In vitro binding assays (GST pulldown); ARM mutagenesis; cellular RNautophagy activity assays; Western blot for HTT aggregates; co-expression/synergy experiments","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro binding reconstitution combined with mutagenesis and functional cellular assay, multiple orthogonal methods in one study","pmids":["31944164"],"is_preprint":false},{"year":2017,"finding":"SIDT2 overexpressed in HEK293 cells reaches the plasma membrane and functions as a spontaneous, non-inactivating monovalent cation channel, causing cell depolarization upon sodium addition; strong overexpression leads to significant reduction/loss of detectable lysosomes.","method":"Heterologous overexpression in HEK293 cells; whole-cell patch clamp electrophysiology; lysosome detection assays","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — direct electrophysiology (patch clamp), but single lab, single study, and the cation channel activity was measured under overexpression conditions that also displace protein to plasma membrane","pmids":["27987306"],"is_preprint":false},{"year":2013,"finding":"Sidt2-deficient (knockout) mice exhibit glucose intolerance, decreased serum insulin, hypertrophic islets with accumulation of insulin secretory granules, and impaired glucose-stimulated insulin secretion; isolated Sidt2−/− islets produce less insulin upon glucose or KCl stimulation, indicating a role for Sidt2 in insulin secretory granule exocytosis.","method":"Global Sidt2 knockout mouse; glucose tolerance tests; isolated islet insulin secretion assays; electron microscopy; Western blot; immunofluorescence","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal readouts (in vivo and ex vivo), electron microscopy of granule morphology, replicated in subsequent studies","pmids":["23776622"],"is_preprint":false},{"year":2016,"finding":"SIDT2 is involved in NAADP-mediated calcium release from intracellular acidic compartments (insulin secretory granules) in pancreatic β-cells; Sidt2−/− β-cells show reduced glucose-induced [Ca2+]i peak, which is normalized by exogenous NAADP application, while bafilomycin A1 treatment equalized [Ca2+]i responses between Sidt2−/− and WT cells.","method":"Primary β-cell culture from Sidt2−/− mice; calcium imaging; pharmacological inhibitors (ryanodine, 2-APB, bafilomycin A1, NAADP); patch clamp for KATP and KV currents","journal":"Journal of molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pharmacological approaches with calcium imaging in primary cells, single lab","pmids":["26744456"],"is_preprint":false},{"year":2018,"finding":"Hepatocyte-specific effects of Sidt2 deficiency include lipid droplet accumulation and impaired hepatic β-oxidation with decreased autophagic flux; Sidt2−/− mice show block of autophagosome maturation as evidenced by elevated p62 and LC3-II and accumulation of autophagolysosomes by electron microscopy.","method":"Global Sidt2 knockout mouse; serum β-hydroxybutyrate measurement; Western blot for p62 and LC3-II; electron microscopy; primary hepatocyte autophagic flux assays","journal":"Journal of lipid research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo knockout with multiple biochemical and ultrastructural readouts, single lab","pmids":["29363559"],"is_preprint":false},{"year":2018,"finding":"Skeletal muscle-specific Sidt2 knockout mice develop a muscular dystrophy-like phenotype with accumulation of autophagolysosomes, increased LC3-II, p62, ubiquitinated aggregates, and LAMP2-positive vacuoles, while proteasome and lysosomal soluble enzyme activities were unimpaired, indicating a specific role for Sidt2 in the late stage of autophagy in muscle.","method":"Muscle-specific Sidt2 knockout mouse (Cre/LoxP); morphologic and functional studies; Western blot; immunostaining; genechip RNA expression analysis; proteasome activity assay; lysosomal enzyme activity assay","journal":"Metabolism: clinical and experimental","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — tissue-specific KO with multiple phenotypic readouts and enzymatic controls, single lab","pmids":["29752955"],"is_preprint":false},{"year":2021,"finding":"Sidt2 deletion in kidney (Sidt2−/− mice) impairs lysosomal function (decreased acidic lysosomes, reduced acid hydrolase activity, elevated lysosomal pH), blocks autophagosome–lysosome fusion and autolysosome degradation, and leads to structural and functional kidney damage (basement membrane thickening, podocyte foot process fusion, proteinuria).","method":"Sidt2 knockout mouse; LysoTracker staining; lysosomal enzyme activity assays; LC3-II/p62 Western blot; immunofluorescence for autophagosome-lysosome fusion; Ad-mcherry-GFP-LC3B; chloroquine experiments; electron microscopy","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal assays in vivo and in vitro, single lab","pmids":["34923568"],"is_preprint":false},{"year":2021,"finding":"Sidt2 deletion in skeletal muscle reduces expression of mitochondrial fusion protein Mfn2, fission protein Drp1, and PGC1-α, blocks autophagosome–lysosome fusion, impairs clearance of damaged mitochondria, and causes accumulation of structurally abnormal mitochondria with reduced muscle tolerance.","method":"Skeletal muscle-selective Sidt2 knockout mice; Western blot for Mfn2, Drp1, PGC1-α; autophagy flux assays; electron microscopy; functional muscle tests","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — tissue-specific KO with multiple molecular and functional readouts, single lab","pmids":["33715196"],"is_preprint":false},{"year":2019,"finding":"SIDT2 promotes tumor development; Sidt2−/− mice with KrasG12D activation develop significantly fewer lung tumors, and loss of SIDT2 delays intestinal tumor development in Apcmin/+ mice; in the intestine, SIDT2 loss leads to dsRNA accumulation associated with increased eIF2α and JNK phosphorylation and elevated apoptosis.","method":"Sidt2 knockout in KrasG12D lung adenocarcinoma model and Apcmin/+ intestinal cancer model; tumor counting; phospho-eIF2α and phospho-JNK Western blot; apoptosis assays","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic epistasis with two tumor models and downstream signaling readouts, single lab","pmids":["31546103"],"is_preprint":false},{"year":2021,"finding":"SIDT2 forms a complex with apolipoprotein A1 (ApoA1) requiring the second CRAC motif (CRAC-2) in SIDT2; overexpression of SIDT2 enhances ApoA1 secretion from HepG2 hepatocytes, and this effect is abolished when the CRAC-2 domain is mutated.","method":"Co-immunoprecipitation; CRAC-2 domain mutagenesis; ApoA1 secretion assay in HepG2 cells","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with mutagenesis and functional secretion assay, single lab","pmids":["37830567"],"is_preprint":false},{"year":2021,"finding":"SIDT2/Val636Ile missense variant shows increased uptake of the cholesterol analog dehydroergosterol compared to wild-type in vitro, indicating that this variant alters SIDT2's sterol transport function.","method":"In vitro site-directed mutagenesis; dehydroergosterol (fluorescent cholesterol analog) uptake assay","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — direct in vitro functional assay with mutagenesis, single lab, single method","pmids":["34233476"],"is_preprint":false},{"year":2022,"finding":"SIDT2 regulates lysosome cellular location, potentially via interaction with microtubule-related proteins; SIDT2 is required for proper co-localization between phosphorothioate antisense oligonucleotides (PS-ASOs) and lysosomes, and SIDT2 loss reduces PS-ASO lysosomal entrapment and increases ASO activity.","method":"SIDT2 knockdown; PS-ASO co-localization imaging; SIDT2 interactome (MS-based identification of microtubule-related binding partners); lysosome positioning assays","journal":"Nucleic acid therapeutics","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — KD with localization assay and MS interactome, functional ASO activity readout, single lab","pmids":["36576400"],"is_preprint":false},{"year":2021,"finding":"In docetaxel-treated cancer cells, SIDT2 expression is upregulated and mediates lysosomal degradation of miR-25, which in turn increases NOX4 expression; this activates ROS/JNK signaling leading to HuR phosphorylation and TNF-α mRNA stabilization, ultimately causing TNF-α-dependent apoptosis.","method":"siRNA knockdown of SIDT2; chloroquine (lysosome inhibitor) pretreatment; miR-25 quantification; NOX4/ROS/JNK/HuR Western blot; cell viability and apoptosis assays","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with pharmacological inhibition and multiple signaling pathway readouts, single lab","pmids":["34863979"],"is_preprint":false},{"year":2025,"finding":"Biallelic SIDT2 missense variants (p.Arg529Trp, p.Arg678Trp) in a human patient disrupted SIDT2's ability to interact with RNA; patient fibroblasts showed impaired autophagy with abnormal accumulation of autophagy markers, mimicking Sidt2 knockout mouse brain phenotypes including motor incoordination and seizures.","method":"Functional RNA-binding studies of patient variants; patient fibroblast autophagy marker analysis; Sidt2 knockout mouse neurological phenotyping; brain expression analysis","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional variant characterization in patient cells plus animal model neurological phenotypes, single study","pmids":["40541391"],"is_preprint":false},{"year":2025,"finding":"SIDT2 overexpression via AAV vectors in the lateral hypothalamus of R6/2 HD mice reduced mutant huntingtin (mHTT) inclusions; in a neuronal cell model, SIDT2 overexpression reduced soluble and insoluble mHTT exon 1 protein levels, consistent with its known ARM-mediated binding to the expanded CAG repeat in mHTT transcript.","method":"AAV-mediated SIDT2 overexpression in R6/2 mouse hypothalamus; mHTT inclusion quantification by immunohistochemistry; neuronal cell model overexpression with Western blot for mHTT","journal":"Brain pathology (Zurich, Switzerland)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo AAV overexpression and cell model with functional mHTT readout, consistent with prior mechanistic data, single lab","pmids":["41736445"],"is_preprint":false},{"year":2015,"finding":"Sidt2 deficiency in islets correlates with significantly decreased expression of SNARE proteins synaptopodin 1 (synap1) and synaptopodin 3 (synap3), suggesting that Sidt2 regulates insulin secretory granule exocytosis via SNARE-dependent mechanisms.","method":"Sidt2 knockout mouse; gene expression analysis (13-gene panel); in vivo and in vitro insulin secretion assays","journal":"International journal of clinical and experimental pathology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — gene expression correlation only (mRNA level changes), no direct mechanistic link established between SIDT2 and SNARE proteins","pmids":["26884831"],"is_preprint":false},{"year":2025,"finding":"SIDT2 (expressed in human cell lines) enhances knockdown activity of gapmer ASOs and promotes their endosomal escape into the cytosol; a specific region in SIDT2 (identified by chimeric SIDT2/SIDT1 protein analysis) is critical for this activity and distinguishes SIDT2 from SIDT1.","method":"Overexpression of SIDT1 and SIDT2 in human cell lines; gapmer ASO knockdown activity assays; chimeric protein domain-swap analysis","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function with domain-swap chimeras and functional ASO readout, single lab","pmids":["39747556"],"is_preprint":false}],"current_model":"SIDT2 is a highly glycosylated, multi-pass lysosomal integral membrane protein that functions as a nucleic acid transporter: it directly translocates RNA and DNA across the lysosomal membrane (RNautophagy/DNautophagy) via an arginine-rich motif (ARM) in its cytosolic domain that binds nucleic acids, is sorted to lysosomes through three cytosolic YxxΦ motifs via AP-1/AP-2 adaptors, and also transports extracellular dsRNA from endosomes into the cytoplasm to activate innate antiviral immunity; additionally, SIDT2 mediates cellular uptake of single-stranded oligonucleotides (gymnosis), regulates lysosome positioning via microtubule-associated proteins, participates in NAADP-mediated calcium release from acidic compartments to regulate insulin secretion, forms a complex with ApoA1 (requiring its CRAC-2 motif) to enhance ApoA1 secretion, conducts monovalent cations when present at the plasma membrane, and is required for proper autophagosome–lysosome fusion, such that its loss across tissues causes impaired autophagic flux, lipid accumulation, mitochondrial dysfunction, and organ pathology."},"narrative":{"mechanistic_narrative":"SIDT2 is a highly glycosylated, multi-pass lysosomal integral membrane protein that functions as a direct transporter of nucleic acids across the lysosomal membrane, mediating the macroautophagy-independent degradation of RNA (RNautophagy) and DNA (DNautophagy) [PMID:27046251, PMID:20965152, PMID:27846365]. Substrate engagement is achieved through an arginine-rich motif (ARM) in its main cytosolic domain that directly binds RNA and DNA; disrupting this ARM abolishes RNautophagic activity, and the ARM acts synergistically with that of LAMP2C [PMID:31944164]. Correct lysosomal delivery of SIDT2 depends on three cytosolic YxxΦ motifs that recruit the clathrin adaptor complexes AP-1 and AP-2, and this targeting is required for its transport function [PMID:28724756]. Beyond the lysosome, SIDT2 transports internalized extracellular dsRNA from endocytic compartments into the cytoplasm to trigger antiviral innate immunity, with Sidt2-deficient mice showing impaired cytokine responses and reduced survival upon EMCV and HSV-1 infection [PMID:28916264], and it mediates cellular uptake of naked single-stranded oligonucleotides (gymnosis) and modulates the activity and lysosomal entrapment of therapeutic antisense oligonucleotides [PMID:28277980, PMID:36576400, PMID:39747556]. Through its ARM-mediated binding to the expanded CAG-repeat HTT transcript, SIDT2 promotes degradation of mutant huntingtin and reduces polyQ aggregates in cell and mouse HD models [PMID:31944164, PMID:41736445]. Across tissues, loss of SIDT2 impairs autophagosome–lysosome fusion and lysosomal acidification, producing lipid droplet accumulation, mitochondrial dysfunction, and organ pathology in liver, muscle, and kidney [PMID:29363559, PMID:34923568, PMID:33715196], and it contributes to insulin secretory granule exocytosis via NAADP-mediated calcium release from acidic compartments [PMID:23776622, PMID:26744456]. Biallelic SIDT2 missense variants that disrupt RNA binding cause a human disorder with impaired autophagy, motor incoordination, and seizures recapitulating the knockout mouse brain phenotype [PMID:40541391].","teleology":[{"year":2010,"claim":"Establishing where SIDT2 resides and its post-translational state was the necessary first step before any transport function could be assigned.","evidence":"Immunofluorescence, subcellular fractionation, and PNGase F deglycosylation","pmids":["20965152"],"confidence":"High","gaps":["Did not define topology or number of transmembrane passes","No functional activity assigned"]},{"year":2013,"claim":"Whole-animal knockout first connected SIDT2 to a physiological process, revealing a requirement for insulin secretory granule exocytosis and glucose homeostasis.","evidence":"Global Sidt2 knockout mouse with glucose tolerance tests, islet secretion assays, and electron microscopy","pmids":["23776622"],"confidence":"High","gaps":["Molecular mechanism linking SIDT2 to granule exocytosis unresolved","Did not connect phenotype to lysosomal transport activity"]},{"year":2015,"claim":"An attempt to mechanistically link SIDT2 to the secretory machinery pointed to SNARE protein expression changes.","evidence":"Knockout mouse islet gene-expression panel and insulin secretion assays","pmids":["26884831"],"confidence":"Low","gaps":["Correlative mRNA changes only, no direct mechanistic link between SIDT2 and SNARE proteins","No protein-level or interaction evidence"]},{"year":2016,"claim":"The defining molecular function emerged: SIDT2 directly translocates RNA, and then DNA, across the lysosomal membrane, accounting for a large fraction of cellular RNA degradation independent of macroautophagy.","evidence":"Reciprocal gain/loss-of-function in isolated lysosomes (RNautophagy); ATP-dependent DNA uptake assays (DNautophagy)","pmids":["27046251","27846365"],"confidence":"High","gaps":["Mechanism of translocation across the bilayer not resolved","DNautophagy shown by single lab"]},{"year":2016,"claim":"Pharmacological dissection placed SIDT2 in NAADP-mediated calcium release from acidic granules, linking its lysosomal role to the earlier insulin phenotype.","evidence":"Calcium imaging in Sidt2−/− primary β-cells with NAADP, bafilomycin A1, and other inhibitors","pmids":["26744456"],"confidence":"Medium","gaps":["Does not establish whether SIDT2 directly conducts or gates calcium release","Single lab"]},{"year":2017,"claim":"The sorting logic and immune relevance of SIDT2 were defined: YxxΦ/AP-dependent lysosomal targeting underlies its degradative function, and it routes extracellular dsRNA to the cytoplasm for antiviral defense.","evidence":"YxxΦ mutagenesis with AP-1/AP-2 Co-IP and RNA degradation assays; Sidt2 knockout mouse viral challenge with cytokine assays","pmids":["28724756","28916264"],"confidence":"High","gaps":["How the same protein switches between lysosomal degradation and endosome-to-cytosol delivery unclear","Cytosolic sensors activated downstream not defined in these findings"]},{"year":2017,"claim":"Additional transport behaviors were characterized — uptake of naked ssOligos (gymnosis) and, under heterologous overexpression, monovalent cation channel activity at the plasma membrane.","evidence":"siRNA/overexpression/single-residue mutagenesis with ssOligo uptake assay; whole-cell patch clamp in HEK293 overexpression","pmids":["28277980","27987306"],"confidence":"Medium","gaps":["Channel activity measured under overexpression that mislocalizes protein to plasma membrane","Physiological relevance of cation conductance unestablished"]},{"year":2018,"claim":"Tissue-specific knockouts established that SIDT2 is broadly required for the late stage of autophagy, with loss blocking autophagosome maturation and causing lipid and aggregate accumulation in liver and muscle.","evidence":"Global and muscle-specific knockout mice with p62/LC3-II Western blot, electron microscopy, and β-oxidation/enzyme-activity controls","pmids":["29363559","29752955"],"confidence":"Medium","gaps":["Mechanistic link between nucleic acid transport and autophagosome–lysosome fusion not resolved","Single lab per tissue"]},{"year":2019,"claim":"Genetic epistasis revealed a pro-tumorigenic role, with SIDT2 loss reducing tumor burden and causing dsRNA accumulation coupled to stress signaling and apoptosis.","evidence":"Sidt2 knockout in KrasG12D lung and Apcmin/+ intestinal tumor models with phospho-eIF2α/JNK and apoptosis readouts","pmids":["31546103"],"confidence":"Medium","gaps":["Causal chain from dsRNA accumulation to tumorigenesis not fully dissected","Single lab"]},{"year":2020,"claim":"The substrate-binding determinant was localized to an arginine-rich motif in the cytosolic domain that directly binds nucleic acids and engages the expanded HTT transcript, providing a molecular handle for its degradative function.","evidence":"GST pulldown in vitro binding, ARM mutagenesis, cellular RNautophagy assays, and HTT aggregate Western blots","pmids":["31944164"],"confidence":"High","gaps":["Structure of the ARM–RNA complex not determined","How ARM binding couples to membrane translocation unknown"]},{"year":2021,"claim":"A series of studies expanded SIDT2 into lysosome positioning, lipid handling, mitochondrial quality control, sterol transport, and ApoA1 secretion, broadening its functional footprint beyond nucleic acid transport.","evidence":"Kidney and muscle tissue-specific knockouts; CRAC-2 mutagenesis and Co-IP with ApoA1; dehydroergosterol uptake with a missense variant; miR-25/NOX4/ROS signaling in docetaxel-treated cells","pmids":["34923568","33715196","34233476","37830567","34863979"],"confidence":"Medium","gaps":["Whether these activities share a common transport mechanism is unresolved","Several rest on single-lab Co-IP or single-method assays"]},{"year":2022,"claim":"An interactome and imaging study connected SIDT2 to microtubule-associated proteins and lysosome positioning, and to entrapment and activity of therapeutic antisense oligonucleotides.","evidence":"SIDT2 knockdown with PS-ASO co-localization imaging and MS-based interactome","pmids":["36576400"],"confidence":"Medium","gaps":["Direct interaction with named motor/microtubule proteins not validated","Mechanism linking SIDT2 to lysosome positioning unknown"]},{"year":2025,"claim":"Human genetics and therapeutic modeling closed the loop: biallelic RNA-binding-disrupting variants cause a neurological disorder mirroring the knockout, and SIDT2 overexpression clears mutant huntingtin in HD models.","evidence":"Patient variant RNA-binding and fibroblast autophagy analysis with knockout mouse phenotyping; AAV-mediated SIDT2 overexpression in R6/2 mouse hypothalamus and neuronal cells; gapmer ASO domain-swap analysis","pmids":["40541391","41736445","39747556"],"confidence":"Medium","gaps":["Disease established from a single patient study","Therapeutic durability and off-target consequences of SIDT2 overexpression unaddressed"]},{"year":null,"claim":"The unifying biophysical question — how SIDT2 physically translocates large nucleic acids and oligonucleotides across a membrane, and whether its diverse reported activities (cation conduction, sterol uptake, calcium release, ApoA1 binding) reflect one transport mechanism or distinct functions — remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of SIDT2 or its transport pore","Transport stoichiometry and energetics undefined","Unclear whether lysosomal and plasma-membrane functions coexist physiologically"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[6,19]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[6,2]},{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,2,3,5]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[3,17]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[10,11,12]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,6]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[4]}],"complexes":[],"partners":["AP1","AP2","LAMP2","APOA1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8NBJ9","full_name":"SID1 transmembrane family member 2","aliases":[],"length_aa":832,"mass_kda":94.5,"function":"Mediates the translocation of RNA and DNA across the lysosomal membrane during RNA and DNA autophagy (RDA), a process in which RNA or DNA is directly imported into lysosomes in an ATP-dependent manner, and degraded (PubMed:27046251, PubMed:27846365). Involved in the uptake of single-stranded oligonucleotides by living cells, a process called gymnosis (PubMed:28277980). In vitro, mediates the uptake of linear DNA more efficiently than that of circular DNA, but exhibits similar uptake efficacy toward RNA and DNA. Binds long double-stranded RNA (dsRNA) (500 - 700 base pairs), but not dsRNA shorter than 100 bp (By similarity)","subcellular_location":"Lysosome membrane; Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q8NBJ9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SIDT2","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":[],"url":"https://opencell.sf.czbiohub.org/search/SIDT2","total_profiled":1310},"omim":[{"mim_id":"617551","title":"SID1 TRANSMEMBRANE FAMILY, MEMBER 2; SIDT2","url":"https://www.omim.org/entry/617551"},{"mim_id":"606816","title":"SID1 TRANSMEMBRANE FAMILY, MEMBER 1; SIDT1","url":"https://www.omim.org/entry/606816"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SIDT2"},"hgnc":{"alias_symbol":["CGI-40"],"prev_symbol":[]},"alphafold":{"accession":"Q8NBJ9","domains":[{"cath_id":"2.60.120.380","chopping":"26-152","consensus_level":"medium","plddt":87.3709,"start":26,"end":152},{"cath_id":"2.60.120.380","chopping":"156-259_274-288","consensus_level":"medium","plddt":91.2046,"start":156,"end":288},{"cath_id":"-","chopping":"426-608_728-829","consensus_level":"high","plddt":89.2651,"start":426,"end":829}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NBJ9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NBJ9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NBJ9-F1-predicted_aligned_error_v6.png","plddt_mean":80.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SIDT2","jax_strain_url":"https://www.jax.org/strain/search?query=SIDT2"},"sequence":{"accession":"Q8NBJ9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8NBJ9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8NBJ9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NBJ9"}},"corpus_meta":[{"pmid":"28916264","id":"PMC_28916264","title":"SIDT2 Transports Extracellular dsRNA into the Cytoplasm for Innate Immune Recognition.","date":"2017","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/28916264","citation_count":107,"is_preprint":false},{"pmid":"27046251","id":"PMC_27046251","title":"Lysosomal putative RNA transporter SIDT2 mediates direct uptake of RNA by lysosomes.","date":"2016","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/27046251","citation_count":84,"is_preprint":false},{"pmid":"20965152","id":"PMC_20965152","title":"SID1 transmembrane family, member 2 (Sidt2): a novel lysosomal membrane protein.","date":"2010","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/20965152","citation_count":57,"is_preprint":false},{"pmid":"31944164","id":"PMC_31944164","title":"Cytosolic domain of SIDT2 carries an arginine-rich motif that binds to RNA/DNA and is important for the direct transport of nucleic acids into lysosomes.","date":"2020","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/31944164","citation_count":45,"is_preprint":false},{"pmid":"27846365","id":"PMC_27846365","title":"Lysosomal membrane protein SIDT2 mediates the direct uptake of DNA by lysosomes.","date":"2016","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/27846365","citation_count":45,"is_preprint":false},{"pmid":"28277980","id":"PMC_28277980","title":"SIDT2 mediates gymnosis, the uptake of naked single-stranded oligonucleotides into living cells.","date":"2017","source":"RNA biology","url":"https://pubmed.ncbi.nlm.nih.gov/28277980","citation_count":38,"is_preprint":false},{"pmid":"29363559","id":"PMC_29363559","title":"Sidt2 regulates hepatocellular lipid metabolism through autophagy.","date":"2018","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/29363559","citation_count":34,"is_preprint":false},{"pmid":"23776622","id":"PMC_23776622","title":"Impaired glucose tolerance in a mouse model of sidt2 deficiency.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23776622","citation_count":34,"is_preprint":false},{"pmid":"34923568","id":"PMC_34923568","title":"Sidt2 is a key protein in the autophagy-lysosomal degradation pathway and is essential for the maintenance of kidney structure and filtration function.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/34923568","citation_count":31,"is_preprint":false},{"pmid":"27233614","id":"PMC_27233614","title":"Spontaneous nonalcoholic fatty liver disease and ER stress in Sidt2 deficiency mice.","date":"2016","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/27233614","citation_count":31,"is_preprint":false},{"pmid":"31546103","id":"PMC_31546103","title":"SIDT2 RNA Transporter Promotes Lung and Gastrointestinal Tumor Development.","date":"2019","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/31546103","citation_count":23,"is_preprint":false},{"pmid":"34781815","id":"PMC_34781815","title":"Long non-coding RNA LIFR-AS1 suppressed the proliferation, angiogenesis, migration and invasion of papillary thyroid cancer cells via the miR-31-5p/SIDT2 axis.","date":"2021","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/34781815","citation_count":22,"is_preprint":false},{"pmid":"26884831","id":"PMC_26884831","title":"Lysosomal integral membrane protein Sidt2 plays a vital role in insulin secretion.","date":"2015","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/26884831","citation_count":21,"is_preprint":false},{"pmid":"34863979","id":"PMC_34863979","title":"Docetaxel-triggered SIDT2/NOX4/JNK/HuR signaling axis is associated with TNF-α-mediated apoptosis of cancer cells.","date":"2021","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/34863979","citation_count":20,"is_preprint":false},{"pmid":"28724756","id":"PMC_28724756","title":"Lysosomal targeting of SIDT2 via multiple YxxΦ motifs is required for SIDT2 function in the process of RNautophagy.","date":"2017","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/28724756","citation_count":19,"is_preprint":false},{"pmid":"30382898","id":"PMC_30382898","title":"Multiple genotype-phenotype association study reveals intronic variant pair on SIDT2 associated with metabolic syndrome in a Korean population.","date":"2018","source":"Human genomics","url":"https://pubmed.ncbi.nlm.nih.gov/30382898","citation_count":18,"is_preprint":false},{"pmid":"26744456","id":"PMC_26744456","title":"SIDT2 is involved in the NAADP-mediated release of calcium from insulin secretory granules.","date":"2016","source":"Journal of molecular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/26744456","citation_count":17,"is_preprint":false},{"pmid":"21334374","id":"PMC_21334374","title":"Cloning, characterization, and biological function analysis of the SidT2 gene from Siniperca chuatsi.","date":"2011","source":"Developmental and comparative immunology","url":"https://pubmed.ncbi.nlm.nih.gov/21334374","citation_count":17,"is_preprint":false},{"pmid":"34233476","id":"PMC_34233476","title":"Genome-Wide Association Study Identifies a Functional SIDT2 Variant Associated With HDL-C (High-Density Lipoprotein Cholesterol) Levels and Premature Coronary Artery Disease.","date":"2021","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/34233476","citation_count":16,"is_preprint":false},{"pmid":"32964053","id":"PMC_32964053","title":"Effect of sidt2 Gene on Cell Insulin Resistance and Its Molecular Mechanism.","date":"2020","source":"Journal of diabetes research","url":"https://pubmed.ncbi.nlm.nih.gov/32964053","citation_count":14,"is_preprint":false},{"pmid":"29752955","id":"PMC_29752955","title":"Skeletal muscle-specific Sidt2 knockout in mice induced muscular dystrophy-like phenotype.","date":"2018","source":"Metabolism: clinical and experimental","url":"https://pubmed.ncbi.nlm.nih.gov/29752955","citation_count":14,"is_preprint":false},{"pmid":"29896245","id":"PMC_29896245","title":"Changes of lysosomal membrane permeabilization and lipid metabolism in sidt2 deficient mice.","date":"2018","source":"Experimental and therapeutic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29896245","citation_count":14,"is_preprint":false},{"pmid":"27987306","id":"PMC_27987306","title":"Identification of Sidt2 as a lysosomal cation-conducting protein.","date":"2017","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/27987306","citation_count":13,"is_preprint":false},{"pmid":"33715196","id":"PMC_33715196","title":"The lysosomal membrane protein Sidt2 is a vital regulator of mitochondrial quality control in skeletal muscle.","date":"2021","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/33715196","citation_count":11,"is_preprint":false},{"pmid":"34800582","id":"PMC_34800582","title":"Pathology-associated change in levels and localization of SIDT2 in postmortem brains of Parkinson's disease and dementia with Lewy bodies patients.","date":"2021","source":"Neurochemistry international","url":"https://pubmed.ncbi.nlm.nih.gov/34800582","citation_count":11,"is_preprint":false},{"pmid":"32565723","id":"PMC_32565723","title":"The Effects of Sidt2 on the Inflammatory Pathway in Mouse Mesangial Cells.","date":"2020","source":"Mediators of inflammation","url":"https://pubmed.ncbi.nlm.nih.gov/32565723","citation_count":10,"is_preprint":false},{"pmid":"37451322","id":"PMC_37451322","title":"Amsacrine downregulates BCL2L1 expression and triggers apoptosis in human chronic myeloid leukemia cells through the SIDT2/NOX4/ERK/HuR pathway.","date":"2023","source":"Toxicology and applied pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/37451322","citation_count":10,"is_preprint":false},{"pmid":"29404214","id":"PMC_29404214","title":"Gene-based association study for lipid traits in diverse cohorts implicates BACE1 and SIDT2 regulation in triglyceride levels.","date":"2018","source":"PeerJ","url":"https://pubmed.ncbi.nlm.nih.gov/29404214","citation_count":10,"is_preprint":false},{"pmid":"35302183","id":"PMC_35302183","title":"Effects of SIDT2 on the miR-25/NOX4/HuR axis and SIRT3 mRNA stability lead to ROS-mediated TNF-α expression in hydroquinone-treated leukemia cells.","date":"2022","source":"Cell biology and toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/35302183","citation_count":9,"is_preprint":false},{"pmid":"36176242","id":"PMC_36176242","title":"The functions of SID1 transmembrane family, member 2 (Sidt2).","date":"2022","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/36176242","citation_count":7,"is_preprint":false},{"pmid":"36678241","id":"PMC_36678241","title":"Interaction between SIDT2 and ABCA1 Variants with Nutrients on HDL-c Levels in Mexican Adults.","date":"2023","source":"Nutrients","url":"https://pubmed.ncbi.nlm.nih.gov/36678241","citation_count":6,"is_preprint":false},{"pmid":"39976027","id":"PMC_39976027","title":"Dihydromyricetin Improves Myocardial Functioning by Influencing Autophagy Through SNHG17/Mir-34a/SIDT2 Axis.","date":"2024","source":"Current molecular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39976027","citation_count":6,"is_preprint":false},{"pmid":"33066450","id":"PMC_33066450","title":"The Variant rs1784042 of the SIDT2 Gene is Associated with Metabolic Syndrome through Low HDL-c Levels in a Mexican Population.","date":"2020","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/33066450","citation_count":6,"is_preprint":false},{"pmid":"37830567","id":"PMC_37830567","title":"SIDT2 Associates with Apolipoprotein A1 (ApoA1) and Facilitates ApoA1 Secretion in Hepatocytes.","date":"2023","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/37830567","citation_count":5,"is_preprint":false},{"pmid":"36576400","id":"PMC_36576400","title":"SIDT2 Inhibits Phosphorothioate Antisense Oligonucleotide Activity by Regulating Cellular Localization of Lysosomes.","date":"2022","source":"Nucleic acid therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/36576400","citation_count":5,"is_preprint":false},{"pmid":"37202201","id":"PMC_37202201","title":"[Lysosomal membrane protein Sidt2 knockout induces apoptosis of human hepatocytes in vitro independent of the autophagy-lysosomal pathway].","date":"2023","source":"Nan fang yi ke da xue xue bao = Journal of Southern Medical University","url":"https://pubmed.ncbi.nlm.nih.gov/37202201","citation_count":3,"is_preprint":false},{"pmid":"40885088","id":"PMC_40885088","title":"Sidt2 ameliorates TNF-α-induced apoptosis and inflammation by promoting autophagic flux via p65 signaling.","date":"2025","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40885088","citation_count":2,"is_preprint":false},{"pmid":"39747556","id":"PMC_39747556","title":"Multispanning membrane protein SIDT2 increases knockdown activity of gapmer antisense oligonucleotides.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/39747556","citation_count":2,"is_preprint":false},{"pmid":"34549712","id":"PMC_34549712","title":"[Lysosomal membrane protein Sidt2 deletion impairs autophagy in human hepatocytes].","date":"2021","source":"Nan fang yi ke da xue xue bao = Journal of Southern Medical University","url":"https://pubmed.ncbi.nlm.nih.gov/34549712","citation_count":2,"is_preprint":false},{"pmid":"40541391","id":"PMC_40541391","title":"Biallelic SIDT2 loss-of-function in a child with cerebellar ataxia and lysosomal dysfunction mimics impairment of SIDT2 in mice.","date":"2025","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/40541391","citation_count":1,"is_preprint":false},{"pmid":"40749831","id":"PMC_40749831","title":"Sidt2 inhibits islet β-cell dedifferentiation by regulating insulin secretion.","date":"2025","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/40749831","citation_count":0,"is_preprint":false},{"pmid":"41736445","id":"PMC_41736445","title":"The DNA/RNA autophagy protein SIDT2 as a novel neuropathological hallmark in Huntington disease.","date":"2026","source":"Brain pathology (Zurich, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/41736445","citation_count":0,"is_preprint":false},{"pmid":"40551976","id":"PMC_40551976","title":"NIR-II Imaging Guided Accurate Identification of Paraspinal Muscle Degeneration Through Targeting the Lysosomal Membrane Protein Sidt2.","date":"2025","source":"International journal of nanomedicine","url":"https://pubmed.ncbi.nlm.nih.gov/40551976","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.01.30.25321073","title":"A genetic map of human metabolism across the allele frequency spectrum","date":"2025-02-02","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.30.25321073","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":24776,"output_tokens":5750,"usd":0.080289,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14467,"output_tokens":4527,"usd":0.092755,"stage2_stop_reason":"end_turn"},"total_usd":0.173044,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2016,\n      \"finding\": \"SIDT2 is a transmembrane lysosomal integral membrane protein that mediates direct RNA translocation across the lysosomal membrane during RNautophagy; gain- and loss-of-function studies with isolated lysosomes showed SIDT2 knockdown inhibited ~50% of total cellular RNA degradation independently of macroautophagy.\",\n      \"method\": \"Gain- and loss-of-function studies with isolated lysosomes; subcellular fractionation; immunofluorescence with lysosomal markers\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain/loss-of-function in isolated lysosomes, replicated across multiple papers from independent groups\",\n      \"pmids\": [\"27046251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SIDT2 is a highly glycosylated lysosomal integral membrane protein; its lysosomal localization was determined by immunofluorescence with lysosomal markers and subcellular fractionation, and its apparent molecular weight (~120–130 kDa) decreases to ~95 kDa after PNGase F digestion, confirming extensive N-glycosylation.\",\n      \"method\": \"Immunofluorescence, subcellular fractionation, PNGase F digestion, Western blot\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (fractionation, immunofluorescence, enzymatic deglycosylation), replicated in subsequent studies\",\n      \"pmids\": [\"20965152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SIDT2 also mediates DNA translocation during DNautophagy, the direct uptake of DNA by lysosomes in an ATP-dependent manner.\",\n      \"method\": \"Gain- and loss-of-function studies with isolated lysosomes\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isolated lysosome assay, single lab, consistent with prior RNA transport findings\",\n      \"pmids\": [\"27846365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SIDT2 is required for transport of internalized extracellular dsRNA from endocytic compartments into the cytoplasm for innate immune activation; Sidt2-deficient mice show impaired antiviral cytokine production and reduced survival upon EMCV and HSV-1 infection.\",\n      \"method\": \"Sidt2 knockout mouse model; virus challenge (EMCV, HSV-1); cytokine production assays; extracellular dsRNA treatment\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockout with defined survival and cytokine phenotypes, multiple viral challenges, replicated across pathogens\",\n      \"pmids\": [\"28916264\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Three cytosolic YxxΦ motifs in SIDT2 are required for its lysosomal localization; SIDT2 interacts with adaptor protein complexes AP-1 and AP-2, and this lysosomal targeting is necessary for its function in RNautophagy. Overexpression of SIDT2 substantially increases endogenous RNA degradation at the cellular level.\",\n      \"method\": \"Mutagenesis of YxxΦ motifs; co-immunoprecipitation with AP-1 and AP-2; live-cell imaging; RNA degradation assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mutagenesis with functional readout, Co-IP with adaptor complexes, multiple orthogonal methods in one study\",\n      \"pmids\": [\"28724756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SIDT2 mediates gymnosis — the uptake of naked single-stranded oligonucleotides (ssOligos) into living cells; SIDT2 knockdown significantly reduced ssOligo uptake, overexpression enhanced it, and a single amino acid mutation in SIDT2 abolished the enhancing effect.\",\n      \"method\": \"siRNA knockdown; overexpression; single amino acid mutagenesis; fluorescent ssOligo uptake assay\",\n      \"journal\": \"RNA biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function, gain-of-function, and mutagenesis with quantitative uptake readout, single lab\",\n      \"pmids\": [\"28277980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SIDT2 directly binds RNA and DNA through an arginine-rich motif (ARM) in its main cytosolic domain; disruption of this ARM dramatically impairs SIDT2-mediated RNautophagic activity. SIDT2 ARM also mediates interaction with the CAG repeat-containing HTT exon 1 transcript, and overexpression of SIDT2 promoted HTT mRNA degradation and reduced polyQ-expanded HTT aggregates. SIDT2 and LAMP2C ARM motifs act synergistically in RNautophagy.\",\n      \"method\": \"In vitro binding assays (GST pulldown); ARM mutagenesis; cellular RNautophagy activity assays; Western blot for HTT aggregates; co-expression/synergy experiments\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro binding reconstitution combined with mutagenesis and functional cellular assay, multiple orthogonal methods in one study\",\n      \"pmids\": [\"31944164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SIDT2 overexpressed in HEK293 cells reaches the plasma membrane and functions as a spontaneous, non-inactivating monovalent cation channel, causing cell depolarization upon sodium addition; strong overexpression leads to significant reduction/loss of detectable lysosomes.\",\n      \"method\": \"Heterologous overexpression in HEK293 cells; whole-cell patch clamp electrophysiology; lysosome detection assays\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — direct electrophysiology (patch clamp), but single lab, single study, and the cation channel activity was measured under overexpression conditions that also displace protein to plasma membrane\",\n      \"pmids\": [\"27987306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Sidt2-deficient (knockout) mice exhibit glucose intolerance, decreased serum insulin, hypertrophic islets with accumulation of insulin secretory granules, and impaired glucose-stimulated insulin secretion; isolated Sidt2−/− islets produce less insulin upon glucose or KCl stimulation, indicating a role for Sidt2 in insulin secretory granule exocytosis.\",\n      \"method\": \"Global Sidt2 knockout mouse; glucose tolerance tests; isolated islet insulin secretion assays; electron microscopy; Western blot; immunofluorescence\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal readouts (in vivo and ex vivo), electron microscopy of granule morphology, replicated in subsequent studies\",\n      \"pmids\": [\"23776622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SIDT2 is involved in NAADP-mediated calcium release from intracellular acidic compartments (insulin secretory granules) in pancreatic β-cells; Sidt2−/− β-cells show reduced glucose-induced [Ca2+]i peak, which is normalized by exogenous NAADP application, while bafilomycin A1 treatment equalized [Ca2+]i responses between Sidt2−/− and WT cells.\",\n      \"method\": \"Primary β-cell culture from Sidt2−/− mice; calcium imaging; pharmacological inhibitors (ryanodine, 2-APB, bafilomycin A1, NAADP); patch clamp for KATP and KV currents\",\n      \"journal\": \"Journal of molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pharmacological approaches with calcium imaging in primary cells, single lab\",\n      \"pmids\": [\"26744456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Hepatocyte-specific effects of Sidt2 deficiency include lipid droplet accumulation and impaired hepatic β-oxidation with decreased autophagic flux; Sidt2−/− mice show block of autophagosome maturation as evidenced by elevated p62 and LC3-II and accumulation of autophagolysosomes by electron microscopy.\",\n      \"method\": \"Global Sidt2 knockout mouse; serum β-hydroxybutyrate measurement; Western blot for p62 and LC3-II; electron microscopy; primary hepatocyte autophagic flux assays\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knockout with multiple biochemical and ultrastructural readouts, single lab\",\n      \"pmids\": [\"29363559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Skeletal muscle-specific Sidt2 knockout mice develop a muscular dystrophy-like phenotype with accumulation of autophagolysosomes, increased LC3-II, p62, ubiquitinated aggregates, and LAMP2-positive vacuoles, while proteasome and lysosomal soluble enzyme activities were unimpaired, indicating a specific role for Sidt2 in the late stage of autophagy in muscle.\",\n      \"method\": \"Muscle-specific Sidt2 knockout mouse (Cre/LoxP); morphologic and functional studies; Western blot; immunostaining; genechip RNA expression analysis; proteasome activity assay; lysosomal enzyme activity assay\",\n      \"journal\": \"Metabolism: clinical and experimental\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific KO with multiple phenotypic readouts and enzymatic controls, single lab\",\n      \"pmids\": [\"29752955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Sidt2 deletion in kidney (Sidt2−/− mice) impairs lysosomal function (decreased acidic lysosomes, reduced acid hydrolase activity, elevated lysosomal pH), blocks autophagosome–lysosome fusion and autolysosome degradation, and leads to structural and functional kidney damage (basement membrane thickening, podocyte foot process fusion, proteinuria).\",\n      \"method\": \"Sidt2 knockout mouse; LysoTracker staining; lysosomal enzyme activity assays; LC3-II/p62 Western blot; immunofluorescence for autophagosome-lysosome fusion; Ad-mcherry-GFP-LC3B; chloroquine experiments; electron microscopy\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal assays in vivo and in vitro, single lab\",\n      \"pmids\": [\"34923568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Sidt2 deletion in skeletal muscle reduces expression of mitochondrial fusion protein Mfn2, fission protein Drp1, and PGC1-α, blocks autophagosome–lysosome fusion, impairs clearance of damaged mitochondria, and causes accumulation of structurally abnormal mitochondria with reduced muscle tolerance.\",\n      \"method\": \"Skeletal muscle-selective Sidt2 knockout mice; Western blot for Mfn2, Drp1, PGC1-α; autophagy flux assays; electron microscopy; functional muscle tests\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific KO with multiple molecular and functional readouts, single lab\",\n      \"pmids\": [\"33715196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SIDT2 promotes tumor development; Sidt2−/− mice with KrasG12D activation develop significantly fewer lung tumors, and loss of SIDT2 delays intestinal tumor development in Apcmin/+ mice; in the intestine, SIDT2 loss leads to dsRNA accumulation associated with increased eIF2α and JNK phosphorylation and elevated apoptosis.\",\n      \"method\": \"Sidt2 knockout in KrasG12D lung adenocarcinoma model and Apcmin/+ intestinal cancer model; tumor counting; phospho-eIF2α and phospho-JNK Western blot; apoptosis assays\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic epistasis with two tumor models and downstream signaling readouts, single lab\",\n      \"pmids\": [\"31546103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SIDT2 forms a complex with apolipoprotein A1 (ApoA1) requiring the second CRAC motif (CRAC-2) in SIDT2; overexpression of SIDT2 enhances ApoA1 secretion from HepG2 hepatocytes, and this effect is abolished when the CRAC-2 domain is mutated.\",\n      \"method\": \"Co-immunoprecipitation; CRAC-2 domain mutagenesis; ApoA1 secretion assay in HepG2 cells\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with mutagenesis and functional secretion assay, single lab\",\n      \"pmids\": [\"37830567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SIDT2/Val636Ile missense variant shows increased uptake of the cholesterol analog dehydroergosterol compared to wild-type in vitro, indicating that this variant alters SIDT2's sterol transport function.\",\n      \"method\": \"In vitro site-directed mutagenesis; dehydroergosterol (fluorescent cholesterol analog) uptake assay\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — direct in vitro functional assay with mutagenesis, single lab, single method\",\n      \"pmids\": [\"34233476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SIDT2 regulates lysosome cellular location, potentially via interaction with microtubule-related proteins; SIDT2 is required for proper co-localization between phosphorothioate antisense oligonucleotides (PS-ASOs) and lysosomes, and SIDT2 loss reduces PS-ASO lysosomal entrapment and increases ASO activity.\",\n      \"method\": \"SIDT2 knockdown; PS-ASO co-localization imaging; SIDT2 interactome (MS-based identification of microtubule-related binding partners); lysosome positioning assays\",\n      \"journal\": \"Nucleic acid therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — KD with localization assay and MS interactome, functional ASO activity readout, single lab\",\n      \"pmids\": [\"36576400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In docetaxel-treated cancer cells, SIDT2 expression is upregulated and mediates lysosomal degradation of miR-25, which in turn increases NOX4 expression; this activates ROS/JNK signaling leading to HuR phosphorylation and TNF-α mRNA stabilization, ultimately causing TNF-α-dependent apoptosis.\",\n      \"method\": \"siRNA knockdown of SIDT2; chloroquine (lysosome inhibitor) pretreatment; miR-25 quantification; NOX4/ROS/JNK/HuR Western blot; cell viability and apoptosis assays\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with pharmacological inhibition and multiple signaling pathway readouts, single lab\",\n      \"pmids\": [\"34863979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Biallelic SIDT2 missense variants (p.Arg529Trp, p.Arg678Trp) in a human patient disrupted SIDT2's ability to interact with RNA; patient fibroblasts showed impaired autophagy with abnormal accumulation of autophagy markers, mimicking Sidt2 knockout mouse brain phenotypes including motor incoordination and seizures.\",\n      \"method\": \"Functional RNA-binding studies of patient variants; patient fibroblast autophagy marker analysis; Sidt2 knockout mouse neurological phenotyping; brain expression analysis\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional variant characterization in patient cells plus animal model neurological phenotypes, single study\",\n      \"pmids\": [\"40541391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SIDT2 overexpression via AAV vectors in the lateral hypothalamus of R6/2 HD mice reduced mutant huntingtin (mHTT) inclusions; in a neuronal cell model, SIDT2 overexpression reduced soluble and insoluble mHTT exon 1 protein levels, consistent with its known ARM-mediated binding to the expanded CAG repeat in mHTT transcript.\",\n      \"method\": \"AAV-mediated SIDT2 overexpression in R6/2 mouse hypothalamus; mHTT inclusion quantification by immunohistochemistry; neuronal cell model overexpression with Western blot for mHTT\",\n      \"journal\": \"Brain pathology (Zurich, Switzerland)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo AAV overexpression and cell model with functional mHTT readout, consistent with prior mechanistic data, single lab\",\n      \"pmids\": [\"41736445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Sidt2 deficiency in islets correlates with significantly decreased expression of SNARE proteins synaptopodin 1 (synap1) and synaptopodin 3 (synap3), suggesting that Sidt2 regulates insulin secretory granule exocytosis via SNARE-dependent mechanisms.\",\n      \"method\": \"Sidt2 knockout mouse; gene expression analysis (13-gene panel); in vivo and in vitro insulin secretion assays\",\n      \"journal\": \"International journal of clinical and experimental pathology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — gene expression correlation only (mRNA level changes), no direct mechanistic link established between SIDT2 and SNARE proteins\",\n      \"pmids\": [\"26884831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SIDT2 (expressed in human cell lines) enhances knockdown activity of gapmer ASOs and promotes their endosomal escape into the cytosol; a specific region in SIDT2 (identified by chimeric SIDT2/SIDT1 protein analysis) is critical for this activity and distinguishes SIDT2 from SIDT1.\",\n      \"method\": \"Overexpression of SIDT1 and SIDT2 in human cell lines; gapmer ASO knockdown activity assays; chimeric protein domain-swap analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function with domain-swap chimeras and functional ASO readout, single lab\",\n      \"pmids\": [\"39747556\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SIDT2 is a highly glycosylated, multi-pass lysosomal integral membrane protein that functions as a nucleic acid transporter: it directly translocates RNA and DNA across the lysosomal membrane (RNautophagy/DNautophagy) via an arginine-rich motif (ARM) in its cytosolic domain that binds nucleic acids, is sorted to lysosomes through three cytosolic YxxΦ motifs via AP-1/AP-2 adaptors, and also transports extracellular dsRNA from endosomes into the cytoplasm to activate innate antiviral immunity; additionally, SIDT2 mediates cellular uptake of single-stranded oligonucleotides (gymnosis), regulates lysosome positioning via microtubule-associated proteins, participates in NAADP-mediated calcium release from acidic compartments to regulate insulin secretion, forms a complex with ApoA1 (requiring its CRAC-2 motif) to enhance ApoA1 secretion, conducts monovalent cations when present at the plasma membrane, and is required for proper autophagosome–lysosome fusion, such that its loss across tissues causes impaired autophagic flux, lipid accumulation, mitochondrial dysfunction, and organ pathology.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SIDT2 is a highly glycosylated, multi-pass lysosomal integral membrane protein that functions as a direct transporter of nucleic acids across the lysosomal membrane, mediating the macroautophagy-independent degradation of RNA (RNautophagy) and DNA (DNautophagy) [#0, #1, #2]. Substrate engagement is achieved through an arginine-rich motif (ARM) in its main cytosolic domain that directly binds RNA and DNA; disrupting this ARM abolishes RNautophagic activity, and the ARM acts synergistically with that of LAMP2C [#6]. Correct lysosomal delivery of SIDT2 depends on three cytosolic YxxΦ motifs that recruit the clathrin adaptor complexes AP-1 and AP-2, and this targeting is required for its transport function [#4]. Beyond the lysosome, SIDT2 transports internalized extracellular dsRNA from endocytic compartments into the cytoplasm to trigger antiviral innate immunity, with Sidt2-deficient mice showing impaired cytokine responses and reduced survival upon EMCV and HSV-1 infection [#3], and it mediates cellular uptake of naked single-stranded oligonucleotides (gymnosis) and modulates the activity and lysosomal entrapment of therapeutic antisense oligonucleotides [#5, #17, #22]. Through its ARM-mediated binding to the expanded CAG-repeat HTT transcript, SIDT2 promotes degradation of mutant huntingtin and reduces polyQ aggregates in cell and mouse HD models [#6, #20]. Across tissues, loss of SIDT2 impairs autophagosome–lysosome fusion and lysosomal acidification, producing lipid droplet accumulation, mitochondrial dysfunction, and organ pathology in liver, muscle, and kidney [#10, #12, #13], and it contributes to insulin secretory granule exocytosis via NAADP-mediated calcium release from acidic compartments [#8, #9]. Biallelic SIDT2 missense variants that disrupt RNA binding cause a human disorder with impaired autophagy, motor incoordination, and seizures recapitulating the knockout mouse brain phenotype [#19].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Establishing where SIDT2 resides and its post-translational state was the necessary first step before any transport function could be assigned.\",\n      \"evidence\": \"Immunofluorescence, subcellular fractionation, and PNGase F deglycosylation\",\n      \"pmids\": [\"20965152\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define topology or number of transmembrane passes\", \"No functional activity assigned\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Whole-animal knockout first connected SIDT2 to a physiological process, revealing a requirement for insulin secretory granule exocytosis and glucose homeostasis.\",\n      \"evidence\": \"Global Sidt2 knockout mouse with glucose tolerance tests, islet secretion assays, and electron microscopy\",\n      \"pmids\": [\"23776622\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism linking SIDT2 to granule exocytosis unresolved\", \"Did not connect phenotype to lysosomal transport activity\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"An attempt to mechanistically link SIDT2 to the secretory machinery pointed to SNARE protein expression changes.\",\n      \"evidence\": \"Knockout mouse islet gene-expression panel and insulin secretion assays\",\n      \"pmids\": [\"26884831\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Correlative mRNA changes only, no direct mechanistic link between SIDT2 and SNARE proteins\", \"No protein-level or interaction evidence\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"The defining molecular function emerged: SIDT2 directly translocates RNA, and then DNA, across the lysosomal membrane, accounting for a large fraction of cellular RNA degradation independent of macroautophagy.\",\n      \"evidence\": \"Reciprocal gain/loss-of-function in isolated lysosomes (RNautophagy); ATP-dependent DNA uptake assays (DNautophagy)\",\n      \"pmids\": [\"27046251\", \"27846365\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of translocation across the bilayer not resolved\", \"DNautophagy shown by single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Pharmacological dissection placed SIDT2 in NAADP-mediated calcium release from acidic granules, linking its lysosomal role to the earlier insulin phenotype.\",\n      \"evidence\": \"Calcium imaging in Sidt2−/− primary β-cells with NAADP, bafilomycin A1, and other inhibitors\",\n      \"pmids\": [\"26744456\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not establish whether SIDT2 directly conducts or gates calcium release\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"The sorting logic and immune relevance of SIDT2 were defined: YxxΦ/AP-dependent lysosomal targeting underlies its degradative function, and it routes extracellular dsRNA to the cytoplasm for antiviral defense.\",\n      \"evidence\": \"YxxΦ mutagenesis with AP-1/AP-2 Co-IP and RNA degradation assays; Sidt2 knockout mouse viral challenge with cytokine assays\",\n      \"pmids\": [\"28724756\", \"28916264\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the same protein switches between lysosomal degradation and endosome-to-cytosol delivery unclear\", \"Cytosolic sensors activated downstream not defined in these findings\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Additional transport behaviors were characterized — uptake of naked ssOligos (gymnosis) and, under heterologous overexpression, monovalent cation channel activity at the plasma membrane.\",\n      \"evidence\": \"siRNA/overexpression/single-residue mutagenesis with ssOligo uptake assay; whole-cell patch clamp in HEK293 overexpression\",\n      \"pmids\": [\"28277980\", \"27987306\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Channel activity measured under overexpression that mislocalizes protein to plasma membrane\", \"Physiological relevance of cation conductance unestablished\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Tissue-specific knockouts established that SIDT2 is broadly required for the late stage of autophagy, with loss blocking autophagosome maturation and causing lipid and aggregate accumulation in liver and muscle.\",\n      \"evidence\": \"Global and muscle-specific knockout mice with p62/LC3-II Western blot, electron microscopy, and β-oxidation/enzyme-activity controls\",\n      \"pmids\": [\"29363559\", \"29752955\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between nucleic acid transport and autophagosome–lysosome fusion not resolved\", \"Single lab per tissue\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Genetic epistasis revealed a pro-tumorigenic role, with SIDT2 loss reducing tumor burden and causing dsRNA accumulation coupled to stress signaling and apoptosis.\",\n      \"evidence\": \"Sidt2 knockout in KrasG12D lung and Apcmin/+ intestinal tumor models with phospho-eIF2α/JNK and apoptosis readouts\",\n      \"pmids\": [\"31546103\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal chain from dsRNA accumulation to tumorigenesis not fully dissected\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The substrate-binding determinant was localized to an arginine-rich motif in the cytosolic domain that directly binds nucleic acids and engages the expanded HTT transcript, providing a molecular handle for its degradative function.\",\n      \"evidence\": \"GST pulldown in vitro binding, ARM mutagenesis, cellular RNautophagy assays, and HTT aggregate Western blots\",\n      \"pmids\": [\"31944164\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the ARM–RNA complex not determined\", \"How ARM binding couples to membrane translocation unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"A series of studies expanded SIDT2 into lysosome positioning, lipid handling, mitochondrial quality control, sterol transport, and ApoA1 secretion, broadening its functional footprint beyond nucleic acid transport.\",\n      \"evidence\": \"Kidney and muscle tissue-specific knockouts; CRAC-2 mutagenesis and Co-IP with ApoA1; dehydroergosterol uptake with a missense variant; miR-25/NOX4/ROS signaling in docetaxel-treated cells\",\n      \"pmids\": [\"34923568\", \"33715196\", \"34233476\", \"37830567\", \"34863979\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether these activities share a common transport mechanism is unresolved\", \"Several rest on single-lab Co-IP or single-method assays\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"An interactome and imaging study connected SIDT2 to microtubule-associated proteins and lysosome positioning, and to entrapment and activity of therapeutic antisense oligonucleotides.\",\n      \"evidence\": \"SIDT2 knockdown with PS-ASO co-localization imaging and MS-based interactome\",\n      \"pmids\": [\"36576400\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct interaction with named motor/microtubule proteins not validated\", \"Mechanism linking SIDT2 to lysosome positioning unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Human genetics and therapeutic modeling closed the loop: biallelic RNA-binding-disrupting variants cause a neurological disorder mirroring the knockout, and SIDT2 overexpression clears mutant huntingtin in HD models.\",\n      \"evidence\": \"Patient variant RNA-binding and fibroblast autophagy analysis with knockout mouse phenotyping; AAV-mediated SIDT2 overexpression in R6/2 mouse hypothalamus and neuronal cells; gapmer ASO domain-swap analysis\",\n      \"pmids\": [\"40541391\", \"41736445\", \"39747556\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Disease established from a single patient study\", \"Therapeutic durability and off-target consequences of SIDT2 overexpression unaddressed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The unifying biophysical question — how SIDT2 physically translocates large nucleic acids and oligonucleotides across a membrane, and whether its diverse reported activities (cation conduction, sterol uptake, calcium release, ApoA1 binding) reflect one transport mechanism or distinct functions — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of SIDT2 or its transport pore\", \"Transport stoichiometry and energetics undefined\", \"Unclear whether lysosomal and plasma-membrane functions coexist physiologically\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [6, 19]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [6, 2]},\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 2, 3, 5]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [3, 17]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [10, 11, 12]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"AP1\", \"AP2\", \"LAMP2\", \"APOA1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}