{"gene":"SIGMAR1","run_date":"2026-06-10T07:46:32","timeline":{"discoveries":[{"year":2024,"finding":"SigmaR1 is a type II integral ER membrane protein specifically enriched at ER sheets. A short N-terminal region promotes its ER-sheet localization. SigmaR1 directly interacts with components of the translocon complex including TRAPα and Nicalin. A β-barrel at the C-terminus of SigmaR1 binds phosphatidylcholine (PC), and PC binding strengthens the association of SigmaR1 with the translocon complex. SigmaR1 knockout systematically impaired cellular protein and lipid homeostasis, resulting in accumulation of lipid droplets in hepatocytes.","method":"Endogenous tagging, cell fractionation, Co-IP, biochemical interaction studies, lipid-binding assays, knockout cells","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal biochemical methods (fractionation, Co-IP, lipid binding, KO phenotype) in a single rigorous study","pmids":["41476177"],"is_preprint":false},{"year":2024,"finding":"SigmaR1 oligomers use extended arrays of amphipathic helices to bind and flatten the lumenal leaflet of ER membranes, opposing membrane curvature and stabilizing rough ER sheets. Structure-guided mutagenesis and in vitro reconstitution on giant unilamellar vesicles supported this mechanism. SigmaR1 levels determine the amount of rough ER sheets in cells.","method":"Proteomics screen, high-resolution live cell imaging, electron tomography, structure-guided mutagenesis, in vitro reconstitution on giant unilamellar vesicles","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with mutagenesis and electron tomography in one study","pmids":["38971154"],"is_preprint":false},{"year":2016,"finding":"ALS-linked SIGMAR1 variants (including p.L95fs) are unstable and incapable of binding to inositol 1,4,5-triphosphate receptor type 3 (IP3R3). Loss of Sig1R function causes mislocalization of IP3R3 from the mitochondria-associated membrane (MAM), calpain activation, and mitochondrial dysfunction. Sig1R deficiency accelerated disease onset in mutant SOD1 ALS mice, indicating MAM collapse is a shared pathomechanism.","method":"Co-IP (Sig1R–IP3R3 interaction), mouse genetic model (Sig1R KO × SOD1 mutant), immunofluorescence, biochemical fractionation","journal":"EMBO molecular medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding assay combined with in vivo genetic epistasis and multiple phenotypic readouts","pmids":["27821430"],"is_preprint":false},{"year":2015,"finding":"Pharmacological or genetic inactivation of SIGMAR1 in motor neurons disrupts ER–mitochondria contacts, impairs intracellular calcium signaling, activates ER stress, and causes defects in mitochondrial dynamics and axonal transport, leading to axonal degeneration and cell death. Inhibition of mitochondrial fission alone recapitulated axonal transport defects and degeneration. Intracellular calcium scavenging and ER stress inhibition restored mitochondrial function and prevented motor neuron degeneration.","method":"Primary motor neuron cultures, pharmacological inhibition, siRNA knockdown, Sigmar1−/− mice, live imaging of mitochondrial dynamics, calcium imaging, epistasis experiments","journal":"Brain : a journal of neurology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (genetic KO, pharmacological, epistasis rescue) with defined cellular phenotypes replicated in vivo and in vitro","pmids":["25678561"],"is_preprint":false},{"year":2019,"finding":"SIGMAR1 knockout impairs autophagosome–lysosome fusion without affecting autophagosome biogenesis markers (BECN1, ATG7) or lysosomal pH/protease activity. SIGMAR1 co-immunoprecipitates with ATG14, STX17, and VAMP8 (but not SNAP29), proteins key to autophagosome–lysosome membrane fusion. Re-expressing SIGMAR1 in null background rescued clearance of mitochondria and autophagosomes.","method":"Sigmar1 knockout (CRISPR), Co-IP (SIGMAR1 with ATG14/STX17/VAMP8), GFP-RFP-LC3 fusion assay, lysosome colocalization, rescue experiments","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with multiple interaction partners, KO + rescue with defined mechanistic step (fusion), multiple orthogonal methods","pmids":["30871407"],"is_preprint":false},{"year":2022,"finding":"SIGMAR1 facilitates TFEB transport into the nucleus by chaperoning the nuclear pore protein POM121, which recruits importin-β1 (KPNB1). In C9orf72-ALS cells, hexanucleotide repeat expansion reduces SIGMAR1–POM121 association, lowering nuclear TFEB, KPNB1, and LC3-II. SIGMAR1 overexpression or agonist treatment (pridopidine) rescued these deficits.","method":"Co-IP (SIGMAR1–POM121), overexpression, pharmacological agonism with pridopidine, nuclear fractionation, LC3-II western blot in NSC34 cells with C9orf72 HRE","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional rescue with defined downstream markers, single lab","pmids":["35507432"],"is_preprint":false},{"year":2024,"finding":"SIGMAR1 stabilizes MAP1LC3B/LC3B and GABARAP mRNAs, promoting their localized translation proximal to the ER for efficient lipidation and autophagosome formation. SIGMAR1 directly binds a conserved region in the 3' UTR of LC3B mRNA. Cells lacking SIGMAR1 show reduced levels of many Atg8-family proteins and impaired autophagic flux.","method":"smFISH, Co-IP (SIGMAR1–LC3B mRNA), SIGMAR1 knockout cells, mRNA stability assays, lipidation assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with mRNA and smFISH, KO with phenotype, single lab with orthogonal methods","pmids":["39369298"],"is_preprint":false},{"year":2016,"finding":"Two novel SIGMAR1 mutations (p.E138Q and p.E150K) reduce cell viability, cause formation of abnormal protein aggregates, prevent correct targeting of sigma-1R to the MAM, and impair global Ca2+ signaling and ER–mitochondria tethering in neuronal cell lines, demonstrating the chaperone activity of sigma-1R at the MAM as critical for motor neuron survival.","method":"Site-directed mutagenesis, cell viability assays, immunofluorescence for MAM localization, Ca2+ imaging, ER–mitochondria contact quantification in neuronal cell lines","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional mutation analysis with multiple orthogonal readouts (localization, Ca2+, viability), single lab","pmids":["27402882"],"is_preprint":false},{"year":2014,"finding":"The ALS-linked SIGMAR1 variant p.E102Q promotes dissociation of sigma-1R from the ER membrane and cytoplasmic aggregation, impairs mitochondrial ATP production and proteasome activity, and causes aberrant extra-nuclear localization of TDP-43. Treatment with the mitochondrial Ca2+ transporter inhibitor Ru360 mimicked these effects, indicating that aberrant sigma-1R-mediated mitochondrial Ca2+ transport underlies TDP-43 mislocalization.","method":"Neuro2A overexpression of mutant vs. wild-type sigma-1R, mitochondrial function assays (ATP production), proteasome activity assay, TDP-43 immunofluorescence, pharmacological inhibition of mitochondrial Ca2+ transport","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple mechanistic assays in single lab, pharmacological epistasis supporting Ca2+ transport mechanism","pmids":["25175561"],"is_preprint":false},{"year":2017,"finding":"SigmaR1 physically binds SK3 (KCNN3, a Ca2+-activated K+ channel) in breast cancer cells. SigmaR1 triggers coupling between SK3 and the Ca2+ channel Orai1, increasing Ca2+ influx. Inhibition of SigmaR1 decreased SK3 current and Ca2+ entry, and diminished SK3 and/or Orai1 levels in lipid nanodomains, reducing cancer cell invasiveness.","method":"Co-IP (SigmaR1–SK3), lipid nanodomain fractionation, patch-clamp electrophysiology, siRNA silencing, sigma ligand (igmesine) treatment","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP demonstrating direct binding plus functional readouts (current, Ca2+ entry, lipid raft levels), single lab","pmids":["28114279"],"is_preprint":false},{"year":2015,"finding":"Sig1R dynamically controls the membrane expression of the hERG voltage-gated K+ channel in myeloid leukemia and colorectal cancer cells. Sig1R promotes formation of hERG/β1-integrin signaling complexes upon extracellular matrix stimulation, triggering PI3K/AKT pathway activation, increasing cell motility and VEGF secretion.","method":"Co-IP (hERG–Sig1R–β1-integrin complex), siRNA knockdown, PI3K/AKT pathway western blot, cell motility assay, in vivo xenograft model","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP with functional downstream pathway validation and in vivo evidence, single lab","pmids":["26645564"],"is_preprint":false},{"year":2021,"finding":"In cardiomyocytes, Sigmar1 localizes to mitochondrial membranes (confirmed by quantum dot electron microscopy, subcellular fractionation, and MitoTracker colocalization) and functions as an integral mitochondrial membrane protein (shown by alkaline extraction and proteinase K protection assays). The N-terminal region is required for mitochondrial localization. Sigmar1 siRNA knockdown significantly altered mitochondrial respiration in cardiomyocytes.","method":"Quantum dot transmission electron microscopy, subcellular fractionation, immunocytochemistry, alkaline extraction, proteinase K treatment, FLAG-tagged truncation constructs, extracellular flux analysis, high-resolution respirometry","journal":"Mitochondrion","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal biochemical and imaging methods for localization with functional KD consequence, single lab","pmids":["34902622"],"is_preprint":false},{"year":2020,"finding":"Methamphetamine inhibits Sigmar1, resulting in inactivation of CREB, decreased expression of mitochondrial fission 1 protein (FIS1), and alteration of mitochondrial dynamics and function, leading to cardiomyopathy.","method":"Mouse 'binge and crash' methamphetamine model, human autopsy cardiac samples, western blot for CREB/FIS1, mitochondrial function assays, Sigmar1 KO mice","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo model with human validation, mechanistic signaling pathway defined, single lab","pmids":["33203971"],"is_preprint":false},{"year":2025,"finding":"SIGMAR1 directly binds neuronal pentraxin-1 (NPTX1), promoting its ubiquitin-proteasome degradation. Downregulation of NPTX1 promotes AMPAR (GluA1 subunit) membrane trafficking and central sensitization, driving neuropathic pain. SIGMAR1 is upregulated in the spinal dorsal horn by mRNA m6A modification during neuropathic pain development.","method":"HPLC-MS/MS, Co-IP (SIGMAR1–NPTX1), methylated RNA immunoprecipitation (m6A), intrathecal SIGMAR1 siRNA/antagonist, AAV-mediated NPTX1 overexpression, AMPAR membrane trafficking assay","journal":"Neuroscience bulletin","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP confirmed by MS, functional epistasis with in vivo gene manipulation, single lab","pmids":["41457187"],"is_preprint":false},{"year":2024,"finding":"CdCl2 exposure activates SEL1L/HRD1-mediated ERAD, which promotes ubiquitinated degradation of SigmaR1 specifically at its K142 site, resulting in Ca2+ dyshomeostasis and mitochondrial dysfunction that activates the p53/p21/Rb neuronal senescence pathway.","method":"In vitro neuron culture, in vivo mouse model, ubiquitination assay with site-specific mutagenesis (K142), Co-IP (SEL1L/HRD1–SigmaR1), western blot for senescence markers, Ca2+ imaging","journal":"Journal of hazardous materials","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-specific ubiquitination with mutagenesis and pathway epistasis, single lab","pmids":["38718507"],"is_preprint":false},{"year":2025,"finding":"STUB1 (an E3 ubiquitin ligase) interacts with Sigmar1 and degrades it via ubiquitination in cardiomyocytes exposed to CVB3. STUB1-mediated Sigmar1 degradation promotes ER stress (upregulation of GRP78, Caspase-12, CHOP). Sigmar1 overexpression reversed CVB3-induced ER stress and cardiomyocyte apoptosis, while STUB1 overexpression counteracted Sigmar1 overexpression effects.","method":"Co-IP (STUB1–Sigmar1), ubiquitination assay, overexpression constructs in neonatal mouse cardiomyocytes, LDH assay, TUNEL apoptosis assay, western blot","journal":"General physiology and biophysics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay with epistasis rescue experiments, single lab","pmids":["40567075"],"is_preprint":false},{"year":2024,"finding":"Sigmar1 suppresses COL1A1 expression and vascular fibrosis by blocking the TGF-β/Smad2/3 signaling pathway in vascular smooth muscle cells exposed to methamphetamine. Sigmar1 KO mice showed higher blood pressure and collagen deposition, while Sigmar1 agonist (PRE-084) prevented these effects.","method":"Sigmar1 KO mice, Sigmar1 antagonist (BD1047) and agonist (PRE-084), western blot for TGF-β/Smad2/3, collagen staining, blood pressure measurement","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO and pharmacological manipulation with defined signaling pathway, single lab","pmids":["38851304"],"is_preprint":false},{"year":2022,"finding":"Veratramine inhibited the expression of SIGMAR1 and the phosphorylation of NMDAR at Ser896 in spinal cord tissue, and inhibited formation of SIGMAR1–NMDAR and NMDAR–CaMKII protein complexes, thereby reducing neuropathic pain in diabetic rats.","method":"Co-IP (SIGMAR1–NMDAR, NMDAR–CaMKII complexes), western blot, in vivo rat diabetic neuropathy model with veratramine treatment","journal":"Pharmaceutical biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP for complex formation, pharmacological intervention without genetic controls, single lab","pmids":["36373991"],"is_preprint":false},{"year":2017,"finding":"Alternatively spliced variants of sigma1 receptor all fail to bind sigma ligands when expressed in HEK293 cells, indicating that each truncated region is important for ligand binding. However, all splice variants retain the ability to physically associate with mu opioid receptor (mMOR-1) by Co-IP, and can disrupt sigma1 receptor dimerization with mMOR-1 in a dominant-negative manner.","method":"Ligand binding assay, Co-IP (splice variants with mMOR-1), competition Co-IP for dimerization, expression in HEK293 cells","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay and Co-IP with competition experiment, multiple splice variants tested, single lab","pmids":["28350844"],"is_preprint":false},{"year":2019,"finding":"Cocaine enhances Sigma1R association with nuclear lamina proteins emerin, lamin A/C, and BANF1, causing Sigma1R-dependent and emerin-dependent transcriptional repression of MAOB1. Novel missense variants (p.Q2P and p.R208W) were identified as tools to study the molecular basis of this association.","method":"Co-IP (Sigma1R with emerin/lamin A/C/BANF1 in cocaine-treated cells), transcriptional repression assay, population genetics (ExAC database for variant identification)","journal":"Experimental biology and medicine (Maywood, N.J.)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP evidence cited from prior work, new variants identified but not functionally validated in this paper, single lab","pmids":["31324122"],"is_preprint":false},{"year":2024,"finding":"CLCC1 co-localizes with SigmaR1 not only at the ER but also at mitochondria-associated ER membranes (MAMs), and SigmaR1 was identified as a CLCC1-interacting protein by LC-MS proteomics, validated by co-immunoprecipitation and microscopy.","method":"LC-MS proteomics, Co-IP (CLCC1–SigmaR1), immunofluorescence co-localization microscopy","journal":"Neuroscience letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP confirming MS-identified interaction, no functional consequence tested for SIGMAR1 specifically","pmids":["38621504"],"is_preprint":false},{"year":2026,"finding":"SIGMAR1 activates SIRT3-mediated mitophagy, which alleviates endothelial ferroptosis and microvascular hyperpermeability in LPS-induced acute lung injury. SIRT3 deacetylates ATP5F1A at lysine 498; this deacetylation is essential for SIGMAR1-mediated PRKN/parkin-dependent mitophagy. Sigmar1 KO worsened ferroptosis and hyperpermeability, effects reversed by SIRT3 activation.","method":"Sigmar1 KO mice, pharmacological agonism (PRE-084), SIRT3 inhibition/activation, acetylation assay (ATP5F1A K498), mitophagy markers, GFP-LC3 puncta, mouse pulmonary microvascular endothelial cells","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO and pharmacological intervention with defined biochemical mechanism (deacetylation site), multiple orthogonal assays, single lab","pmids":["41655128"],"is_preprint":false},{"year":2015,"finding":"A splice-site mutation in SIGMAR1 (c.151+1G>T) generates a truncated protein σ1R(31_50del) that is degraded by the proteasome and forms nuclear aggregates upon proteasome inhibition. Stable expression of σ1R(31_50del) induces ER stress and enhances apoptosis in cell lines.","method":"RNA analysis of patient peripheral blood, stable cell line expression of mutant σ1R, proteasome inhibitor treatment, immunofluorescence, western blot, apoptosis assay","journal":"Neurology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, cell line overexpression with indirect mechanistic inference","pmids":["26078401"],"is_preprint":false},{"year":2016,"finding":"Sigma-1 receptor agonist (+)-pentazocine promotes retinal ganglion cell survival after NMDA-induced excitotoxicity through a σR1-dependent mechanism and enhances activation of ERK1/2 (MAPK) at 6 hours post-NMDA. In σR1 knockout mice, (+)-pentazocine failed to protect RGCs and failed to activate ERK, placing σR1 upstream of ERK in the neuroprotective pathway.","method":"Intravitreal NMDA injection in WT and σR1 KO mice, intraperitoneal (+)-pentazocine treatment, retinal flat-mount RGC counting, TUNEL assay, western blot for ERK1/2 phosphorylation","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (KO abolishes both protection and ERK activation) with in vivo model, single lab","pmids":["26868747"],"is_preprint":false},{"year":2011,"finding":"Absence of σR1 in knockout mice leads to late-onset inner retinal dysfunction (decreased ERG b-wave amplitudes, loss of ganglion cell layer cells, increased apoptosis by TUNEL/caspase-3), preceded by ultrastructural axonal disruption in the optic nerve head, establishing a direct role for σR1 in maintaining inner retinal neuron survival.","method":"σR1 knockout mice, electroretinography, morphometric analysis, TUNEL assay, active caspase-3 immunostaining, electron microscopy","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with multiple phenotypic readouts and ultrastructural evidence, single lab","pmids":["21862648"],"is_preprint":false},{"year":2008,"finding":"Gut microbiota-derived short-chain fatty acids (SCFAs) ameliorate methamphetamine-induced depression- and anxiety-like behaviors through a SIGMAR1-dependent mechanism: Sigmar1 knockout (Sigmar1−/−) repressed the BDNF/TRKB pathway and produced behavioral phenotypes similar to methamphetamine exposure, and eliminated the anti-anxiety and anti-depression effects of SCFAs. Fluvoxamine-mediated SIGMAR1 activation attenuated methamphetamine-induced behaviors.","method":"Sigmar1 KO mice, fecal microbiota transplant, SCFA supplementation, fluvoxamine pharmacological activation, behavioral assays, western blot for SIGMAR1/BDNF/TRKB pathway","journal":"Acta pharmaceutica Sinica. B","confidence":"Low","confidence_rationale":"Tier 3 / Weak — genetic KO epistasis for pathway placement (SIGMAR1→BDNF/TRKB), but mechanistic link is indirect and single lab","pmids":["38045052"],"is_preprint":false}],"current_model":"SIGMAR1 (sigma-1 receptor) is a type II integral ER membrane protein enriched at ER sheets, where its oligomeric amphipathic helices flatten the lumenal leaflet to stabilize rough ER sheet morphology; it functions as an auxiliary translocon factor by binding phosphatidylcholine and interacting with TRAPα and Nicalin to regulate protein and lipid homeostasis. At the mitochondria-associated ER membrane (MAM), SIGMAR1 acts as a chaperone that binds and stabilizes IP3R3, maintaining ER–mitochondria calcium transfer and tethering; loss-of-function mutations disrupt IP3R3 localization, impair mitochondrial Ca2+ transport and ATP production, activate calpain and ER stress, and cause motor neuron degeneration. SIGMAR1 also regulates autophagy at multiple steps: it stabilizes LC3B/GABARAP mRNAs for localized ER-proximal translation, interacts with ATG14/STX17/VAMP8 to facilitate autophagosome–lysosome fusion, and chaperones the nucleoporin POM121 to enable KPNB1-dependent nuclear import of the autophagy transcription factor TFEB. Additional mechanistic roles include regulation of ion channels (SK3/Orai1, hERG/β1-integrin/PI3K–AKT), neuroprotection via the ERK1/2 MAPK pathway, promotion of AMPAR trafficking through NPTX1 ubiquitination in nociceptive neurons, and suppression of vascular fibrosis through the TGF-β/Smad2/3 pathway; SIGMAR1 protein stability is regulated by STUB1-mediated ubiquitination and by SEL1L/HRD1-mediated ERAD at lysine 142."},"narrative":{"mechanistic_narrative":"SIGMAR1 (sigma-1 receptor) is a type II integral ER membrane protein enriched at ER sheets that couples ER membrane architecture, lipid and protein homeostasis, and inter-organelle calcium signaling [PMID:41476177, PMID:38971154]. Its oligomers use extended arrays of amphipathic helices to bind and flatten the lumenal leaflet of ER membranes, opposing curvature and stabilizing rough ER sheets, with cellular SIGMAR1 levels setting the amount of rough ER sheets [PMID:38971154]; a C-terminal β-barrel binds phosphatidylcholine, and this lipid binding strengthens association with the translocon components TRAPα and Nicalin, such that SIGMAR1 loss disrupts cellular protein and lipid homeostasis [PMID:41476177]. At mitochondria-associated ER membranes (MAM), SIGMAR1 acts as a chaperone that binds and stabilizes IP3R3 to maintain ER–mitochondria contacts and calcium transfer; ALS-linked variants are unstable, fail to bind IP3R3, mislocalize from the MAM, and trigger calpain activation, impaired mitochondrial ATP production, and ER stress, driving motor neuron degeneration [PMID:27821430, PMID:25678561, PMID:27402882, PMID:25175561]. SIGMAR1 promotes autophagy at several steps: it stabilizes LC3B and GABARAP mRNAs for localized ER-proximal translation [PMID:39369298], interacts with the fusion machinery ATG14, STX17, and VAMP8 to enable autophagosome–lysosome fusion [PMID:30871407], and chaperones the nucleoporin POM121 to support KPNB1-dependent nuclear import of TFEB [PMID:35507432]. It also controls SIRT3-mediated, parkin-dependent mitophagy that limits endothelial ferroptosis [PMID:41655128]. Beyond these core roles, SIGMAR1 regulates ion-channel signaling complexes (SK3/Orai1; hERG/β1-integrin/PI3K–AKT) [PMID:28114279, PMID:26645564], supports retinal and motor neuron survival through ERK1/2 MAPK signaling [PMID:26868747, PMID:21862648], promotes AMPAR trafficking via ubiquitin-dependent degradation of NPTX1 in nociceptive neurons [PMID:41457187], and suppresses vascular fibrosis through the TGF-β/Smad2/3 pathway [PMID:38851304]. SIGMAR1 protein abundance is controlled by ubiquitin-dependent turnover, including STUB1-mediated ubiquitination [PMID:40567075] and SEL1L/HRD1-mediated ERAD at lysine 142 [PMID:38718507].","teleology":[{"year":2011,"claim":"Established that sigma-1 receptor is required for survival of inner retinal neurons in vivo, moving the protein from a pharmacological binding site to a cell-survival factor.","evidence":"σR1 knockout mice analyzed by electroretinography, morphometry, TUNEL/caspase-3, and electron microscopy","pmids":["21862648"],"confidence":"Medium","gaps":["Molecular pathway linking σR1 loss to neuronal death not defined here","Does not address whether the role is cell-autonomous in ganglion cells"]},{"year":2014,"claim":"Linked an ALS-associated SIGMAR1 variant to mitochondrial Ca2+ handling, showing that aberrant Ca2+ transport, not just protein aggregation, drives TDP-43 mislocalization.","evidence":"Overexpression of p.E102Q vs wild-type in Neuro2A, ATP/proteasome assays, TDP-43 imaging, Ru360 pharmacological mimicry","pmids":["25175561"],"confidence":"Medium","gaps":["Overexpression system may not reflect endogenous stoichiometry","Direct molecular target of Ca2+ transport not identified in this study"]},{"year":2015,"claim":"Demonstrated that SIGMAR1 maintains ER–mitochondria contacts and mitochondrial dynamics in motor neurons, defining a contact-site mechanism for axonal degeneration.","evidence":"Primary motor neuron cultures, pharmacological/siRNA inactivation, Sigmar1-/- mice, mitochondrial and calcium live imaging, epistasis rescue","pmids":["25678561"],"confidence":"High","gaps":["Molecular tether partner at the contact site not resolved in this work","Relative contribution of fission defect vs Ca2+ defect not fully separated"]},{"year":2016,"claim":"Identified IP3R3 as the SIGMAR1 client at the MAM and showed ALS variants fail to bind and stabilize it, unifying chaperone activity with the degenerative phenotype.","evidence":"Co-IP of Sig1R–IP3R3, Sig1R KO × SOD1 mutant mouse epistasis, immunofluorescence, fractionation; plus mutagenesis of p.E138Q/p.E150K with Ca2+ and viability readouts","pmids":["27821430","27402882"],"confidence":"High","gaps":["Structural basis of IP3R3 binding not defined","Whether IP3R3 is the sole relevant MAM client unaddressed"]},{"year":2019,"claim":"Placed SIGMAR1 at the autophagosome–lysosome fusion step, distinguishing its role from autophagosome biogenesis.","evidence":"CRISPR Sigmar1 KO, reciprocal Co-IP with ATG14/STX17/VAMP8, GFP-RFP-LC3 flux assay, rescue","pmids":["30871407"],"confidence":"High","gaps":["How an ER-resident protein engages the fusion SNARE complex spatially unclear","Direct vs indirect nature of SNARE interactions not dissected"]},{"year":2022,"claim":"Extended SIGMAR1's autophagy role to nuclear import of TFEB via POM121 chaperoning, connecting it to nucleocytoplasmic transport in C9orf72-ALS.","evidence":"Co-IP of SIGMAR1–POM121, nuclear fractionation, pridopidine agonism, LC3-II readouts in NSC34 C9orf72 HRE cells","pmids":["35507432"],"confidence":"Medium","gaps":["Single lab; reciprocal validation limited","Generality beyond C9orf72 context not established"]},{"year":2024,"claim":"Resolved the structural mechanism of SIGMAR1 as an ER-sheet morphogen, showing amphipathic-helix oligomers flatten the membrane lumenal leaflet.","evidence":"Proteomics, live imaging, electron tomography, structure-guided mutagenesis, in vitro reconstitution on GUVs","pmids":["38971154"],"confidence":"High","gaps":["Link between sheet-shaping and downstream homeostasis phenotypes not directly demonstrated","Regulation of oligomerization in vivo unknown"]},{"year":2024,"claim":"Defined SIGMAR1 as a translocon-associated, phosphatidylcholine-binding factor governing protein and lipid homeostasis at ER sheets.","evidence":"Endogenous tagging, fractionation, Co-IP with TRAPα/Nicalin, lipid-binding assays, knockout phenotype (hepatocyte lipid droplets)","pmids":["41476177"],"confidence":"High","gaps":["Mechanistic link from PC binding to translocon function not fully traced","Substrate proteins affected at the translocon not enumerated"]},{"year":2024,"claim":"Added an RNA-level function: SIGMAR1 stabilizes Atg8-family mRNAs for ER-proximal localized translation, coupling autophagy to membrane biology.","evidence":"smFISH, Co-IP of SIGMAR1 with LC3B mRNA (3'UTR), KO cells, mRNA stability and lipidation assays","pmids":["39369298"],"confidence":"Medium","gaps":["Direct vs indirect mRNA binding mechanism for an ER membrane protein unclear","Breadth of mRNA targets beyond LC3B/GABARAP not mapped"]},{"year":2024,"claim":"Identified SEL1L/HRD1 ERAD as a regulator of SIGMAR1 abundance via K142 ubiquitination, linking SIGMAR1 turnover to Ca2+ homeostasis and senescence.","evidence":"Neuron cultures, mouse model, site-specific (K142) ubiquitination assay, Co-IP of SEL1L/HRD1–SigmaR1, senescence markers","pmids":["38718507"],"confidence":"Medium","gaps":["Physiological triggers of SIGMAR1 ERAD beyond CdCl2 unknown","Single lab"]},{"year":2025,"claim":"Defined a second degradation route (STUB1) and a substrate-level signaling output (NPTX1 ubiquitination driving AMPAR trafficking).","evidence":"Co-IP/ubiquitination of STUB1–Sigmar1 with ER-stress epistasis in cardiomyocytes; HPLC-MS/MS, Co-IP, m6A MeRIP, intrathecal manipulation, AMPAR trafficking assay for NPTX1","pmids":["40567075","41457187"],"confidence":"Medium","gaps":["Whether STUB1 and SEL1L/HRD1 act on overlapping pools of SIGMAR1 unknown","Both single-lab studies"]},{"year":2026,"claim":"Connected SIGMAR1 to a mitophagy program (SIRT3/ATP5F1A K498 deacetylation, parkin-dependent) that restrains ferroptosis, broadening its mitochondrial quality-control role.","evidence":"Sigmar1 KO mice, PRE-084 agonism, SIRT3 modulation, ATP5F1A acetylation assay, GFP-LC3 mitophagy readouts in pulmonary microvascular endothelial cells","pmids":["41655128"],"confidence":"Medium","gaps":["Mechanism by which SIGMAR1 controls SIRT3 activity not defined","Single lab and disease-model specific"]},{"year":null,"claim":"How SIGMAR1's structural ER-sheet/translocon role mechanistically gives rise to its diverse downstream activities (MAM Ca2+ chaperone, autophagy regulator, ion-channel modulator) remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking membrane-shaping to chaperone and signaling outputs","Endogenous ligand and conformational regulation not established in the corpus","Direct structural data on client/partner complexes lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[2,3,5,7]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[6]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[9,10]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[2,3,7]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[11]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[4,5,6,21]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[6]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[10,16,23]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,3]}],"complexes":[],"partners":["IP3R3","ATG14","STX17","VAMP8","POM121","NPTX1","STUB1","TRAPALPHA"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q99720","full_name":"Sigma non-opioid intracellular receptor 1","aliases":["Aging-associated gene 8 protein","SR31747-binding protein","SR-BP","Sigma 1-type opioid receptor","SIG-1R","Sigma1-receptor","Sigma1R","hSigmaR1"],"length_aa":223,"mass_kda":25.1,"function":"Functions in lipid transport from the endoplasmic reticulum and is involved in a wide array of cellular functions probably through regulation of the biogenesis of lipid microdomains at the plasma membrane. 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what do we know?","date":"2025","source":"Neurologia i neurochirurgia polska","url":"https://pubmed.ncbi.nlm.nih.gov/41334667","citation_count":0,"is_preprint":false},{"pmid":"41655128","id":"PMC_41655128","title":"SIRT3-mediated mitophagy by deacetylating ATP5F1A involved in the protective effects of SIGMAR1/Sigma-1 receptor against ferroptosis and microvascular hyperpermeability in lipopolysaccharide-induced acute lung injury.","date":"2026","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/41655128","citation_count":0,"is_preprint":false},{"pmid":"40770335","id":"PMC_40770335","title":"Letter to editor: SIGMAR1 screened by a GPCR-related classifier regulates endoplasmic reticulum stress in bladder cancer.","date":"2025","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40770335","citation_count":0,"is_preprint":false},{"pmid":"38204277","id":"PMC_38204277","title":"Amiodarone Advances the Apoptosis of Cardiomyocytes by Repressing Sigmar1 Expression and Blocking KCNH2-related Potassium Channels.","date":"2025","source":"Current molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38204277","citation_count":0,"is_preprint":false},{"pmid":"41543792","id":"PMC_41543792","title":"A Novel YTHDF2/SIGMAR1 Axis in Astrocytes Regulates Neuroinflammation and Cognitive Impairment in Diabetic Encephalopathy.","date":"2026","source":"Inflammation","url":"https://pubmed.ncbi.nlm.nih.gov/41543792","citation_count":0,"is_preprint":false},{"pmid":"40285994","id":"PMC_40285994","title":"In silico-based analysis and in vitro experiments identify SIGMAR1 as a potential marker of putative lung cancer stem cells.","date":"2025","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40285994","citation_count":0,"is_preprint":false},{"pmid":"40257692","id":"PMC_40257692","title":"Genomic Insights into Oral Cancer Highlight Mutant SIGMAR1 as a Critical Target to Overcome Chemoresistance.","date":"2025","source":"Biochemical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/40257692","citation_count":0,"is_preprint":false},{"pmid":"42172984","id":"PMC_42172984","title":"Linking intestinal distribution to pharmacological mechanism: Berberine prevents and treats colorectal cancer by targeting SIGMAR1.","date":"2026","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/42172984","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.27.25336656","title":"Oral Blarcamesine Phase IIb/III Trial Confirms Identified Precision Medicine Patient Population – Significant Broad Clinical and Quality of Life Improvements for Early Alzheimer’s Disease Patients","date":"2025-09-29","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.27.25336656","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":37187,"output_tokens":7298,"usd":0.110516,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16795,"output_tokens":4604,"usd":0.099538,"stage2_stop_reason":"end_turn"},"total_usd":0.210054,"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\": 2024,\n      \"finding\": \"SigmaR1 is a type II integral ER membrane protein specifically enriched at ER sheets. A short N-terminal region promotes its ER-sheet localization. SigmaR1 directly interacts with components of the translocon complex including TRAPα and Nicalin. A β-barrel at the C-terminus of SigmaR1 binds phosphatidylcholine (PC), and PC binding strengthens the association of SigmaR1 with the translocon complex. SigmaR1 knockout systematically impaired cellular protein and lipid homeostasis, resulting in accumulation of lipid droplets in hepatocytes.\",\n      \"method\": \"Endogenous tagging, cell fractionation, Co-IP, biochemical interaction studies, lipid-binding assays, knockout cells\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal biochemical methods (fractionation, Co-IP, lipid binding, KO phenotype) in a single rigorous study\",\n      \"pmids\": [\"41476177\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SigmaR1 oligomers use extended arrays of amphipathic helices to bind and flatten the lumenal leaflet of ER membranes, opposing membrane curvature and stabilizing rough ER sheets. Structure-guided mutagenesis and in vitro reconstitution on giant unilamellar vesicles supported this mechanism. SigmaR1 levels determine the amount of rough ER sheets in cells.\",\n      \"method\": \"Proteomics screen, high-resolution live cell imaging, electron tomography, structure-guided mutagenesis, in vitro reconstitution on giant unilamellar vesicles\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with mutagenesis and electron tomography in one study\",\n      \"pmids\": [\"38971154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ALS-linked SIGMAR1 variants (including p.L95fs) are unstable and incapable of binding to inositol 1,4,5-triphosphate receptor type 3 (IP3R3). Loss of Sig1R function causes mislocalization of IP3R3 from the mitochondria-associated membrane (MAM), calpain activation, and mitochondrial dysfunction. Sig1R deficiency accelerated disease onset in mutant SOD1 ALS mice, indicating MAM collapse is a shared pathomechanism.\",\n      \"method\": \"Co-IP (Sig1R–IP3R3 interaction), mouse genetic model (Sig1R KO × SOD1 mutant), immunofluorescence, biochemical fractionation\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding assay combined with in vivo genetic epistasis and multiple phenotypic readouts\",\n      \"pmids\": [\"27821430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Pharmacological or genetic inactivation of SIGMAR1 in motor neurons disrupts ER–mitochondria contacts, impairs intracellular calcium signaling, activates ER stress, and causes defects in mitochondrial dynamics and axonal transport, leading to axonal degeneration and cell death. Inhibition of mitochondrial fission alone recapitulated axonal transport defects and degeneration. Intracellular calcium scavenging and ER stress inhibition restored mitochondrial function and prevented motor neuron degeneration.\",\n      \"method\": \"Primary motor neuron cultures, pharmacological inhibition, siRNA knockdown, Sigmar1−/− mice, live imaging of mitochondrial dynamics, calcium imaging, epistasis experiments\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (genetic KO, pharmacological, epistasis rescue) with defined cellular phenotypes replicated in vivo and in vitro\",\n      \"pmids\": [\"25678561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SIGMAR1 knockout impairs autophagosome–lysosome fusion without affecting autophagosome biogenesis markers (BECN1, ATG7) or lysosomal pH/protease activity. SIGMAR1 co-immunoprecipitates with ATG14, STX17, and VAMP8 (but not SNAP29), proteins key to autophagosome–lysosome membrane fusion. Re-expressing SIGMAR1 in null background rescued clearance of mitochondria and autophagosomes.\",\n      \"method\": \"Sigmar1 knockout (CRISPR), Co-IP (SIGMAR1 with ATG14/STX17/VAMP8), GFP-RFP-LC3 fusion assay, lysosome colocalization, rescue experiments\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with multiple interaction partners, KO + rescue with defined mechanistic step (fusion), multiple orthogonal methods\",\n      \"pmids\": [\"30871407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SIGMAR1 facilitates TFEB transport into the nucleus by chaperoning the nuclear pore protein POM121, which recruits importin-β1 (KPNB1). In C9orf72-ALS cells, hexanucleotide repeat expansion reduces SIGMAR1–POM121 association, lowering nuclear TFEB, KPNB1, and LC3-II. SIGMAR1 overexpression or agonist treatment (pridopidine) rescued these deficits.\",\n      \"method\": \"Co-IP (SIGMAR1–POM121), overexpression, pharmacological agonism with pridopidine, nuclear fractionation, LC3-II western blot in NSC34 cells with C9orf72 HRE\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional rescue with defined downstream markers, single lab\",\n      \"pmids\": [\"35507432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SIGMAR1 stabilizes MAP1LC3B/LC3B and GABARAP mRNAs, promoting their localized translation proximal to the ER for efficient lipidation and autophagosome formation. SIGMAR1 directly binds a conserved region in the 3' UTR of LC3B mRNA. Cells lacking SIGMAR1 show reduced levels of many Atg8-family proteins and impaired autophagic flux.\",\n      \"method\": \"smFISH, Co-IP (SIGMAR1–LC3B mRNA), SIGMAR1 knockout cells, mRNA stability assays, lipidation assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with mRNA and smFISH, KO with phenotype, single lab with orthogonal methods\",\n      \"pmids\": [\"39369298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Two novel SIGMAR1 mutations (p.E138Q and p.E150K) reduce cell viability, cause formation of abnormal protein aggregates, prevent correct targeting of sigma-1R to the MAM, and impair global Ca2+ signaling and ER–mitochondria tethering in neuronal cell lines, demonstrating the chaperone activity of sigma-1R at the MAM as critical for motor neuron survival.\",\n      \"method\": \"Site-directed mutagenesis, cell viability assays, immunofluorescence for MAM localization, Ca2+ imaging, ER–mitochondria contact quantification in neuronal cell lines\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional mutation analysis with multiple orthogonal readouts (localization, Ca2+, viability), single lab\",\n      \"pmids\": [\"27402882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The ALS-linked SIGMAR1 variant p.E102Q promotes dissociation of sigma-1R from the ER membrane and cytoplasmic aggregation, impairs mitochondrial ATP production and proteasome activity, and causes aberrant extra-nuclear localization of TDP-43. Treatment with the mitochondrial Ca2+ transporter inhibitor Ru360 mimicked these effects, indicating that aberrant sigma-1R-mediated mitochondrial Ca2+ transport underlies TDP-43 mislocalization.\",\n      \"method\": \"Neuro2A overexpression of mutant vs. wild-type sigma-1R, mitochondrial function assays (ATP production), proteasome activity assay, TDP-43 immunofluorescence, pharmacological inhibition of mitochondrial Ca2+ transport\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple mechanistic assays in single lab, pharmacological epistasis supporting Ca2+ transport mechanism\",\n      \"pmids\": [\"25175561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SigmaR1 physically binds SK3 (KCNN3, a Ca2+-activated K+ channel) in breast cancer cells. SigmaR1 triggers coupling between SK3 and the Ca2+ channel Orai1, increasing Ca2+ influx. Inhibition of SigmaR1 decreased SK3 current and Ca2+ entry, and diminished SK3 and/or Orai1 levels in lipid nanodomains, reducing cancer cell invasiveness.\",\n      \"method\": \"Co-IP (SigmaR1–SK3), lipid nanodomain fractionation, patch-clamp electrophysiology, siRNA silencing, sigma ligand (igmesine) treatment\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP demonstrating direct binding plus functional readouts (current, Ca2+ entry, lipid raft levels), single lab\",\n      \"pmids\": [\"28114279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Sig1R dynamically controls the membrane expression of the hERG voltage-gated K+ channel in myeloid leukemia and colorectal cancer cells. Sig1R promotes formation of hERG/β1-integrin signaling complexes upon extracellular matrix stimulation, triggering PI3K/AKT pathway activation, increasing cell motility and VEGF secretion.\",\n      \"method\": \"Co-IP (hERG–Sig1R–β1-integrin complex), siRNA knockdown, PI3K/AKT pathway western blot, cell motility assay, in vivo xenograft model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP with functional downstream pathway validation and in vivo evidence, single lab\",\n      \"pmids\": [\"26645564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In cardiomyocytes, Sigmar1 localizes to mitochondrial membranes (confirmed by quantum dot electron microscopy, subcellular fractionation, and MitoTracker colocalization) and functions as an integral mitochondrial membrane protein (shown by alkaline extraction and proteinase K protection assays). The N-terminal region is required for mitochondrial localization. Sigmar1 siRNA knockdown significantly altered mitochondrial respiration in cardiomyocytes.\",\n      \"method\": \"Quantum dot transmission electron microscopy, subcellular fractionation, immunocytochemistry, alkaline extraction, proteinase K treatment, FLAG-tagged truncation constructs, extracellular flux analysis, high-resolution respirometry\",\n      \"journal\": \"Mitochondrion\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal biochemical and imaging methods for localization with functional KD consequence, single lab\",\n      \"pmids\": [\"34902622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Methamphetamine inhibits Sigmar1, resulting in inactivation of CREB, decreased expression of mitochondrial fission 1 protein (FIS1), and alteration of mitochondrial dynamics and function, leading to cardiomyopathy.\",\n      \"method\": \"Mouse 'binge and crash' methamphetamine model, human autopsy cardiac samples, western blot for CREB/FIS1, mitochondrial function assays, Sigmar1 KO mice\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo model with human validation, mechanistic signaling pathway defined, single lab\",\n      \"pmids\": [\"33203971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SIGMAR1 directly binds neuronal pentraxin-1 (NPTX1), promoting its ubiquitin-proteasome degradation. Downregulation of NPTX1 promotes AMPAR (GluA1 subunit) membrane trafficking and central sensitization, driving neuropathic pain. SIGMAR1 is upregulated in the spinal dorsal horn by mRNA m6A modification during neuropathic pain development.\",\n      \"method\": \"HPLC-MS/MS, Co-IP (SIGMAR1–NPTX1), methylated RNA immunoprecipitation (m6A), intrathecal SIGMAR1 siRNA/antagonist, AAV-mediated NPTX1 overexpression, AMPAR membrane trafficking assay\",\n      \"journal\": \"Neuroscience bulletin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP confirmed by MS, functional epistasis with in vivo gene manipulation, single lab\",\n      \"pmids\": [\"41457187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CdCl2 exposure activates SEL1L/HRD1-mediated ERAD, which promotes ubiquitinated degradation of SigmaR1 specifically at its K142 site, resulting in Ca2+ dyshomeostasis and mitochondrial dysfunction that activates the p53/p21/Rb neuronal senescence pathway.\",\n      \"method\": \"In vitro neuron culture, in vivo mouse model, ubiquitination assay with site-specific mutagenesis (K142), Co-IP (SEL1L/HRD1–SigmaR1), western blot for senescence markers, Ca2+ imaging\",\n      \"journal\": \"Journal of hazardous materials\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-specific ubiquitination with mutagenesis and pathway epistasis, single lab\",\n      \"pmids\": [\"38718507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"STUB1 (an E3 ubiquitin ligase) interacts with Sigmar1 and degrades it via ubiquitination in cardiomyocytes exposed to CVB3. STUB1-mediated Sigmar1 degradation promotes ER stress (upregulation of GRP78, Caspase-12, CHOP). Sigmar1 overexpression reversed CVB3-induced ER stress and cardiomyocyte apoptosis, while STUB1 overexpression counteracted Sigmar1 overexpression effects.\",\n      \"method\": \"Co-IP (STUB1–Sigmar1), ubiquitination assay, overexpression constructs in neonatal mouse cardiomyocytes, LDH assay, TUNEL apoptosis assay, western blot\",\n      \"journal\": \"General physiology and biophysics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay with epistasis rescue experiments, single lab\",\n      \"pmids\": [\"40567075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Sigmar1 suppresses COL1A1 expression and vascular fibrosis by blocking the TGF-β/Smad2/3 signaling pathway in vascular smooth muscle cells exposed to methamphetamine. Sigmar1 KO mice showed higher blood pressure and collagen deposition, while Sigmar1 agonist (PRE-084) prevented these effects.\",\n      \"method\": \"Sigmar1 KO mice, Sigmar1 antagonist (BD1047) and agonist (PRE-084), western blot for TGF-β/Smad2/3, collagen staining, blood pressure measurement\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO and pharmacological manipulation with defined signaling pathway, single lab\",\n      \"pmids\": [\"38851304\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Veratramine inhibited the expression of SIGMAR1 and the phosphorylation of NMDAR at Ser896 in spinal cord tissue, and inhibited formation of SIGMAR1–NMDAR and NMDAR–CaMKII protein complexes, thereby reducing neuropathic pain in diabetic rats.\",\n      \"method\": \"Co-IP (SIGMAR1–NMDAR, NMDAR–CaMKII complexes), western blot, in vivo rat diabetic neuropathy model with veratramine treatment\",\n      \"journal\": \"Pharmaceutical biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP for complex formation, pharmacological intervention without genetic controls, single lab\",\n      \"pmids\": [\"36373991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Alternatively spliced variants of sigma1 receptor all fail to bind sigma ligands when expressed in HEK293 cells, indicating that each truncated region is important for ligand binding. However, all splice variants retain the ability to physically associate with mu opioid receptor (mMOR-1) by Co-IP, and can disrupt sigma1 receptor dimerization with mMOR-1 in a dominant-negative manner.\",\n      \"method\": \"Ligand binding assay, Co-IP (splice variants with mMOR-1), competition Co-IP for dimerization, expression in HEK293 cells\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay and Co-IP with competition experiment, multiple splice variants tested, single lab\",\n      \"pmids\": [\"28350844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Cocaine enhances Sigma1R association with nuclear lamina proteins emerin, lamin A/C, and BANF1, causing Sigma1R-dependent and emerin-dependent transcriptional repression of MAOB1. Novel missense variants (p.Q2P and p.R208W) were identified as tools to study the molecular basis of this association.\",\n      \"method\": \"Co-IP (Sigma1R with emerin/lamin A/C/BANF1 in cocaine-treated cells), transcriptional repression assay, population genetics (ExAC database for variant identification)\",\n      \"journal\": \"Experimental biology and medicine (Maywood, N.J.)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP evidence cited from prior work, new variants identified but not functionally validated in this paper, single lab\",\n      \"pmids\": [\"31324122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CLCC1 co-localizes with SigmaR1 not only at the ER but also at mitochondria-associated ER membranes (MAMs), and SigmaR1 was identified as a CLCC1-interacting protein by LC-MS proteomics, validated by co-immunoprecipitation and microscopy.\",\n      \"method\": \"LC-MS proteomics, Co-IP (CLCC1–SigmaR1), immunofluorescence co-localization microscopy\",\n      \"journal\": \"Neuroscience letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP confirming MS-identified interaction, no functional consequence tested for SIGMAR1 specifically\",\n      \"pmids\": [\"38621504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SIGMAR1 activates SIRT3-mediated mitophagy, which alleviates endothelial ferroptosis and microvascular hyperpermeability in LPS-induced acute lung injury. SIRT3 deacetylates ATP5F1A at lysine 498; this deacetylation is essential for SIGMAR1-mediated PRKN/parkin-dependent mitophagy. Sigmar1 KO worsened ferroptosis and hyperpermeability, effects reversed by SIRT3 activation.\",\n      \"method\": \"Sigmar1 KO mice, pharmacological agonism (PRE-084), SIRT3 inhibition/activation, acetylation assay (ATP5F1A K498), mitophagy markers, GFP-LC3 puncta, mouse pulmonary microvascular endothelial cells\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO and pharmacological intervention with defined biochemical mechanism (deacetylation site), multiple orthogonal assays, single lab\",\n      \"pmids\": [\"41655128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"A splice-site mutation in SIGMAR1 (c.151+1G>T) generates a truncated protein σ1R(31_50del) that is degraded by the proteasome and forms nuclear aggregates upon proteasome inhibition. Stable expression of σ1R(31_50del) induces ER stress and enhances apoptosis in cell lines.\",\n      \"method\": \"RNA analysis of patient peripheral blood, stable cell line expression of mutant σ1R, proteasome inhibitor treatment, immunofluorescence, western blot, apoptosis assay\",\n      \"journal\": \"Neurology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, cell line overexpression with indirect mechanistic inference\",\n      \"pmids\": [\"26078401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Sigma-1 receptor agonist (+)-pentazocine promotes retinal ganglion cell survival after NMDA-induced excitotoxicity through a σR1-dependent mechanism and enhances activation of ERK1/2 (MAPK) at 6 hours post-NMDA. In σR1 knockout mice, (+)-pentazocine failed to protect RGCs and failed to activate ERK, placing σR1 upstream of ERK in the neuroprotective pathway.\",\n      \"method\": \"Intravitreal NMDA injection in WT and σR1 KO mice, intraperitoneal (+)-pentazocine treatment, retinal flat-mount RGC counting, TUNEL assay, western blot for ERK1/2 phosphorylation\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (KO abolishes both protection and ERK activation) with in vivo model, single lab\",\n      \"pmids\": [\"26868747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Absence of σR1 in knockout mice leads to late-onset inner retinal dysfunction (decreased ERG b-wave amplitudes, loss of ganglion cell layer cells, increased apoptosis by TUNEL/caspase-3), preceded by ultrastructural axonal disruption in the optic nerve head, establishing a direct role for σR1 in maintaining inner retinal neuron survival.\",\n      \"method\": \"σR1 knockout mice, electroretinography, morphometric analysis, TUNEL assay, active caspase-3 immunostaining, electron microscopy\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with multiple phenotypic readouts and ultrastructural evidence, single lab\",\n      \"pmids\": [\"21862648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Gut microbiota-derived short-chain fatty acids (SCFAs) ameliorate methamphetamine-induced depression- and anxiety-like behaviors through a SIGMAR1-dependent mechanism: Sigmar1 knockout (Sigmar1−/−) repressed the BDNF/TRKB pathway and produced behavioral phenotypes similar to methamphetamine exposure, and eliminated the anti-anxiety and anti-depression effects of SCFAs. Fluvoxamine-mediated SIGMAR1 activation attenuated methamphetamine-induced behaviors.\",\n      \"method\": \"Sigmar1 KO mice, fecal microbiota transplant, SCFA supplementation, fluvoxamine pharmacological activation, behavioral assays, western blot for SIGMAR1/BDNF/TRKB pathway\",\n      \"journal\": \"Acta pharmaceutica Sinica. B\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — genetic KO epistasis for pathway placement (SIGMAR1→BDNF/TRKB), but mechanistic link is indirect and single lab\",\n      \"pmids\": [\"38045052\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SIGMAR1 (sigma-1 receptor) is a type II integral ER membrane protein enriched at ER sheets, where its oligomeric amphipathic helices flatten the lumenal leaflet to stabilize rough ER sheet morphology; it functions as an auxiliary translocon factor by binding phosphatidylcholine and interacting with TRAPα and Nicalin to regulate protein and lipid homeostasis. At the mitochondria-associated ER membrane (MAM), SIGMAR1 acts as a chaperone that binds and stabilizes IP3R3, maintaining ER–mitochondria calcium transfer and tethering; loss-of-function mutations disrupt IP3R3 localization, impair mitochondrial Ca2+ transport and ATP production, activate calpain and ER stress, and cause motor neuron degeneration. SIGMAR1 also regulates autophagy at multiple steps: it stabilizes LC3B/GABARAP mRNAs for localized ER-proximal translation, interacts with ATG14/STX17/VAMP8 to facilitate autophagosome–lysosome fusion, and chaperones the nucleoporin POM121 to enable KPNB1-dependent nuclear import of the autophagy transcription factor TFEB. Additional mechanistic roles include regulation of ion channels (SK3/Orai1, hERG/β1-integrin/PI3K–AKT), neuroprotection via the ERK1/2 MAPK pathway, promotion of AMPAR trafficking through NPTX1 ubiquitination in nociceptive neurons, and suppression of vascular fibrosis through the TGF-β/Smad2/3 pathway; SIGMAR1 protein stability is regulated by STUB1-mediated ubiquitination and by SEL1L/HRD1-mediated ERAD at lysine 142.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SIGMAR1 (sigma-1 receptor) is a type II integral ER membrane protein enriched at ER sheets that couples ER membrane architecture, lipid and protein homeostasis, and inter-organelle calcium signaling [#0, #1]. Its oligomers use extended arrays of amphipathic helices to bind and flatten the lumenal leaflet of ER membranes, opposing curvature and stabilizing rough ER sheets, with cellular SIGMAR1 levels setting the amount of rough ER sheets [#1]; a C-terminal β-barrel binds phosphatidylcholine, and this lipid binding strengthens association with the translocon components TRAPα and Nicalin, such that SIGMAR1 loss disrupts cellular protein and lipid homeostasis [#0]. At mitochondria-associated ER membranes (MAM), SIGMAR1 acts as a chaperone that binds and stabilizes IP3R3 to maintain ER–mitochondria contacts and calcium transfer; ALS-linked variants are unstable, fail to bind IP3R3, mislocalize from the MAM, and trigger calpain activation, impaired mitochondrial ATP production, and ER stress, driving motor neuron degeneration [#2, #3, #7, #8]. SIGMAR1 promotes autophagy at several steps: it stabilizes LC3B and GABARAP mRNAs for localized ER-proximal translation [#6], interacts with the fusion machinery ATG14, STX17, and VAMP8 to enable autophagosome–lysosome fusion [#4], and chaperones the nucleoporin POM121 to support KPNB1-dependent nuclear import of TFEB [#5]. It also controls SIRT3-mediated, parkin-dependent mitophagy that limits endothelial ferroptosis [#21]. Beyond these core roles, SIGMAR1 regulates ion-channel signaling complexes (SK3/Orai1; hERG/β1-integrin/PI3K–AKT) [#9, #10], supports retinal and motor neuron survival through ERK1/2 MAPK signaling [#23, #24], promotes AMPAR trafficking via ubiquitin-dependent degradation of NPTX1 in nociceptive neurons [#13], and suppresses vascular fibrosis through the TGF-β/Smad2/3 pathway [#16]. SIGMAR1 protein abundance is controlled by ubiquitin-dependent turnover, including STUB1-mediated ubiquitination [#15] and SEL1L/HRD1-mediated ERAD at lysine 142 [#14].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Established that sigma-1 receptor is required for survival of inner retinal neurons in vivo, moving the protein from a pharmacological binding site to a cell-survival factor.\",\n      \"evidence\": \"σR1 knockout mice analyzed by electroretinography, morphometry, TUNEL/caspase-3, and electron microscopy\",\n      \"pmids\": [\"21862648\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular pathway linking σR1 loss to neuronal death not defined here\", \"Does not address whether the role is cell-autonomous in ganglion cells\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Linked an ALS-associated SIGMAR1 variant to mitochondrial Ca2+ handling, showing that aberrant Ca2+ transport, not just protein aggregation, drives TDP-43 mislocalization.\",\n      \"evidence\": \"Overexpression of p.E102Q vs wild-type in Neuro2A, ATP/proteasome assays, TDP-43 imaging, Ru360 pharmacological mimicry\",\n      \"pmids\": [\"25175561\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Overexpression system may not reflect endogenous stoichiometry\", \"Direct molecular target of Ca2+ transport not identified in this study\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated that SIGMAR1 maintains ER–mitochondria contacts and mitochondrial dynamics in motor neurons, defining a contact-site mechanism for axonal degeneration.\",\n      \"evidence\": \"Primary motor neuron cultures, pharmacological/siRNA inactivation, Sigmar1-/- mice, mitochondrial and calcium live imaging, epistasis rescue\",\n      \"pmids\": [\"25678561\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular tether partner at the contact site not resolved in this work\", \"Relative contribution of fission defect vs Ca2+ defect not fully separated\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified IP3R3 as the SIGMAR1 client at the MAM and showed ALS variants fail to bind and stabilize it, unifying chaperone activity with the degenerative phenotype.\",\n      \"evidence\": \"Co-IP of Sig1R–IP3R3, Sig1R KO × SOD1 mutant mouse epistasis, immunofluorescence, fractionation; plus mutagenesis of p.E138Q/p.E150K with Ca2+ and viability readouts\",\n      \"pmids\": [\"27821430\", \"27402882\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of IP3R3 binding not defined\", \"Whether IP3R3 is the sole relevant MAM client unaddressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed SIGMAR1 at the autophagosome–lysosome fusion step, distinguishing its role from autophagosome biogenesis.\",\n      \"evidence\": \"CRISPR Sigmar1 KO, reciprocal Co-IP with ATG14/STX17/VAMP8, GFP-RFP-LC3 flux assay, rescue\",\n      \"pmids\": [\"30871407\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How an ER-resident protein engages the fusion SNARE complex spatially unclear\", \"Direct vs indirect nature of SNARE interactions not dissected\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended SIGMAR1's autophagy role to nuclear import of TFEB via POM121 chaperoning, connecting it to nucleocytoplasmic transport in C9orf72-ALS.\",\n      \"evidence\": \"Co-IP of SIGMAR1–POM121, nuclear fractionation, pridopidine agonism, LC3-II readouts in NSC34 C9orf72 HRE cells\",\n      \"pmids\": [\"35507432\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; reciprocal validation limited\", \"Generality beyond C9orf72 context not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved the structural mechanism of SIGMAR1 as an ER-sheet morphogen, showing amphipathic-helix oligomers flatten the membrane lumenal leaflet.\",\n      \"evidence\": \"Proteomics, live imaging, electron tomography, structure-guided mutagenesis, in vitro reconstitution on GUVs\",\n      \"pmids\": [\"38971154\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Link between sheet-shaping and downstream homeostasis phenotypes not directly demonstrated\", \"Regulation of oligomerization in vivo unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined SIGMAR1 as a translocon-associated, phosphatidylcholine-binding factor governing protein and lipid homeostasis at ER sheets.\",\n      \"evidence\": \"Endogenous tagging, fractionation, Co-IP with TRAPα/Nicalin, lipid-binding assays, knockout phenotype (hepatocyte lipid droplets)\",\n      \"pmids\": [\"41476177\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic link from PC binding to translocon function not fully traced\", \"Substrate proteins affected at the translocon not enumerated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Added an RNA-level function: SIGMAR1 stabilizes Atg8-family mRNAs for ER-proximal localized translation, coupling autophagy to membrane biology.\",\n      \"evidence\": \"smFISH, Co-IP of SIGMAR1 with LC3B mRNA (3'UTR), KO cells, mRNA stability and lipidation assays\",\n      \"pmids\": [\"39369298\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect mRNA binding mechanism for an ER membrane protein unclear\", \"Breadth of mRNA targets beyond LC3B/GABARAP not mapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified SEL1L/HRD1 ERAD as a regulator of SIGMAR1 abundance via K142 ubiquitination, linking SIGMAR1 turnover to Ca2+ homeostasis and senescence.\",\n      \"evidence\": \"Neuron cultures, mouse model, site-specific (K142) ubiquitination assay, Co-IP of SEL1L/HRD1–SigmaR1, senescence markers\",\n      \"pmids\": [\"38718507\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological triggers of SIGMAR1 ERAD beyond CdCl2 unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a second degradation route (STUB1) and a substrate-level signaling output (NPTX1 ubiquitination driving AMPAR trafficking).\",\n      \"evidence\": \"Co-IP/ubiquitination of STUB1–Sigmar1 with ER-stress epistasis in cardiomyocytes; HPLC-MS/MS, Co-IP, m6A MeRIP, intrathecal manipulation, AMPAR trafficking assay for NPTX1\",\n      \"pmids\": [\"40567075\", \"41457187\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether STUB1 and SEL1L/HRD1 act on overlapping pools of SIGMAR1 unknown\", \"Both single-lab studies\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Connected SIGMAR1 to a mitophagy program (SIRT3/ATP5F1A K498 deacetylation, parkin-dependent) that restrains ferroptosis, broadening its mitochondrial quality-control role.\",\n      \"evidence\": \"Sigmar1 KO mice, PRE-084 agonism, SIRT3 modulation, ATP5F1A acetylation assay, GFP-LC3 mitophagy readouts in pulmonary microvascular endothelial cells\",\n      \"pmids\": [\"41655128\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which SIGMAR1 controls SIRT3 activity not defined\", \"Single lab and disease-model specific\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SIGMAR1's structural ER-sheet/translocon role mechanistically gives rise to its diverse downstream activities (MAM Ca2+ chaperone, autophagy regulator, ion-channel modulator) remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking membrane-shaping to chaperone and signaling outputs\", \"Endogenous ligand and conformational regulation not established in the corpus\", \"Direct structural data on client/partner complexes lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [2, 3, 5, 7]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [9, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [2, 3, 7]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [4, 5, 6, 21]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [10, 16, 23]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"IP3R3\", \"ATG14\", \"STX17\", \"VAMP8\", \"POM121\", \"NPTX1\", \"STUB1\", \"TRAPalpha\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}