{"gene":"CERS2","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2009,"finding":"CERS2 (CerS2/LASS2) encodes a ceramide synthase with substrate specificity toward very-long-chain fatty acid residues (C22–C24); knockout mice lack ceramide synthase activity toward C24:1 in brain and liver, and show strongly reduced ceramide species with acyl chains ≥C22 in liver, kidney, and brain, establishing CERS2 as the principal enzyme responsible for very-long-chain ceramide synthesis in vivo.","method":"Gene-trap knockout mouse (lacZ reporter), ceramide synthase activity assays, lipidomic analysis of brain/liver/kidney","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vivo genetic knockout with direct enzymatic activity assays and lipidomic quantification; comprehensive functional characterization","pmids":["19801672"],"is_preprint":false},{"year":2009,"finding":"CERS2 deficiency in mice causes progressive loss of myelin stainability (~50% loss of compacted myelin, ~80% loss of myelin basic protein), vesiculation and multifocal detachment of inner myelin lamellae in ~20% of peripheral nervous system axons, and cerebellar degeneration with microcysts, establishing CERS2 activity as required for myelin maintenance.","method":"Gene-trap knockout mouse, myelin biochemistry (MBP western blot), electron microscopy of peripheral nerve","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic KO with multiple orthogonal readouts (biochemical, morphological, histological) in a well-characterized animal model","pmids":["19801672"],"is_preprint":false},{"year":2007,"finding":"CerS2 expression in mouse brain is specifically localized to white matter tracts (oligodendrocytes) and is transiently increased during the period of active myelination; CerS2 is also the predominant ceramide synthase in Schwann cells of sciatic nerves, establishing its cell-type-specific role in myelin sphingolipid synthesis.","method":"In situ hybridization, Northern blot, real-time RT-PCR in mouse brain during postnatal development","journal":"Histochemistry and cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (ISH, Northern blot, RT-PCR) replicated across brain regions and cell types; well-characterized in context of CERS2 KO data","pmids":["17901973"],"is_preprint":false},{"year":2009,"finding":"CerS2 knockdown by siRNA causes broad disruption of ceramide homeostasis: VLC ceramides (C24, C24:1) decrease, while LC ceramides (C14, C16) increase via a ceramide-synthase-independent mechanism; this results in growth arrest without apoptosis, induction of autophagy, and activation of PERK and IRE1 arms of the unfolded protein response.","method":"siRNA knockdown, mass spectrometry-based sphingolipid analysis, autophagy and UPR assays","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single lab, multiple orthogonal assays (lipidomics, UPR pathway reporters, autophagy markers)","pmids":["19728861"],"is_preprint":false},{"year":2016,"finding":"CERS2 (and CERS3–6) are phosphorylated at cytoplasmic C-terminal residues, predominantly by casein kinase 2 (CK2); phosphorylation of CERS2 is especially important for its catalytic activity, primarily increasing its Vmax. Treatment with CK2-specific inhibitor CX-4945 lowered phosphorylation and reduced CERS2 activity; dephosphorylation of brain ceramide synthases severely reduced activity toward C22:0/C24:0-CoA substrates.","method":"Phosphoproteomic analysis, CK2 inhibitor (CX-4945) treatment, in vitro ceramide synthase activity assays, site-directed mutagenesis of phosphorylation sites, mouse brain dephosphorylation experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic activity assays combined with mutagenesis and pharmacological inhibition; replicated in cell and mouse brain contexts","pmids":["26887952"],"is_preprint":false},{"year":2013,"finding":"LASS2/CERS2 protein interacts directly with the C subunit of vacuolar H+-ATPase (V-ATPase, ATP6V0C), and this interaction is mediated specifically through the homeodomain of LASS2; loss of the homeodomain abolishes the ability to regulate V-ATPase activity and intracellular pH, while variants retaining the homeodomain reduce V-ATPase activity.","method":"Co-immunoprecipitation, immunofluorescence, immuno-electron microscopy, domain-deletion mutant transfection, BCECF/AM pH fluorescence assay","journal":"Journal of cellular biochemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reciprocal co-IP, immunoelectron microscopy, and pH functional assays; multiple orthogonal methods in one study confirming the interaction and its functional domain","pmids":["22991218"],"is_preprint":false},{"year":2012,"finding":"LASS2/CERS2 overexpression in MCF-7/ADR breast cancer cells increases extracellular and lysosomal pH by inhibiting V-ATPase activity, resulting in increased intracellular retention of doxorubicin and increased chemosensitivity; LASS2 knockdown in MCF-7 cells decreased chemosensitivity.","method":"LASS2 overexpression/siRNA knockdown, pH measurement, drug uptake assays, apoptosis assays, nude mouse xenograft","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function in cell lines plus in vivo xenograft; single lab, multiple readouts","pmids":["22580606"],"is_preprint":false},{"year":2015,"finding":"CERS2 overexpression in highly invasive MDA-MB-231 breast cancer cells inhibits migration and invasion by reducing V-ATPase activity, increasing extracellular pH, and decreasing pH-dependent activation of secreted MMP-2 and MMP-9; conversely, CERS2 knockdown in MCF7 cells increases V-ATPase activity, decreases extracellular pH, and increases MMP-2/9 activity and invasiveness.","method":"Overexpression/siRNA knockdown, V-ATPase activity assay, extracellular pH measurement, gelatin zymography for MMP-2/9, transwell invasion assay","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional (gain and loss of function), multiple mechanistic readouts; single lab","pmids":["25213553"],"is_preprint":false},{"year":2012,"finding":"Silencing of LASS2/TMSG1 in the prostate cancer cell line PC-3M-2B4 increases V-ATPase activity, raises extracellular hydrogen ion concentration, activates secreted MMP-2, and enhances migration and invasion in vitro, confirming that LASS2 suppresses cancer invasion through regulation of V-ATPase activity.","method":"siRNA knockdown, V-ATPase activity assay, pH-sensitive fluorescence probes, gelatin zymography, Matrigel invasion assay","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single lab, multiple functional readouts supporting the V-ATPase mechanism","pmids":["22573553"],"is_preprint":false},{"year":2010,"finding":"LASS2 overexpression in hepatocellular carcinoma HCCLM3 cells (which lack endogenous LASS2) increases intracellular H+ and decreases extracellular H+ via interaction with V-ATPase, and induces apoptosis through a mitochondrial pathway involving cytochrome c release from mitochondria and caspase-3 activation.","method":"Transient transfection, BCECF/BCECF-AM pH fluorescence probes, Annexin V/PI flow cytometry, cytochrome c western blot","journal":"Acta physiologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single lab, multiple functional readouts (pH, apoptosis, mitochondrial pathway markers)","pmids":["20571735"],"is_preprint":false},{"year":2021,"finding":"Phosphorylated LASS2 promotes β-catenin degradation through physical interaction with STK38, SCYL2, and ATP6V0C via the ubiquitin-proteasome pathway; phosphorylation at serine residue 248 of LASS2 is essential for this function. Dephosphorylation of LASS2 at S248 significantly enhances prostate cancer cell growth and metastasis in vivo.","method":"Co-immunoprecipitation, phosphorylation-deficient mutant (S248A), ubiquitin-proteasome pathway assays, in vivo xenograft","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with multiple partners plus mutant functional validation in vivo; single lab","pmids":["33852174"],"is_preprint":false},{"year":2025,"finding":"Dephosphorylation of LASS2 at serine residue 348 (identified by mass spectrometry) significantly enhances prostate cancer cell growth, migration and invasion through increasing V-ATPase activity, extracellular hydrogen ion concentration, and secretion of active MMP-2; the phosphatase inhibitor calyculin A reduces growth and invasion of aggressive prostate cancer cells.","method":"Mass spectrometry phosphosite mapping, phosphorylation-deficient mutants (S341A, S348A, S349A), V-ATPase activity assay, pH measurement, gelatin zymography, Matrigel invasion, pharmacological calyculin A treatment","journal":"Beijing da xue xue bao. Yi xue ban","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — MS-identified phosphosite validated with mutagenesis and multiple functional assays; single lab","pmids":["41399074"],"is_preprint":false},{"year":2019,"finding":"The S248A phosphorylation-deficient mutant of LASS2 promotes proliferation, migration and invasion of prostate cancer cells through increasing ATP6V0C (V-ATPase C subunit) expression, establishing that phosphorylation at aa248–250 is a key functional site for LASS2-mediated invasion suppression.","method":"Phosphorylation-deficient mutant construction, co-immunofluorescence colocalization with ATP6V0C, western blot, MTT, migration and invasion assays","journal":"Beijing da xue xue bao. Yi xue ban","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis with functional validation and co-localization; single lab","pmids":["30996356"],"is_preprint":false},{"year":2016,"finding":"ASGR1 (asialoglycoprotein receptor) directly interacts with LASS2/CERS2; ASGR1 overexpression decreases V-ATPase activity in hepatoma cells, and this effect is reversed by LASS2 knockdown, placing LASS2 downstream of ASGR1 in regulating V-ATPase-mediated tumor cell invasion.","method":"Co-immunoprecipitation (direct protein-protein interaction), LASS2 siRNA knockdown, V-ATPase activity assay, Matrigel invasion assay","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus epistasis by LASS2 knockdown rescue; single lab","pmids":["27241665"],"is_preprint":false},{"year":2018,"finding":"LASS2 overexpression induces mitochondrial fusion (elongation), reduces p-Drp1 and Fis1 expression, decreases mitochondrial membrane potential, and inhibits bladder cancer invasion and chemoresistance; these effects are mediated upstream through inhibition of ERK phosphorylation, which normally activates Drp1. ERK inhibitor PD98059 phenocopies LASS2 overexpression on Drp1 status.","method":"LASS2 plasmid transfection and siRNA knockdown, MitoTracker and JC-1 staining, western blot (p-ERK, p-Drp1, Fis1), Drp1 inhibitor Mdivi-1, ERK inhibitor PD98059, Matrigel invasion and apoptosis assays","journal":"Journal of Cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological epistasis (Mdivi-1, PD98059) plus gain/loss of function; single lab, multiple assays","pmids":["29581781"],"is_preprint":false},{"year":2018,"finding":"LASS2 overexpression in hepatocytes decreases V-ATPase activity and increases ROS, activating p38 MAPK and ERK1/2 signaling; hepatocyte-specific LASS2 knockout mice are resistant to high-fat diet-induced hepatic steatosis and insulin resistance, associated with elevated V-ATPase activity and reduced ROS and downstream MAPK signaling.","method":"Hepatocyte-specific CERS2 knockout (Cre-LoxP), high-fat diet feeding, V-ATPase activity assay, ROS measurement, western blot (p38 MAPK, ERK1/2), LASS2 overexpression in AML12 cells","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — tissue-specific KO plus gain-of-function, multiple mechanistic readouts; single lab","pmids":["29626628"],"is_preprint":false},{"year":2013,"finding":"Hepatocyte-specific Lass2/CERS2 knockout mice exposed to diethylnitrosamine (DEN) show enhanced liver tumorigenesis and elevated expression of PAI-1, TGF-β1 and Smad4 (not Smad7), suggesting LASS2 suppresses liver carcinogenesis in part by restraining the TGF-β1–Smad4–PAI-1 axis.","method":"Hepatocyte-specific knockout mouse, DEN carcinogenesis model, PCNA/EdU proliferation assay, TUNEL apoptosis assay, qPCR, western blot","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — tissue-specific KO in DEN model with multiple pathway readouts; single lab","pmids":["24337404"],"is_preprint":false},{"year":2017,"finding":"Liver-specific LASS2/CERS2 deletion delays liver regeneration after partial hepatectomy, with reduced PCNA, Ki67, cyclin A, CDK2, p-Rb, and decreased CDK4/cyclin D1 complex formation; delayed regeneration is partially compensated by late Akt phosphorylation activation.","method":"Liver-specific CERS2 knockout (Cre-LoxP), partial hepatectomy, co-immunoprecipitation (CDK4/cyclin D1), immunohistochemistry, western blot","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — tissue-specific KO, co-IP for complex detection, multiple cell-cycle readouts; single lab","pmids":["28958935"],"is_preprint":false},{"year":2021,"finding":"CerS2 downregulation by siRNA blocks the increase in VLC ceramides (C24, C24:1, C26:1) induced by SK1 knockdown and phenocopies fumonisin B1 (a pan-CerS inhibitor) in blocking p21 upregulation during oncogene-induced senescence in MCF10A cells expressing oncogenic K-Ras, demonstrating that CerS2-generated VLC ceramides are required for VLC ceramide accumulation and oncogene-induced senescence downstream of SK1 inhibition.","method":"siRNA knockdown of CerS2 and SK1, sphingolipid mass spectrometry, SA-β-gal assay, p21 western blot, fumonisin B1 treatment, cell-cycle analysis","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (CerS2 siRNA vs. SK1 KD vs. FB1 pharmacology) with lipidomic and phenotypic validation; single lab","pmids":["33414460"],"is_preprint":false},{"year":2024,"finding":"LASS2/CERS2 directly interacts with transferrin receptor (TFRC) as identified by co-IP coupled LC-MS; LASS2 overexpression regulates iron homeostasis and ferroptosis status in thyroid, breast, and liver cancer cells, inhibiting tumor migration, invasion and EMT, and this anti-metastatic effect is reversed by ferroptosis inhibitor Fer-1.","method":"Co-IP LC-MS proteomics, protein-protein docking, co-IP western blot, immunofluorescence, proximity ligation assay, ferroptosis assays (Fer-1/erastin treatment), invasion and EMT assays","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP validated by proximity ligation assay and functional epistasis; single lab, multiple cancer types","pmids":["38419028"],"is_preprint":false},{"year":2023,"finding":"LASS2 interacts with MDM2 and MDMX, causing dual inhibition that disrupts p53 degradation; LASS2 overexpression induces p53 phosphorylation at Ser15 and acetylation at Lys373, promoting p53 translocation from cytoplasm to nucleus in hepatoma cells (HepG2, HCCLM3, HuCCT1), establishing a p53-dependent tumor suppressor mechanism for LASS2 in liver cancer.","method":"Co-immunoprecipitation, gene set enrichment analysis, immunofluorescence, western blot (p-p53, acetyl-p53), gain-of-function overexpression","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with MDM2/MDMX, PTM detection by western blot, subcellular localization; single lab","pmids":["37963859"],"is_preprint":false},{"year":2024,"finding":"LASS2 inhibits PP2A activity and dissociates PP2A from β-catenin, preventing dephosphorylation of β-catenin and leading to accumulation of cytosolic phospho-β-catenin, which decreases transcription of ABCC2 and CD44 in bladder cancer stem cells, thereby sensitizing them to cisplatin.","method":"Co-immunoprecipitation, LC-MS proteomic identification of PP2A interaction, luciferase reporter assay, chromatin immunoprecipitation, PP2A activity assay, cell-derived and patient-derived xenograft models, LASS2 gain/loss of function","journal":"BMC medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP + LC-MS + ChIP + functional epistasis + in vivo PDX; single lab, multiple orthogonal methods","pmids":["38191448"],"is_preprint":false},{"year":2021,"finding":"Nrf2 transcriptionally activates LASS2/CERS2 expression by binding to antioxidant response elements (AREs) in the LASS2 promoter (three AREs identified), as demonstrated by luciferase reporter assay; Nrf2/LASS2 overexpression results in progestin resistance in endometrial cancer cells.","method":"Luciferase reporter assay (ARE-containing LASS2 promoter constructs), Nrf2 siRNA knockdown, western blot, RT-PCR, proliferation/apoptosis assays","journal":"American journal of translational research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter for direct transcriptional regulation plus functional KD; single lab","pmids":["33841656"],"is_preprint":false},{"year":2021,"finding":"Whole-body Cers2 knockout and rs267738 (E115A) CRISPR knock-in mice both exhibit glucose intolerance and impaired insulin secretion in vivo; islets from these models show reduced β-cell function with decreased insulin secretion ex vivo, and knock-in mice have reduced liver CERS2 activity, establishing this SNP as a partial loss-of-function allele that impairs glucose homeostasis.","method":"CRISPR knock-in mouse (rs267738), whole-body CERS2 knockout mouse, glucose tolerance tests, insulin secretion assays, ex vivo islet function, liver ceramide synthase activity assay, targeted lipidomics","journal":"The Journal of clinical endocrinology and metabolism","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — two independent genetic mouse models (KO and CRISPR KI) with in vivo metabolic and ex vivo islet function assays; enzymatic activity directly measured","pmids":["33705551"],"is_preprint":false},{"year":2025,"finding":"Both whole-body Cers2 knockout and rs267738 knock-in mice show glucose intolerance and impaired insulin secretion; islets from these models show reduced β-cell function (decreased ex vivo insulin secretion), confirming that CERS2 activity is required for normal β-cell function and glucose homeostasis.","method":"Cers2 knockout mouse, rs267738 knock-in mouse, glucose tolerance tests, in vivo and ex vivo insulin secretion, lipidomics, GWAS integration","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — independently replicates the knock-in finding from PMID 33705551 in a different cohort with additional ex vivo islet data and lipidomic integration","pmids":["39792658"],"is_preprint":false},{"year":2020,"finding":"LASS2 interacts with NDUFS2 (a subunit of mitochondrial complex I/OXPHOS), as identified by co-IP combined with LC-MS; LASS2 overexpression increases mitochondrial ROS (mtROS) and promotes AMPK phosphorylation, leading to inhibition of lipogenesis (decreased SREBP1, FAS) and promotion of lipolysis (increased ATGL, HSL), thereby reducing hepatocyte steatosis.","method":"Co-immunoprecipitation + LC-MS (NDUFS2 identification), LASS2 overexpression/knockdown in FFA-treated Hepa1-6 cells and mouse primary hepatocytes, mtROS measurement, AMPK/ACC phosphorylation western blot","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Moderate — single co-IP/LC-MS identification of NDUFS2 interaction with functional correlates; single lab, single method for interaction","pmids":["32279995"],"is_preprint":false},{"year":2014,"finding":"Renal sulfatide distribution is regionally determined by sphingoid base composition (C18-sphingosine in cortex/medulla, C18-phytosphingosine restricted to cortical structures, C20-sphingosine exclusively in papillae); CerS2 deletion causes bulk loss of C23/C24-acyl sulfatides and complete depletion of phytosphingosine-containing cortical sulfatides without compensation, revealing that CERS2 is required for synthesis of this specific sulfatide subclass.","method":"MALDI imaging mass spectrometry, LC-MS/MS of regional renal lipids, CerS2 knockout mouse, regional mRNA analysis of biosynthetic enzymes","journal":"Journal of lipid research","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — imaging MS plus LC-MS/MS with genetic KO; single lab but multiple orthogonal lipid analysis methods","pmids":["25267995"],"is_preprint":false},{"year":2017,"finding":"Knockdown of CerS2 in CHO-IgG cells alters cellular ceramide composition and, in combination with knockdown of Tbc1D20, recapitulates the increased antibody secretory productivity induced by mitosRNA-1978, suggesting CERS2 function at the ER influences vesicular trafficking in the secretory pathway.","method":"siRNA/shRNA knockdown in CHO cells, ceramide composition analysis, IgG productivity measurement, fed-batch production assay","journal":"Metabolic engineering","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, combination KD only, ceramide composition altered but mechanism of secretory pathway link not directly interrogated for CERS2 alone","pmids":["28088541"],"is_preprint":false},{"year":2025,"finding":"A novel small-molecule agonist DH20931 directly activates CerS2 (genetic evidence: CerS2 KO cells are resistant to DH20931), causing VLCC accumulation that induces ER stress via ATF4/CHOP/PUMA; CerS2 physically interacts with the ER calcium channel IP3R1 (co-IP), and DH20931 promotes this interaction, enhancing ER–mitochondria proximity and Ca²⁺ flux into mitochondria to trigger apoptosis.","method":"CerS2 knockout genetic validation, in vitro ceramide synthase activity assay, co-immunoprecipitation (CerS2–IP3R1), ER stress pathway western blots, ER–mitochondria proximity assay, mitochondrial Ca²⁺ measurement, orthotopic and PDX xenograft models","journal":"Molecular cancer therapeutics","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct enzymatic agonist validated by KO resistance, co-IP for novel interaction, multiple mechanistic pathway assays, in vivo confirmation; single lab but multiple orthogonal methods","pmids":["42012500"],"is_preprint":false},{"year":2005,"finding":"LASS2/CERS2 cannot functionally complement yeast Lag1p even when expressed from the strong ADH1 promoter or its natural LAG1 promoter; neither full-length LASS2 nor the LASS2ΔHOX fragment (lacking the homeodomain/HOX domain) rescues the slow growth defect of lag1Δlac1Δ double mutants, establishing functional non-equivalence between LASS2 and its yeast ortholog Lag1p.","method":"Yeast complementation (shuffling test, tetrad analysis) with LASS2 and LASS2ΔHOX expressed from LAG1 or ADH1 promoters","journal":"Microbiological research","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — direct genetic complementation assay; negative functional result is itself mechanistically informative about domain requirements; single lab","pmids":["16765836"],"is_preprint":false}],"current_model":"CERS2 is an ER-resident ceramide synthase with strong substrate specificity for very-long-chain acyl-CoAs (C22–C24), whose catalytic activity is positively regulated by casein kinase 2-mediated phosphorylation at cytoplasmic C-terminal residues (including Ser-348); in vivo it is essential for myelin sphingolipid synthesis (oligodendrocyte/Schwann cell-specific), β-cell function and glucose homeostasis, and liver integrity; mechanistically it suppresses tumor invasion by directly binding the V-ATPase C subunit (ATP6V0C) through its homeodomain to inhibit proton pump activity and reduce extracellular acidification/MMP activation, interacts with MDM2/MDMX to stabilize p53, inhibits PP2A to promote β-catenin phospho-degradation, interacts with TFRC to regulate iron homeostasis and ferroptosis, and physically associates with the IP3R1 ER calcium channel to modulate ER–mitochondria Ca²⁺ flux and apoptosis."},"narrative":{"mechanistic_narrative":"CERS2 (LASS2) is an endoplasmic reticulum-resident ceramide synthase that selectively acylates sphingoid bases with very-long-chain acyl-CoAs (C22–C24), making it the principal enzyme generating very-long-chain (VLC) ceramides in vivo [PMID:19801672]. Its catalytic output is set post-translationally: casein kinase 2 phosphorylates cytoplasmic C-terminal residues to raise its Vmax, and dephosphorylation collapses activity toward C22:0/C24:0-CoA substrates [PMID:26887952]. Through this VLC-ceramide supply, CERS2 governs tissue-specific physiology — it is expressed in oligodendrocytes and Schwann cells during active myelination and is required for myelin maintenance, as its loss causes myelin and cerebellar degeneration [PMID:19801672, PMID:17901973], and it is required for β-cell insulin secretion and glucose homeostasis, with a partial loss-of-function allele (rs267738/E115A) impairing both [PMID:33705551, PMID:39792658]. Disrupting CERS2 distorts the ceramide pool (falling VLC, rising long-chain species), triggering growth arrest, autophagy, and PERK/IRE1 unfolded-protein-response activation [PMID:19728861]. Beyond its enzymatic role, CERS2 acts as a tumor suppressor through a distinct protein-interaction module: it binds the V-ATPase C subunit ATP6V0C via its homeodomain to inhibit proton-pump activity, raising extracellular pH and suppressing pH-dependent MMP-2/9 activation, migration, and invasion [PMID:22991218, PMID:25213553]; this anti-invasive function is itself gated by phosphorylation at C-terminal serines [PMID:41399074, PMID:30996356]. CERS2 additionally engages MDM2/MDMX to stabilize and activate p53 [PMID:37963859], physically associates with the calcium channel IP3R1 to drive ER–mitochondria Ca²⁺ flux and apoptosis upon pharmacologic activation [PMID:42012500], and binds TFRC to modulate iron homeostasis and ferroptosis [PMID:38419028].","teleology":[{"year":2005,"claim":"Tested whether human LASS2/CERS2 is functionally equivalent to its yeast ortholog Lag1p, probing the role of its homeodomain.","evidence":"Yeast complementation shuffling/tetrad tests with full-length and ΔHOX LASS2 from LAG1 or ADH1 promoters","pmids":["16765836"],"confidence":"Medium","gaps":["Negative complementation does not define the biochemical activity LASS2 actually carries","Does not establish the homeodomain's true binding function"]},{"year":2007,"claim":"Established where and when CERS2 acts, localizing its expression to myelinating glia during active myelination.","evidence":"In situ hybridization, Northern blot, RT-PCR across mouse brain development and sciatic nerve","pmids":["17901973"],"confidence":"High","gaps":["Expression mapping alone does not prove a causal myelin requirement"]},{"year":2009,"claim":"Defined CERS2 as the principal enzyme for very-long-chain ceramide synthesis and showed its loss disrupts myelin maintenance, connecting an enzymatic activity to a tissue phenotype.","evidence":"Gene-trap knockout mouse with ceramide synthase activity assays, lipidomics, myelin biochemistry, and electron microscopy","pmids":["19801672"],"confidence":"High","gaps":["Does not resolve how altered ceramide chain length mechanically destabilizes myelin","Whole-body knockout cannot separate glial-intrinsic from systemic effects"]},{"year":2009,"claim":"Showed that CERS2 loss not only depletes VLC ceramides but reciprocally raises long-chain ceramides and triggers stress programs, linking ceramide-pool balance to autophagy and the UPR.","evidence":"siRNA knockdown with mass spectrometry sphingolipid profiling and UPR/autophagy assays","pmids":["19728861"],"confidence":"Medium","gaps":["The ceramide-synthase-independent rise in C14/C16 ceramide is unexplained","Single-lab cell-based system"]},{"year":2010,"claim":"Opened a non-catalytic, pH-based tumor-suppressor axis by linking CERS2 to V-ATPase and mitochondrial apoptosis.","evidence":"Overexpression in V-ATPase-related pH and apoptosis assays in hepatocellular carcinoma cells","pmids":["20571735"],"confidence":"Medium","gaps":["Did not yet demonstrate direct CERS2–V-ATPase binding","Mechanistic link between pH and apoptosis correlative"]},{"year":2013,"claim":"Identified the molecular basis of CERS2's pH control by demonstrating a direct homeodomain-mediated interaction with the V-ATPase C subunit ATP6V0C.","evidence":"Reciprocal co-IP, immuno-electron microscopy, domain-deletion mutants, BCECF pH assay","pmids":["22991218"],"confidence":"High","gaps":["Structural details of the homeodomain–ATP6V0C contact not resolved","Relationship between catalytic and V-ATPase-regulatory functions unclear"]},{"year":2012,"claim":"Generalized the V-ATPase-dependent invasion-suppression mechanism across breast and prostate cancer models, tying it to MMP activation and chemosensitivity.","evidence":"Gain/loss-of-function in cancer cell lines with pH, MMP zymography, invasion, drug-uptake and xenograft assays","pmids":["22580606","22573553"],"confidence":"Medium","gaps":["Single-lab models","Contribution of CERS2 enzymatic activity to these effects not isolated"]},{"year":2015,"claim":"Solidified the V-ATPase/pH/MMP invasion axis bidirectionally, showing CERS2 dose tunes extracellular acidification and MMP-2/9 activity.","evidence":"Bidirectional overexpression/knockdown with V-ATPase, pH, zymography, transwell assays","pmids":["25213553"],"confidence":"Medium","gaps":["Single-lab","Does not connect to phosphorylation control identified later"]},{"year":2016,"claim":"Revealed CK2 phosphorylation of CERS2's cytoplasmic C-terminus as the principal post-translational switch controlling its catalytic rate, and identified ASGR1 as an upstream regulator of its V-ATPase function.","evidence":"Phosphoproteomics, CK2 inhibitor CX-4945, site-directed mutagenesis, brain dephosphorylation activity assays; separately co-IP and knockdown epistasis for ASGR1","pmids":["26887952","27241665"],"confidence":"High","gaps":["How phosphorylation alters Vmax structurally unknown","Whether the same phosphosites govern catalytic and V-ATPase roles not resolved"]},{"year":2018,"claim":"Extended CERS2 tumor-suppressor signaling to mitochondrial dynamics, ROS/MAPK signaling, and hepatic metabolism through tissue-specific deletion.","evidence":"Hepatocyte-specific knockout and gain-of-function with ERK/Drp1 inhibitors, mitochondrial staining, ROS and MAPK readouts","pmids":["29581781","29626628"],"confidence":"Medium","gaps":["Relationship between V-ATPase, ROS and ERK/Drp1 effects not fully ordered","Single-lab models"]},{"year":2021,"claim":"Mapped specific phosphoserines (S248) controlling CERS2-driven β-catenin degradation and tied CERS2 activity to oncogene-induced senescence and β-cell glucose homeostasis.","evidence":"Phospho-deficient mutants and co-IP with STK38/SCYL2/ATP6V0C; CerS2/SK1 siRNA epistasis with senescence markers; CRISPR knock-in and knockout mice with glucose/islet assays","pmids":["33852174","33414460","33705551"],"confidence":"High","gaps":["How a single enzyme coordinates V-ATPase, β-catenin and metabolic roles is unresolved","Phosphosite numbering varies across studies"]},{"year":2023,"claim":"Defined a p53-dependent tumor-suppressor mechanism whereby CERS2 binds MDM2/MDMX to block p53 degradation and promote its nuclear activation.","evidence":"Co-IP with MDM2/MDMX, p53 PTM western blots, immunofluorescence localization in hepatoma cells","pmids":["37963859"],"confidence":"Medium","gaps":["Direct vs. indirect MDM2/MDMX binding not structurally defined","Single-lab overexpression-based"]},{"year":2024,"claim":"Broadened CERS2's interactome to PP2A/β-catenin chemoresistance control and to TFRC-mediated iron homeostasis and ferroptosis as anti-metastatic mechanisms.","evidence":"Co-IP/LC-MS, ChIP, PP2A activity and PDX assays; reciprocal co-IP, PLA and ferroptosis epistasis (Fer-1/erastin) across multiple cancer types","pmids":["38191448","38419028"],"confidence":"Medium","gaps":["Whether these interactions occur in the same cells/conditions as the V-ATPase axis is unknown","Single-lab studies"]},{"year":2025,"claim":"Demonstrated that direct pharmacologic activation of CERS2 drives VLC-ceramide accumulation, ER stress, and an IP3R1-dependent ER–mitochondria Ca²⁺/apoptosis axis, providing a druggable mechanistic loop.","evidence":"Small-molecule agonist DH20931 with CerS2-KO resistance, enzymatic assay, CerS2–IP3R1 co-IP, ER stress blots, ER–mito proximity and Ca²⁺ measurements, xenografts","pmids":["42012500","39792658"],"confidence":"High","gaps":["Structural basis of agonist binding not defined","Whether the IP3R1 interaction depends on catalytic activity unresolved"]},{"year":null,"claim":"It remains unresolved how the single CERS2 protein partitions between its VLC-ceramide catalytic activity and its many non-catalytic protein interactions (V-ATPase, MDM2/MDMX, PP2A, TFRC, IP3R1), and whether these interactions are mutually exclusive, context-specific, or coordinately regulated by phosphorylation.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of CERS2 or its interaction interfaces","No study isolating catalytic-dead vs. interaction-dead alleles across the diverse phenotypes","Most interaction findings come from single labs without reciprocal cross-validation"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,4,26]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[5,20,21]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,7,21]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[3,28]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,23]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[3,28]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[9,28]}],"complexes":[],"partners":["ATP6V0C","IP3R1","TFRC","MDM2","MDMX","ASGR1","NDUFS2","STK38"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96G23","full_name":"Ceramide synthase 2","aliases":["LAG1 longevity assurance homolog 2","SP260","Sphingosine N-acyltransferase CERS2","Tumor metastasis-suppressor gene 1 protein","Very-long-chain ceramide synthase CERS2"],"length_aa":380,"mass_kda":44.9,"function":"Ceramide synthase that catalyzes the transfer of the acyl chain from acyl-CoA to a sphingoid base, with high selectivity toward very-long-chain fatty acyl-CoA (chain length C22-C27) (PubMed:17977534, PubMed:18165233, PubMed:18541923, PubMed:19728861, PubMed:20937905, PubMed:22144673, PubMed:22661289, PubMed:26887952, PubMed:29632068). N-acylates sphinganine and sphingosine bases to form dihydroceramides and ceramides in de novo synthesis and salvage pathways, respectively (By similarity) (PubMed:17977534, PubMed:18165233, PubMed:18541923, PubMed:19728861, PubMed:20937905, PubMed:22144673, PubMed:22661289, PubMed:26887952, PubMed:29632068). Plays a non-redundant role in the synthesis of ceramides with very-long-chain fatty acids in kidney, liver and brain. Regulates the abundance of myelin-specific sphingolipids galactosylceramide and sulfatide that affects myelin sheath architecture and motor neuron functions (By similarity)","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q96G23/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CERS2","classification":"Not Classified","n_dependent_lines":316,"n_total_lines":1208,"dependency_fraction":0.26158940397350994},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2},{"gene":"CSNK2B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CERS2","total_profiled":1310},"omim":[{"mim_id":"619822","title":"BCL2-LIKE 13; BCL2L13","url":"https://www.omim.org/entry/619822"},{"mim_id":"615336","title":"CERAMIDE SYNTHASE 6; CERS6","url":"https://www.omim.org/entry/615336"},{"mim_id":"615335","title":"CERAMIDE SYNTHASE 5; CERS5","url":"https://www.omim.org/entry/615335"},{"mim_id":"615334","title":"CERAMIDE SYNTHASE 4; CERS4","url":"https://www.omim.org/entry/615334"},{"mim_id":"611813","title":"ELONGATION OF VERY LONG CHAIN FATTY ACIDS-LIKE 1; ELOVL1","url":"https://www.omim.org/entry/611813"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear membrane","reliability":"Supported"},{"location":"Endoplasmic reticulum","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"liver","ntpm":683.9}],"url":"https://www.proteinatlas.org/search/CERS2"},"hgnc":{"alias_symbol":["SP260","FLJ10243"],"prev_symbol":["LASS2"]},"alphafold":{"accession":"Q96G23","domains":[{"cath_id":"1.10.10.60","chopping":"81-124","consensus_level":"high","plddt":92.9423,"start":81,"end":124},{"cath_id":"-","chopping":"127-331","consensus_level":"high","plddt":94.714,"start":127,"end":331}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96G23","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96G23-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96G23-F1-predicted_aligned_error_v6.png","plddt_mean":86.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CERS2","jax_strain_url":"https://www.jax.org/strain/search?query=CERS2"},"sequence":{"accession":"Q96G23","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96G23.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96G23/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96G23"}},"corpus_meta":[{"pmid":"19801672","id":"PMC_19801672","title":"Adult 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oligodendrocyte-specific expression of CerS2/Lass2.","date":"2007","source":"Histochemistry and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/17901973","citation_count":93,"is_preprint":false},{"pmid":"22580606","id":"PMC_22580606","title":"LASS2 enhances chemosensitivity of breast cancer by counteracting acidic tumor microenvironment through inhibiting activity of V-ATPase proton pump.","date":"2012","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/22580606","citation_count":85,"is_preprint":false},{"pmid":"26887952","id":"PMC_26887952","title":"Enzyme Activities of the Ceramide Synthases CERS2-6 Are Regulated by Phosphorylation in the C-terminal Region.","date":"2016","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26887952","citation_count":73,"is_preprint":false},{"pmid":"26150338","id":"PMC_26150338","title":"miR-9 promotes cell proliferation and inhibits apoptosis by targeting LASS2 in bladder 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of V-ATPase activity.","date":"2016","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/27241665","citation_count":36,"is_preprint":false},{"pmid":"22573553","id":"PMC_22573553","title":"Silencing of a novel tumor metastasis suppressor gene LASS2/TMSG1 promotes invasion of prostate cancer cell in vitro through increase of vacuolar ATPase activity.","date":"2012","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22573553","citation_count":36,"is_preprint":false},{"pmid":"30463687","id":"PMC_30463687","title":"MicroRNA-98 promotes drug resistance and regulates mitochondrial dynamics by targeting LASS2 in bladder cancer cells.","date":"2018","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/30463687","citation_count":35,"is_preprint":false},{"pmid":"25238615","id":"PMC_25238615","title":"A gene variant in CERS2 is associated with rate of increase in albuminuria in patients with diabetes from ONTARGET and 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Sinica]","url":"https://pubmed.ncbi.nlm.nih.gov/20571735","citation_count":17,"is_preprint":false},{"pmid":"23407876","id":"PMC_23407876","title":"Expression of a tumor-associated gene, LASS2, in the human bladder carcinoma cell lines BIU-87, T24, EJ and EJ-M3.","date":"2013","source":"Experimental and therapeutic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/23407876","citation_count":17,"is_preprint":false},{"pmid":"30898713","id":"PMC_30898713","title":"miR-3622a promotes proliferation and invasion of bladder cancer cells by downregulating LASS2.","date":"2019","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/30898713","citation_count":16,"is_preprint":false},{"pmid":"28088541","id":"PMC_28088541","title":"Secretory pathway optimization of CHO producer cells by co-engineering of the mitosRNA-1978 target genes CerS2 and Tbc1D20.","date":"2017","source":"Metabolic 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Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/35517425","citation_count":6,"is_preprint":false},{"pmid":"32279995","id":"PMC_32279995","title":"LASS2 regulates hepatocyte steatosis by interacting with NDUFS2/OXPHOS related proteins.","date":"2020","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/32279995","citation_count":5,"is_preprint":false},{"pmid":"16765836","id":"PMC_16765836","title":"Expression of LASS2 controlled by LAG1 or ADH1 promoters cannot functionally complement Lag1p.","date":"2005","source":"Microbiological research","url":"https://pubmed.ncbi.nlm.nih.gov/16765836","citation_count":4,"is_preprint":false},{"pmid":"37963859","id":"PMC_37963859","title":"LASS2 enhances p53 protein stability and nuclear import to suppress liver cancer progression through interaction with MDM2/MDMX.","date":"2023","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/37963859","citation_count":3,"is_preprint":false},{"pmid":"36300249","id":"PMC_36300249","title":"LASS2 overexpression enhances early apoptosis of lung cancer cells through the caspase‑dependent pathway.","date":"2022","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/36300249","citation_count":3,"is_preprint":false},{"pmid":"31577563","id":"PMC_31577563","title":"Association of rs8444 polymorphism in the LASS2 3'-UTR and bladder cancer risk in Chinese population.","date":"2020","source":"European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation (ECP)","url":"https://pubmed.ncbi.nlm.nih.gov/31577563","citation_count":2,"is_preprint":false},{"pmid":"24842017","id":"PMC_24842017","title":"[LASS2/TMSG1 gene silencing promotes the invasiveness and metastatic of human prostatic carcinoma cells through increase in vacuolar ATPase activity].","date":"2014","source":"Zhonghua bing li xue za zhi = Chinese journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/24842017","citation_count":2,"is_preprint":false},{"pmid":"39233348","id":"PMC_39233348","title":"Downregulation of CerS4 Instead of CerS2 in Liver Effectively Alleviates Hepatic Insulin Resistance in HFD Male Mice.","date":"2024","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/39233348","citation_count":2,"is_preprint":false},{"pmid":"38757331","id":"PMC_38757331","title":"Expression of LASS2 Can be Regulated by Dihydroartemisinin to Regulate Cisplatin Chemosensitivity in Bladder Cancer Cells.","date":"2025","source":"Current pharmaceutical biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/38757331","citation_count":1,"is_preprint":false},{"pmid":"30996356","id":"PMC_30996356","title":"[Novel tumor metastasis suppressorgene LASS2/TMSG1 S248A mutant promotes invasion of prostate cancer cells through increasing ATP6V0C expression].","date":"2019","source":"Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30996356","citation_count":1,"is_preprint":false},{"pmid":"40894709","id":"PMC_40894709","title":"CerS2 is a druggable target in triple-negative breast cancer.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/40894709","citation_count":0,"is_preprint":false},{"pmid":"36946034","id":"PMC_36946034","title":"[LASS2/TMSG1 overexpression inhibits proliferation and promotes apoptosis of human lung cancer A549 cells possibly by upregulating ceramide and p38 MAPK to activate a signaling cascade].","date":"2023","source":"Nan fang yi ke da xue xue bao = Journal of Southern Medical University","url":"https://pubmed.ncbi.nlm.nih.gov/36946034","citation_count":0,"is_preprint":false},{"pmid":"15969039","id":"PMC_15969039","title":"[Study of the expression membrane protein LASS2].","date":"2003","source":"Sheng wu gong cheng xue bao = Chinese journal of biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/15969039","citation_count":0,"is_preprint":false},{"pmid":"41399074","id":"PMC_41399074","title":"[Effect of dephosphorylation of tumor metastasis suppressor gene LASS2 on vacuolar ATPase activity and invasiveness of prostate cancer].","date":"2025","source":"Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41399074","citation_count":0,"is_preprint":false},{"pmid":"42012500","id":"PMC_42012500","title":"CerS2 is a druggable target in triple-negative breast cancer.","date":"2026","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/42012500","citation_count":0,"is_preprint":false},{"pmid":"41483315","id":"PMC_41483315","title":"Discovery of a potential CERS2 inhibitor: hit compound identification via structure-based virtual screening and molecular dynamics simulations.","date":"2026","source":"Molecular diversity","url":"https://pubmed.ncbi.nlm.nih.gov/41483315","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.11.28.691118","title":"Uncoupling of nutrient sensing and cell size control by specific defects in ceramide structure","date":"2025-12-01","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.28.691118","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.05.13.653734","title":"Very long chain fatty acids drive 1-deoxy-Sphingolipid toxicity","date":"2025-05-16","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.13.653734","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.05.14.653935","title":"Serine palmitoyltransferase-mediated de novo sphingolipid biosynthesis is required for normal insulin production and glucose tolerance","date":"2025-05-17","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.14.653935","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.08.23.609447","title":"BCL2L13 Influences Autophagy and Ceramide Metabolism without Affecting Temozolomide Resistance in Glioblastoma","date":"2024-08-26","source":"bioRxiv","url":"https://doi.org/10.1101/2024.08.23.609447","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":36952,"output_tokens":8104,"usd":0.116208,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":17753,"output_tokens":4589,"usd":0.101745,"stage2_stop_reason":"end_turn"},"total_usd":0.217953,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2009,\n      \"finding\": \"CERS2 (CerS2/LASS2) encodes a ceramide synthase with substrate specificity toward very-long-chain fatty acid residues (C22–C24); knockout mice lack ceramide synthase activity toward C24:1 in brain and liver, and show strongly reduced ceramide species with acyl chains ≥C22 in liver, kidney, and brain, establishing CERS2 as the principal enzyme responsible for very-long-chain ceramide synthesis in vivo.\",\n      \"method\": \"Gene-trap knockout mouse (lacZ reporter), ceramide synthase activity assays, lipidomic analysis of brain/liver/kidney\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vivo genetic knockout with direct enzymatic activity assays and lipidomic quantification; comprehensive functional characterization\",\n      \"pmids\": [\"19801672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CERS2 deficiency in mice causes progressive loss of myelin stainability (~50% loss of compacted myelin, ~80% loss of myelin basic protein), vesiculation and multifocal detachment of inner myelin lamellae in ~20% of peripheral nervous system axons, and cerebellar degeneration with microcysts, establishing CERS2 activity as required for myelin maintenance.\",\n      \"method\": \"Gene-trap knockout mouse, myelin biochemistry (MBP western blot), electron microscopy of peripheral nerve\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic KO with multiple orthogonal readouts (biochemical, morphological, histological) in a well-characterized animal model\",\n      \"pmids\": [\"19801672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CerS2 expression in mouse brain is specifically localized to white matter tracts (oligodendrocytes) and is transiently increased during the period of active myelination; CerS2 is also the predominant ceramide synthase in Schwann cells of sciatic nerves, establishing its cell-type-specific role in myelin sphingolipid synthesis.\",\n      \"method\": \"In situ hybridization, Northern blot, real-time RT-PCR in mouse brain during postnatal development\",\n      \"journal\": \"Histochemistry and cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (ISH, Northern blot, RT-PCR) replicated across brain regions and cell types; well-characterized in context of CERS2 KO data\",\n      \"pmids\": [\"17901973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CerS2 knockdown by siRNA causes broad disruption of ceramide homeostasis: VLC ceramides (C24, C24:1) decrease, while LC ceramides (C14, C16) increase via a ceramide-synthase-independent mechanism; this results in growth arrest without apoptosis, induction of autophagy, and activation of PERK and IRE1 arms of the unfolded protein response.\",\n      \"method\": \"siRNA knockdown, mass spectrometry-based sphingolipid analysis, autophagy and UPR assays\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single lab, multiple orthogonal assays (lipidomics, UPR pathway reporters, autophagy markers)\",\n      \"pmids\": [\"19728861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CERS2 (and CERS3–6) are phosphorylated at cytoplasmic C-terminal residues, predominantly by casein kinase 2 (CK2); phosphorylation of CERS2 is especially important for its catalytic activity, primarily increasing its Vmax. Treatment with CK2-specific inhibitor CX-4945 lowered phosphorylation and reduced CERS2 activity; dephosphorylation of brain ceramide synthases severely reduced activity toward C22:0/C24:0-CoA substrates.\",\n      \"method\": \"Phosphoproteomic analysis, CK2 inhibitor (CX-4945) treatment, in vitro ceramide synthase activity assays, site-directed mutagenesis of phosphorylation sites, mouse brain dephosphorylation experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic activity assays combined with mutagenesis and pharmacological inhibition; replicated in cell and mouse brain contexts\",\n      \"pmids\": [\"26887952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"LASS2/CERS2 protein interacts directly with the C subunit of vacuolar H+-ATPase (V-ATPase, ATP6V0C), and this interaction is mediated specifically through the homeodomain of LASS2; loss of the homeodomain abolishes the ability to regulate V-ATPase activity and intracellular pH, while variants retaining the homeodomain reduce V-ATPase activity.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, immuno-electron microscopy, domain-deletion mutant transfection, BCECF/AM pH fluorescence assay\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reciprocal co-IP, immunoelectron microscopy, and pH functional assays; multiple orthogonal methods in one study confirming the interaction and its functional domain\",\n      \"pmids\": [\"22991218\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"LASS2/CERS2 overexpression in MCF-7/ADR breast cancer cells increases extracellular and lysosomal pH by inhibiting V-ATPase activity, resulting in increased intracellular retention of doxorubicin and increased chemosensitivity; LASS2 knockdown in MCF-7 cells decreased chemosensitivity.\",\n      \"method\": \"LASS2 overexpression/siRNA knockdown, pH measurement, drug uptake assays, apoptosis assays, nude mouse xenograft\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function in cell lines plus in vivo xenograft; single lab, multiple readouts\",\n      \"pmids\": [\"22580606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CERS2 overexpression in highly invasive MDA-MB-231 breast cancer cells inhibits migration and invasion by reducing V-ATPase activity, increasing extracellular pH, and decreasing pH-dependent activation of secreted MMP-2 and MMP-9; conversely, CERS2 knockdown in MCF7 cells increases V-ATPase activity, decreases extracellular pH, and increases MMP-2/9 activity and invasiveness.\",\n      \"method\": \"Overexpression/siRNA knockdown, V-ATPase activity assay, extracellular pH measurement, gelatin zymography for MMP-2/9, transwell invasion assay\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional (gain and loss of function), multiple mechanistic readouts; single lab\",\n      \"pmids\": [\"25213553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Silencing of LASS2/TMSG1 in the prostate cancer cell line PC-3M-2B4 increases V-ATPase activity, raises extracellular hydrogen ion concentration, activates secreted MMP-2, and enhances migration and invasion in vitro, confirming that LASS2 suppresses cancer invasion through regulation of V-ATPase activity.\",\n      \"method\": \"siRNA knockdown, V-ATPase activity assay, pH-sensitive fluorescence probes, gelatin zymography, Matrigel invasion assay\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single lab, multiple functional readouts supporting the V-ATPase mechanism\",\n      \"pmids\": [\"22573553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"LASS2 overexpression in hepatocellular carcinoma HCCLM3 cells (which lack endogenous LASS2) increases intracellular H+ and decreases extracellular H+ via interaction with V-ATPase, and induces apoptosis through a mitochondrial pathway involving cytochrome c release from mitochondria and caspase-3 activation.\",\n      \"method\": \"Transient transfection, BCECF/BCECF-AM pH fluorescence probes, Annexin V/PI flow cytometry, cytochrome c western blot\",\n      \"journal\": \"Acta physiologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single lab, multiple functional readouts (pH, apoptosis, mitochondrial pathway markers)\",\n      \"pmids\": [\"20571735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Phosphorylated LASS2 promotes β-catenin degradation through physical interaction with STK38, SCYL2, and ATP6V0C via the ubiquitin-proteasome pathway; phosphorylation at serine residue 248 of LASS2 is essential for this function. Dephosphorylation of LASS2 at S248 significantly enhances prostate cancer cell growth and metastasis in vivo.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation-deficient mutant (S248A), ubiquitin-proteasome pathway assays, in vivo xenograft\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with multiple partners plus mutant functional validation in vivo; single lab\",\n      \"pmids\": [\"33852174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Dephosphorylation of LASS2 at serine residue 348 (identified by mass spectrometry) significantly enhances prostate cancer cell growth, migration and invasion through increasing V-ATPase activity, extracellular hydrogen ion concentration, and secretion of active MMP-2; the phosphatase inhibitor calyculin A reduces growth and invasion of aggressive prostate cancer cells.\",\n      \"method\": \"Mass spectrometry phosphosite mapping, phosphorylation-deficient mutants (S341A, S348A, S349A), V-ATPase activity assay, pH measurement, gelatin zymography, Matrigel invasion, pharmacological calyculin A treatment\",\n      \"journal\": \"Beijing da xue xue bao. Yi xue ban\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — MS-identified phosphosite validated with mutagenesis and multiple functional assays; single lab\",\n      \"pmids\": [\"41399074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The S248A phosphorylation-deficient mutant of LASS2 promotes proliferation, migration and invasion of prostate cancer cells through increasing ATP6V0C (V-ATPase C subunit) expression, establishing that phosphorylation at aa248–250 is a key functional site for LASS2-mediated invasion suppression.\",\n      \"method\": \"Phosphorylation-deficient mutant construction, co-immunofluorescence colocalization with ATP6V0C, western blot, MTT, migration and invasion assays\",\n      \"journal\": \"Beijing da xue xue bao. Yi xue ban\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis with functional validation and co-localization; single lab\",\n      \"pmids\": [\"30996356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ASGR1 (asialoglycoprotein receptor) directly interacts with LASS2/CERS2; ASGR1 overexpression decreases V-ATPase activity in hepatoma cells, and this effect is reversed by LASS2 knockdown, placing LASS2 downstream of ASGR1 in regulating V-ATPase-mediated tumor cell invasion.\",\n      \"method\": \"Co-immunoprecipitation (direct protein-protein interaction), LASS2 siRNA knockdown, V-ATPase activity assay, Matrigel invasion assay\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus epistasis by LASS2 knockdown rescue; single lab\",\n      \"pmids\": [\"27241665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"LASS2 overexpression induces mitochondrial fusion (elongation), reduces p-Drp1 and Fis1 expression, decreases mitochondrial membrane potential, and inhibits bladder cancer invasion and chemoresistance; these effects are mediated upstream through inhibition of ERK phosphorylation, which normally activates Drp1. ERK inhibitor PD98059 phenocopies LASS2 overexpression on Drp1 status.\",\n      \"method\": \"LASS2 plasmid transfection and siRNA knockdown, MitoTracker and JC-1 staining, western blot (p-ERK, p-Drp1, Fis1), Drp1 inhibitor Mdivi-1, ERK inhibitor PD98059, Matrigel invasion and apoptosis assays\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological epistasis (Mdivi-1, PD98059) plus gain/loss of function; single lab, multiple assays\",\n      \"pmids\": [\"29581781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"LASS2 overexpression in hepatocytes decreases V-ATPase activity and increases ROS, activating p38 MAPK and ERK1/2 signaling; hepatocyte-specific LASS2 knockout mice are resistant to high-fat diet-induced hepatic steatosis and insulin resistance, associated with elevated V-ATPase activity and reduced ROS and downstream MAPK signaling.\",\n      \"method\": \"Hepatocyte-specific CERS2 knockout (Cre-LoxP), high-fat diet feeding, V-ATPase activity assay, ROS measurement, western blot (p38 MAPK, ERK1/2), LASS2 overexpression in AML12 cells\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific KO plus gain-of-function, multiple mechanistic readouts; single lab\",\n      \"pmids\": [\"29626628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Hepatocyte-specific Lass2/CERS2 knockout mice exposed to diethylnitrosamine (DEN) show enhanced liver tumorigenesis and elevated expression of PAI-1, TGF-β1 and Smad4 (not Smad7), suggesting LASS2 suppresses liver carcinogenesis in part by restraining the TGF-β1–Smad4–PAI-1 axis.\",\n      \"method\": \"Hepatocyte-specific knockout mouse, DEN carcinogenesis model, PCNA/EdU proliferation assay, TUNEL apoptosis assay, qPCR, western blot\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific KO in DEN model with multiple pathway readouts; single lab\",\n      \"pmids\": [\"24337404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Liver-specific LASS2/CERS2 deletion delays liver regeneration after partial hepatectomy, with reduced PCNA, Ki67, cyclin A, CDK2, p-Rb, and decreased CDK4/cyclin D1 complex formation; delayed regeneration is partially compensated by late Akt phosphorylation activation.\",\n      \"method\": \"Liver-specific CERS2 knockout (Cre-LoxP), partial hepatectomy, co-immunoprecipitation (CDK4/cyclin D1), immunohistochemistry, western blot\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific KO, co-IP for complex detection, multiple cell-cycle readouts; single lab\",\n      \"pmids\": [\"28958935\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CerS2 downregulation by siRNA blocks the increase in VLC ceramides (C24, C24:1, C26:1) induced by SK1 knockdown and phenocopies fumonisin B1 (a pan-CerS inhibitor) in blocking p21 upregulation during oncogene-induced senescence in MCF10A cells expressing oncogenic K-Ras, demonstrating that CerS2-generated VLC ceramides are required for VLC ceramide accumulation and oncogene-induced senescence downstream of SK1 inhibition.\",\n      \"method\": \"siRNA knockdown of CerS2 and SK1, sphingolipid mass spectrometry, SA-β-gal assay, p21 western blot, fumonisin B1 treatment, cell-cycle analysis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (CerS2 siRNA vs. SK1 KD vs. FB1 pharmacology) with lipidomic and phenotypic validation; single lab\",\n      \"pmids\": [\"33414460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LASS2/CERS2 directly interacts with transferrin receptor (TFRC) as identified by co-IP coupled LC-MS; LASS2 overexpression regulates iron homeostasis and ferroptosis status in thyroid, breast, and liver cancer cells, inhibiting tumor migration, invasion and EMT, and this anti-metastatic effect is reversed by ferroptosis inhibitor Fer-1.\",\n      \"method\": \"Co-IP LC-MS proteomics, protein-protein docking, co-IP western blot, immunofluorescence, proximity ligation assay, ferroptosis assays (Fer-1/erastin treatment), invasion and EMT assays\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP validated by proximity ligation assay and functional epistasis; single lab, multiple cancer types\",\n      \"pmids\": [\"38419028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LASS2 interacts with MDM2 and MDMX, causing dual inhibition that disrupts p53 degradation; LASS2 overexpression induces p53 phosphorylation at Ser15 and acetylation at Lys373, promoting p53 translocation from cytoplasm to nucleus in hepatoma cells (HepG2, HCCLM3, HuCCT1), establishing a p53-dependent tumor suppressor mechanism for LASS2 in liver cancer.\",\n      \"method\": \"Co-immunoprecipitation, gene set enrichment analysis, immunofluorescence, western blot (p-p53, acetyl-p53), gain-of-function overexpression\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with MDM2/MDMX, PTM detection by western blot, subcellular localization; single lab\",\n      \"pmids\": [\"37963859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LASS2 inhibits PP2A activity and dissociates PP2A from β-catenin, preventing dephosphorylation of β-catenin and leading to accumulation of cytosolic phospho-β-catenin, which decreases transcription of ABCC2 and CD44 in bladder cancer stem cells, thereby sensitizing them to cisplatin.\",\n      \"method\": \"Co-immunoprecipitation, LC-MS proteomic identification of PP2A interaction, luciferase reporter assay, chromatin immunoprecipitation, PP2A activity assay, cell-derived and patient-derived xenograft models, LASS2 gain/loss of function\",\n      \"journal\": \"BMC medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP + LC-MS + ChIP + functional epistasis + in vivo PDX; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"38191448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Nrf2 transcriptionally activates LASS2/CERS2 expression by binding to antioxidant response elements (AREs) in the LASS2 promoter (three AREs identified), as demonstrated by luciferase reporter assay; Nrf2/LASS2 overexpression results in progestin resistance in endometrial cancer cells.\",\n      \"method\": \"Luciferase reporter assay (ARE-containing LASS2 promoter constructs), Nrf2 siRNA knockdown, western blot, RT-PCR, proliferation/apoptosis assays\",\n      \"journal\": \"American journal of translational research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter for direct transcriptional regulation plus functional KD; single lab\",\n      \"pmids\": [\"33841656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Whole-body Cers2 knockout and rs267738 (E115A) CRISPR knock-in mice both exhibit glucose intolerance and impaired insulin secretion in vivo; islets from these models show reduced β-cell function with decreased insulin secretion ex vivo, and knock-in mice have reduced liver CERS2 activity, establishing this SNP as a partial loss-of-function allele that impairs glucose homeostasis.\",\n      \"method\": \"CRISPR knock-in mouse (rs267738), whole-body CERS2 knockout mouse, glucose tolerance tests, insulin secretion assays, ex vivo islet function, liver ceramide synthase activity assay, targeted lipidomics\",\n      \"journal\": \"The Journal of clinical endocrinology and metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — two independent genetic mouse models (KO and CRISPR KI) with in vivo metabolic and ex vivo islet function assays; enzymatic activity directly measured\",\n      \"pmids\": [\"33705551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Both whole-body Cers2 knockout and rs267738 knock-in mice show glucose intolerance and impaired insulin secretion; islets from these models show reduced β-cell function (decreased ex vivo insulin secretion), confirming that CERS2 activity is required for normal β-cell function and glucose homeostasis.\",\n      \"method\": \"Cers2 knockout mouse, rs267738 knock-in mouse, glucose tolerance tests, in vivo and ex vivo insulin secretion, lipidomics, GWAS integration\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — independently replicates the knock-in finding from PMID 33705551 in a different cohort with additional ex vivo islet data and lipidomic integration\",\n      \"pmids\": [\"39792658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LASS2 interacts with NDUFS2 (a subunit of mitochondrial complex I/OXPHOS), as identified by co-IP combined with LC-MS; LASS2 overexpression increases mitochondrial ROS (mtROS) and promotes AMPK phosphorylation, leading to inhibition of lipogenesis (decreased SREBP1, FAS) and promotion of lipolysis (increased ATGL, HSL), thereby reducing hepatocyte steatosis.\",\n      \"method\": \"Co-immunoprecipitation + LC-MS (NDUFS2 identification), LASS2 overexpression/knockdown in FFA-treated Hepa1-6 cells and mouse primary hepatocytes, mtROS measurement, AMPK/ACC phosphorylation western blot\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single co-IP/LC-MS identification of NDUFS2 interaction with functional correlates; single lab, single method for interaction\",\n      \"pmids\": [\"32279995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Renal sulfatide distribution is regionally determined by sphingoid base composition (C18-sphingosine in cortex/medulla, C18-phytosphingosine restricted to cortical structures, C20-sphingosine exclusively in papillae); CerS2 deletion causes bulk loss of C23/C24-acyl sulfatides and complete depletion of phytosphingosine-containing cortical sulfatides without compensation, revealing that CERS2 is required for synthesis of this specific sulfatide subclass.\",\n      \"method\": \"MALDI imaging mass spectrometry, LC-MS/MS of regional renal lipids, CerS2 knockout mouse, regional mRNA analysis of biosynthetic enzymes\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — imaging MS plus LC-MS/MS with genetic KO; single lab but multiple orthogonal lipid analysis methods\",\n      \"pmids\": [\"25267995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Knockdown of CerS2 in CHO-IgG cells alters cellular ceramide composition and, in combination with knockdown of Tbc1D20, recapitulates the increased antibody secretory productivity induced by mitosRNA-1978, suggesting CERS2 function at the ER influences vesicular trafficking in the secretory pathway.\",\n      \"method\": \"siRNA/shRNA knockdown in CHO cells, ceramide composition analysis, IgG productivity measurement, fed-batch production assay\",\n      \"journal\": \"Metabolic engineering\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, combination KD only, ceramide composition altered but mechanism of secretory pathway link not directly interrogated for CERS2 alone\",\n      \"pmids\": [\"28088541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A novel small-molecule agonist DH20931 directly activates CerS2 (genetic evidence: CerS2 KO cells are resistant to DH20931), causing VLCC accumulation that induces ER stress via ATF4/CHOP/PUMA; CerS2 physically interacts with the ER calcium channel IP3R1 (co-IP), and DH20931 promotes this interaction, enhancing ER–mitochondria proximity and Ca²⁺ flux into mitochondria to trigger apoptosis.\",\n      \"method\": \"CerS2 knockout genetic validation, in vitro ceramide synthase activity assay, co-immunoprecipitation (CerS2–IP3R1), ER stress pathway western blots, ER–mitochondria proximity assay, mitochondrial Ca²⁺ measurement, orthotopic and PDX xenograft models\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct enzymatic agonist validated by KO resistance, co-IP for novel interaction, multiple mechanistic pathway assays, in vivo confirmation; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"42012500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"LASS2/CERS2 cannot functionally complement yeast Lag1p even when expressed from the strong ADH1 promoter or its natural LAG1 promoter; neither full-length LASS2 nor the LASS2ΔHOX fragment (lacking the homeodomain/HOX domain) rescues the slow growth defect of lag1Δlac1Δ double mutants, establishing functional non-equivalence between LASS2 and its yeast ortholog Lag1p.\",\n      \"method\": \"Yeast complementation (shuffling test, tetrad analysis) with LASS2 and LASS2ΔHOX expressed from LAG1 or ADH1 promoters\",\n      \"journal\": \"Microbiological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct genetic complementation assay; negative functional result is itself mechanistically informative about domain requirements; single lab\",\n      \"pmids\": [\"16765836\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CERS2 is an ER-resident ceramide synthase with strong substrate specificity for very-long-chain acyl-CoAs (C22–C24), whose catalytic activity is positively regulated by casein kinase 2-mediated phosphorylation at cytoplasmic C-terminal residues (including Ser-348); in vivo it is essential for myelin sphingolipid synthesis (oligodendrocyte/Schwann cell-specific), β-cell function and glucose homeostasis, and liver integrity; mechanistically it suppresses tumor invasion by directly binding the V-ATPase C subunit (ATP6V0C) through its homeodomain to inhibit proton pump activity and reduce extracellular acidification/MMP activation, interacts with MDM2/MDMX to stabilize p53, inhibits PP2A to promote β-catenin phospho-degradation, interacts with TFRC to regulate iron homeostasis and ferroptosis, and physically associates with the IP3R1 ER calcium channel to modulate ER–mitochondria Ca²⁺ flux and apoptosis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CERS2 (LASS2) is an endoplasmic reticulum-resident ceramide synthase that selectively acylates sphingoid bases with very-long-chain acyl-CoAs (C22–C24), making it the principal enzyme generating very-long-chain (VLC) ceramides in vivo [#0]. Its catalytic output is set post-translationally: casein kinase 2 phosphorylates cytoplasmic C-terminal residues to raise its Vmax, and dephosphorylation collapses activity toward C22:0/C24:0-CoA substrates [#4]. Through this VLC-ceramide supply, CERS2 governs tissue-specific physiology — it is expressed in oligodendrocytes and Schwann cells during active myelination and is required for myelin maintenance, as its loss causes myelin and cerebellar degeneration [#1, #2], and it is required for β-cell insulin secretion and glucose homeostasis, with a partial loss-of-function allele (rs267738/E115A) impairing both [#23, #24]. Disrupting CERS2 distorts the ceramide pool (falling VLC, rising long-chain species), triggering growth arrest, autophagy, and PERK/IRE1 unfolded-protein-response activation [#3]. Beyond its enzymatic role, CERS2 acts as a tumor suppressor through a distinct protein-interaction module: it binds the V-ATPase C subunit ATP6V0C via its homeodomain to inhibit proton-pump activity, raising extracellular pH and suppressing pH-dependent MMP-2/9 activation, migration, and invasion [#5, #7]; this anti-invasive function is itself gated by phosphorylation at C-terminal serines [#11, #12]. CERS2 additionally engages MDM2/MDMX to stabilize and activate p53 [#20], physically associates with the calcium channel IP3R1 to drive ER–mitochondria Ca²⁺ flux and apoptosis upon pharmacologic activation [#28], and binds TFRC to modulate iron homeostasis and ferroptosis [#19].\"\n  ,\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Tested whether human LASS2/CERS2 is functionally equivalent to its yeast ortholog Lag1p, probing the role of its homeodomain.\",\n      \"evidence\": \"Yeast complementation shuffling/tetrad tests with full-length and ΔHOX LASS2 from LAG1 or ADH1 promoters\",\n      \"pmids\": [\"16765836\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Negative complementation does not define the biochemical activity LASS2 actually carries\", \"Does not establish the homeodomain's true binding function\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Established where and when CERS2 acts, localizing its expression to myelinating glia during active myelination.\",\n      \"evidence\": \"In situ hybridization, Northern blot, RT-PCR across mouse brain development and sciatic nerve\",\n      \"pmids\": [\"17901973\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Expression mapping alone does not prove a causal myelin requirement\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined CERS2 as the principal enzyme for very-long-chain ceramide synthesis and showed its loss disrupts myelin maintenance, connecting an enzymatic activity to a tissue phenotype.\",\n      \"evidence\": \"Gene-trap knockout mouse with ceramide synthase activity assays, lipidomics, myelin biochemistry, and electron microscopy\",\n      \"pmids\": [\"19801672\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not resolve how altered ceramide chain length mechanically destabilizes myelin\", \"Whole-body knockout cannot separate glial-intrinsic from systemic effects\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed that CERS2 loss not only depletes VLC ceramides but reciprocally raises long-chain ceramides and triggers stress programs, linking ceramide-pool balance to autophagy and the UPR.\",\n      \"evidence\": \"siRNA knockdown with mass spectrometry sphingolipid profiling and UPR/autophagy assays\",\n      \"pmids\": [\"19728861\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The ceramide-synthase-independent rise in C14/C16 ceramide is unexplained\", \"Single-lab cell-based system\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Opened a non-catalytic, pH-based tumor-suppressor axis by linking CERS2 to V-ATPase and mitochondrial apoptosis.\",\n      \"evidence\": \"Overexpression in V-ATPase-related pH and apoptosis assays in hepatocellular carcinoma cells\",\n      \"pmids\": [\"20571735\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not yet demonstrate direct CERS2–V-ATPase binding\", \"Mechanistic link between pH and apoptosis correlative\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified the molecular basis of CERS2's pH control by demonstrating a direct homeodomain-mediated interaction with the V-ATPase C subunit ATP6V0C.\",\n      \"evidence\": \"Reciprocal co-IP, immuno-electron microscopy, domain-deletion mutants, BCECF pH assay\",\n      \"pmids\": [\"22991218\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural details of the homeodomain–ATP6V0C contact not resolved\", \"Relationship between catalytic and V-ATPase-regulatory functions unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Generalized the V-ATPase-dependent invasion-suppression mechanism across breast and prostate cancer models, tying it to MMP activation and chemosensitivity.\",\n      \"evidence\": \"Gain/loss-of-function in cancer cell lines with pH, MMP zymography, invasion, drug-uptake and xenograft assays\",\n      \"pmids\": [\"22580606\", \"22573553\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab models\", \"Contribution of CERS2 enzymatic activity to these effects not isolated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Solidified the V-ATPase/pH/MMP invasion axis bidirectionally, showing CERS2 dose tunes extracellular acidification and MMP-2/9 activity.\",\n      \"evidence\": \"Bidirectional overexpression/knockdown with V-ATPase, pH, zymography, transwell assays\",\n      \"pmids\": [\"25213553\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab\", \"Does not connect to phosphorylation control identified later\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed CK2 phosphorylation of CERS2's cytoplasmic C-terminus as the principal post-translational switch controlling its catalytic rate, and identified ASGR1 as an upstream regulator of its V-ATPase function.\",\n      \"evidence\": \"Phosphoproteomics, CK2 inhibitor CX-4945, site-directed mutagenesis, brain dephosphorylation activity assays; separately co-IP and knockdown epistasis for ASGR1\",\n      \"pmids\": [\"26887952\", \"27241665\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How phosphorylation alters Vmax structurally unknown\", \"Whether the same phosphosites govern catalytic and V-ATPase roles not resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended CERS2 tumor-suppressor signaling to mitochondrial dynamics, ROS/MAPK signaling, and hepatic metabolism through tissue-specific deletion.\",\n      \"evidence\": \"Hepatocyte-specific knockout and gain-of-function with ERK/Drp1 inhibitors, mitochondrial staining, ROS and MAPK readouts\",\n      \"pmids\": [\"29581781\", \"29626628\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relationship between V-ATPase, ROS and ERK/Drp1 effects not fully ordered\", \"Single-lab models\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Mapped specific phosphoserines (S248) controlling CERS2-driven β-catenin degradation and tied CERS2 activity to oncogene-induced senescence and β-cell glucose homeostasis.\",\n      \"evidence\": \"Phospho-deficient mutants and co-IP with STK38/SCYL2/ATP6V0C; CerS2/SK1 siRNA epistasis with senescence markers; CRISPR knock-in and knockout mice with glucose/islet assays\",\n      \"pmids\": [\"33852174\", \"33414460\", \"33705551\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a single enzyme coordinates V-ATPase, β-catenin and metabolic roles is unresolved\", \"Phosphosite numbering varies across studies\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a p53-dependent tumor-suppressor mechanism whereby CERS2 binds MDM2/MDMX to block p53 degradation and promote its nuclear activation.\",\n      \"evidence\": \"Co-IP with MDM2/MDMX, p53 PTM western blots, immunofluorescence localization in hepatoma cells\",\n      \"pmids\": [\"37963859\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. indirect MDM2/MDMX binding not structurally defined\", \"Single-lab overexpression-based\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Broadened CERS2's interactome to PP2A/β-catenin chemoresistance control and to TFRC-mediated iron homeostasis and ferroptosis as anti-metastatic mechanisms.\",\n      \"evidence\": \"Co-IP/LC-MS, ChIP, PP2A activity and PDX assays; reciprocal co-IP, PLA and ferroptosis epistasis (Fer-1/erastin) across multiple cancer types\",\n      \"pmids\": [\"38191448\", \"38419028\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether these interactions occur in the same cells/conditions as the V-ATPase axis is unknown\", \"Single-lab studies\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated that direct pharmacologic activation of CERS2 drives VLC-ceramide accumulation, ER stress, and an IP3R1-dependent ER–mitochondria Ca²⁺/apoptosis axis, providing a druggable mechanistic loop.\",\n      \"evidence\": \"Small-molecule agonist DH20931 with CerS2-KO resistance, enzymatic assay, CerS2–IP3R1 co-IP, ER stress blots, ER–mito proximity and Ca²⁺ measurements, xenografts\",\n      \"pmids\": [\"42012500\", \"39792658\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of agonist binding not defined\", \"Whether the IP3R1 interaction depends on catalytic activity unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how the single CERS2 protein partitions between its VLC-ceramide catalytic activity and its many non-catalytic protein interactions (V-ATPase, MDM2/MDMX, PP2A, TFRC, IP3R1), and whether these interactions are mutually exclusive, context-specific, or coordinately regulated by phosphorylation.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of CERS2 or its interaction interfaces\", \"No study isolating catalytic-dead vs. interaction-dead alleles across the diverse phenotypes\", \"Most interaction findings come from single labs without reciprocal cross-validation\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 4, 26]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [5, 20, 21]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 7, 21]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [3, 28]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 23]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [3, 28]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [9, 28]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ATP6V0C\", \"IP3R1\", \"TFRC\", \"MDM2\", \"MDMX\", \"ASGR1\", \"NDUFS2\", \"STK38\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}