2025
Predicting adenine base editing efficiencies in different cellular contexts by deep learning
Kissling L, Mollaysa A, Janjuha S, Mathis N, Marquart K, Weber Y, Moon W, Lin P, Fan S, Muramatsu H, Vadovics M, Allam A, Pardi N, Tam Y, Krauthammer M, Schwank G. Predicting adenine base editing efficiencies in different cellular contexts by deep learning. Genome Biology 2025, 26: 115. PMID: 40340964, PMCID: PMC12060317, DOI: 10.1186/s13059-025-03586-7.Peer-Reviewed Original ResearchConceptsBase editing efficiencyEditing efficiencyCell linesPathogenic mutationsBase editingPrimary cells in vivoBase editing screensBase editing outcomesCells in vivoHEK293T cellsAdenine base editingIn vivo settingTarget lociT cellsLipid nanoparticlesCellular contextTarget sequenceMRNA deliveryBase pairsOn-target editingBystander effectEditing outcomesBase editorsIn vitro datasetsMurine liverThe bridge-like lipid transport protein VPS13C/PARK23 mediates ER–lysosome contacts following lysosome damage
Wang X, Xu P, Bentley-DeSousa A, Hancock-Cerutti W, Cai S, Johnson B, Tonelli F, Shao L, Talaia G, Alessi D, Ferguson S, De Camilli P. The bridge-like lipid transport protein VPS13C/PARK23 mediates ER–lysosome contacts following lysosome damage. Nature Cell Biology 2025, 27: 776-789. PMID: 40211074, PMCID: PMC12081312, DOI: 10.1038/s41556-025-01653-6.Peer-Reviewed Original ResearchConceptsDisease genesResponse to lysosomal damageSurface of lysosomesER–lysosome contactsParkinson's disease genesDelivery to lysosomesLipid transport proteinsLysosomal damageVPS13 proteinsLysosomal surfaceDisease proteinsGenetic studiesDamaged lysosomesVPS13CLysosomal stressLipid transportLysosomesInhibited stateMembrane perturbationRab7Lysosomal dysfunctionProteinVps13LipidGenesTANGO2 is an acyl-CoA binding protein
Lujan A, Foresti O, Wojnacki J, Bigliani G, Brouwers N, Pena M, Androulaki S, Hashidate-Yoshida T, Kalyukina M, Novoselov S, Shindou H, Malhotra V. TANGO2 is an acyl-CoA binding protein. Journal Of Cell Biology 2025, 224: e202410001. PMID: 40015245, PMCID: PMC11867700, DOI: 10.1083/jcb.202410001.Peer-Reviewed Original ResearchConceptsAcyl-CoA binding proteinPeriphery of lipid dropletsAcyl-coenzyme A binding proteinA-binding proteinsAcyl-coenzyme AMitochondrial lumenHeme transportBinding proteinTANGO2Cellular localizationLipid dropletsStructural regionsLipid metabolismHeightened energy demandsMutationsProteinResiduesNrdEMetabolic crisisBindingMetabolismHemeSevere cardiomyopathyLipidGenome-scale CRISPR/Cas9 screening reveals the role of PSMD4 in colibactin-mediated cell cycle arrest
Dougherty M, Hoffmann R, Hernandez M, Airan Y, Gharaibeh R, Herzon S, Yang Y, Jobin C. Genome-scale CRISPR/Cas9 screening reveals the role of PSMD4 in colibactin-mediated cell cycle arrest. MSphere 2025, 10: e00692-24. PMID: 39918307, PMCID: PMC11934320, DOI: 10.1128/msphere.00692-24.Peer-Reviewed Original ResearchConceptsCell cycle arrestCycle arrestCRISPR/Cas9 screenDNA damageGenome-scale CRISPR/Cas9 screensGenome-wide CRISPR/Cas9 knockout screenRegulating cell cycle arrestRNA polymerase IIIRNA processing factorsCRISPR/Cas9 knockout screenG2-M cell cycle arrestGenotoxic secondary metabolitesHT-29 cellsHost response pathwaysPolymerase IIIKnockout screenHost pathwaysCell fateProteasome subunitsColony sizeColibactin-producing bacteriaColibactinRNA sequencingColony formation rateGene expressionNav1.8, an analgesic target for nonpsychotomimetic phytocannabinoids
Ghovanloo M, Tyagi S, Zhao P, Waxman S. Nav1.8, an analgesic target for nonpsychotomimetic phytocannabinoids. Proceedings Of The National Academy Of Sciences Of The United States Of America 2025, 122: e2416886122. PMID: 39835903, PMCID: PMC11789019, DOI: 10.1073/pnas.2416886122.Peer-Reviewed Original ResearchConceptsExcitation of peripheral sensory neuronsTherapeutic potential of cannabinoidsPotential of cannabinoidsPeripheral sensory neuronsVoltage-gated sodiumSpectrum of adverse effectsNociceptor excitabilityPain signalsIn vivo studiesAnalgesic targetsPain treatmentAttenuate painRepetitive firingNav1.8Sensory neuronsTreatment optionsClinical studiesInhibit excitabilityAnalgesic compoundsPainTherapeutic potentialCannabigerolProof-of-principalAdverse effectsTreatmentA STING–CASM–GABARAP pathway activates LRRK2 at lysosomes
Bentley-DeSousa A, Roczniak-Ferguson A, Ferguson S. A STING–CASM–GABARAP pathway activates LRRK2 at lysosomes. Journal Of Cell Biology 2025, 224: e202310150. PMID: 39812709, PMCID: PMC11734622, DOI: 10.1083/jcb.202310150.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAnimalsApoptosis Regulatory ProteinsAutophagy-Related Protein 8 FamilyEnzyme ActivationHEK293 CellsHumansLeucine-Rich Repeat Serine-Threonine Protein Kinase-2LysosomesMembrane ProteinsMiceMicrotubule-Associated ProteinsProtein Serine-Threonine KinasesSignal TransductionConceptsLRRK2 kinase activityKinase activityStimulator of interferon genesKinase activity of LRRK2Protein family membersLysosomal recruitmentLysosomal homeostasisEndogenous cellular mechanismsAberrant activationLRRK2Interferon genesLysosomesSingle membraneLysosomal damageMultiple chemical stimuliKinaseCellular mechanismsPathwayFamily membersChemical stimuliGABARAPMultiple stimuliGenesMutationsActivity
2024
Identification of polycystin 2 missense mutants targeted for endoplasmic reticulum-associated degradation
Guerriero C, Carattino M, Sharp K, Kantz L, Gresko N, Caplan M, Brodsky J. Identification of polycystin 2 missense mutants targeted for endoplasmic reticulum-associated degradation. American Journal Of Physiology - Cell Physiology 2024, 328: c483-c499. PMID: 39714991, DOI: 10.1152/ajpcell.00776.2024.Peer-Reviewed Original ResearchConceptsEndoplasmic reticulum-associated degradationPolycystin-2Autosomal dominant polycystic kidney diseaseEndoplasmic reticulum-associated degradation pathwayMissense mutationsGrowth of yeast strainsDisease-causing missense mutationsDisease-associated mutantsProteasome-dependent degradationHEK293 cellsConsistent with defectsDisease-linked mutationsHEK293 cell modelYeast modelYeast systemYeast strainsGenetic systemTreat autosomal dominant polycystic kidney diseaseMissense variantsProtein misfoldingProtein foldingCellular processesIncreased polyubiquitinationMisfolding phenotypeChemical chaperonesQuantitative profiling of human translation initiation reveals elements that potently regulate endogenous and therapeutically modified mRNAs
Lewis C, Xie L, Bhandarkar S, Jin D, Abdallah K, Draycott A, Chen Y, Thoreen C, Gilbert W. Quantitative profiling of human translation initiation reveals elements that potently regulate endogenous and therapeutically modified mRNAs. Molecular Cell 2024, 85: 445-459.e5. PMID: 39706187, PMCID: PMC11780321, DOI: 10.1016/j.molcel.2024.11.030.Peer-Reviewed Original ResearchConceptsTranslation initiationUntranslated regionHuman 5'-untranslated regionChemically modified nucleotidesHigh-throughput methodRibosome recruitmentAlternative isoformsRegulatory elementsEnhanced translationDissecting mechanismsTherapeutic mRNANucleotideTherapeutic proteinsMRNADelivery of therapeutic proteinsSequenceMRNA vaccinesEndogenous RNAQuantitative profilingWidespread effectsTranslation outputRNATherapeuticsIsoformsCellular immunogenicityUBXN9 governs GLUT4-mediated spatial confinement of RIG-I-like receptors and signaling
Harrison A, Yang D, Cahoon J, Geng T, Cao Z, Karginov T, Hu Y, Li X, Chiari C, Qyang Y, Vella A, Fan Z, Vanaja S, Rathinam V, Witczak C, Bogan J, Wang P. UBXN9 governs GLUT4-mediated spatial confinement of RIG-I-like receptors and signaling. Nature Immunology 2024, 25: 2234-2246. PMID: 39567760, DOI: 10.1038/s41590-024-02004-7.Peer-Reviewed Original ResearchConceptsRIG-I-like receptorsRIG-I-like receptor signalingCytosolic RIG-I-like receptorsAntiviral immunityPlasma membrane tetheringRNA virus infectionGlucose transportInnate antiviral immunityCytoplasmic RIG-I-like receptorsGolgi matrixGLUT4 translocationRLR signalingViral RNACell surfaceGLUT4GLUT4 expressionGlucose uptakeInterferon responseRNAGlycolytic reprogrammingVirus infectionHuman inflammatory myopathiesGolgiSignalUbiquitinStructures of complete extracellular assemblies of type I and type II Oncostatin M receptor complexes
Zhou Y, Stevis P, Cao J, Ehrlich G, Jones J, Rafique A, Sleeman M, Olson W, Franklin M. Structures of complete extracellular assemblies of type I and type II Oncostatin M receptor complexes. Nature Communications 2024, 15: 9776. PMID: 39532904, PMCID: PMC11557873, DOI: 10.1038/s41467-024-54124-1.Peer-Reviewed Original ResearchConceptsLeukemia inhibitory factor receptorOncostatin MExtracellular assemblyReceptor complexOSM receptorOncostatin M signalingOncostatin M receptorJuxtamembrane domainGp130 bindingCryogenic electron microscopyStructural basisGlycoprotein 130Cryo-EMFamily cytokinesBiological eventsGp130Therapeutic targetComplex formationFactor receptorType IMouse typesReceptorsAssemblyJuxtamembraneMutagenesisAntagonistic nanobodies implicate mechanism of GSDMD pore formation and potential therapeutic application
Schiffelers L, Tesfamariam Y, Jenster L, Diehl S, Binder S, Normann S, Mayr J, Pritzl S, Hagelauer E, Kopp A, Alon A, Geyer M, Ploegh H, Schmidt F. Antagonistic nanobodies implicate mechanism of GSDMD pore formation and potential therapeutic application. Nature Communications 2024, 15: 8266. PMID: 39327452, PMCID: PMC11427689, DOI: 10.1038/s41467-024-52110-1.Peer-Reviewed Original ResearchConceptsMembrane insertionGasdermin DN-terminal domainCleavage of gasdermin DPore formationPro-inflammatory caspasesPyroptosis to apoptosisActivated caspase-3Caspase-1 activationTarget membraneCaspase-3Assembled poresPlasma membraneCytosolic expressionLiving cellsConformational changesEnhanced caspase-1 activityOligomerizationPotential therapeutic applicationsInflammasome activationNanobodiesPyroptosisStudy pore formationMembraneTherapeutic applicationsGAD65 tunes the functions of Best1 as a GABA receptor and a neurotransmitter conducting channel
Wang J, Owji A, Kittredge A, Clark Z, Zhang Y, Yang T. GAD65 tunes the functions of Best1 as a GABA receptor and a neurotransmitter conducting channel. Nature Communications 2024, 15: 8051. PMID: 39277606, PMCID: PMC11401937, DOI: 10.1038/s41467-024-52039-5.Peer-Reviewed Original ResearchConceptsCl- currentsRetinal pigment epithelial cellsIsoform of glutamic acid decarboxylasePigment epithelial cellsGlutamic acid decarboxylaseG-aminobutyric acidBestrophin-1BEST1GABA receptorsTransport metabolonEpithelial cellsGAD65Glutamate metabolizing enzymesAcid decarboxylaseGAD67Bestrophin channelsGABAExtracellular sitesNo effectAnion channelMetabolic enzymesPhysiological roleGlutamateCellsBestrophinHIV-1 usurps mixed-charge domain-dependent CPSF6 phase separation for higher-order capsid binding, nuclear entry and viral DNA integration
Jang S, Bedwell G, Singh S, Yu H, Arnarson B, Singh P, Radhakrishnan R, Douglas A, Ingram Z, Freniere C, Akkermans O, Sarafianos S, Ambrose Z, Xiong Y, Anekal P, Llopis P, KewalRamani V, Francis A, Engelman A. HIV-1 usurps mixed-charge domain-dependent CPSF6 phase separation for higher-order capsid binding, nuclear entry and viral DNA integration. Nucleic Acids Research 2024, 52: 11060-11082. PMID: 39258548, PMCID: PMC11472059, DOI: 10.1093/nar/gkae769.Peer-Reviewed Original ResearchConceptsHIV-1 infectionHIV-1Viral DNA integrationCPSF6 knockout cellsActivity in vitroHIV-1 pathogenesisHIV-1 integrationDNA integrityLiquid-liquid phase separationViral infectionNuclear specklesInfectionCapsids in vitroCPSF6NS depletionNuclear entryCapsid bindingCapsid-binding proteinKnockout cellsBinding proteinSR proteinsNuclear rimCo-aggregationDisordered regionsLysosomal TMEM106B interacts with galactosylceramidase to regulate myelin lipid metabolism
Takahashi H, Perez-Canamas A, Lee C, Ye H, Han X, Strittmatter S. Lysosomal TMEM106B interacts with galactosylceramidase to regulate myelin lipid metabolism. Communications Biology 2024, 7: 1088. PMID: 39237682, PMCID: PMC11377756, DOI: 10.1038/s42003-024-06810-5.Peer-Reviewed Original ResearchConceptsMyelin lipid metabolismCo-immunoprecipitation assaysSulfated derivative sulfatideLipid metabolismAssociated with multiple neurological disordersCo-immunoprecipitationTMEM106BTransmembrane proteinsAmyloid fibrilsTMEM106B deficiencyHypomyelinating leukodystrophyAlzheimer's diseasePhysiological functionsFrontotemporal dementiaMolecular levelNeurodegenerative brainGalactosylceramidaseLipidomic analysisMultiple neurological disordersMetabolismMyelin lipidsDecreased levelsEndolysosomesAmyloidGalactosylceramidase activityTRPV1 corneal neuralgia mutation: Enhanced pH response, bradykinin sensitization, and capsaicin desensitization
Gualdani R, Barbeau S, Yuan J, Jacobs D, Gailly P, Dib-Hajj S, Waxman S. TRPV1 corneal neuralgia mutation: Enhanced pH response, bradykinin sensitization, and capsaicin desensitization. Proceedings Of The National Academy Of Sciences Of The United States Of America 2024, 121: e2406186121. PMID: 39226353, PMCID: PMC11406256, DOI: 10.1073/pnas.2406186121.Peer-Reviewed Original ResearchConceptsLaser-assisted in situ keratomileusisPhotorefractive keratectomyOcular Surface Disease Index scoreCapsaicin-induced desensitizationPhotorefractive keratectomy enhancementDisease Index scorePhysiological membrane potentialsCorneal neuralgiaTRPV1 variantsCorneal painRefractive surgeryRefractive errorCapsaicin desensitizationPersistent painBradykinin sensitivityNerve injuryM mutationPatch clampChannel activitySurgical techniqueLeftward shiftInflammatory mediatorsM-channelPainIndex scoreA complex of the lipid transport ER proteins TMEM24 and C2CD2 with band 4.1 at cell–cell contacts
Johnson B, Iuliano M, Lam T, Biederer T, De Camilli P. A complex of the lipid transport ER proteins TMEM24 and C2CD2 with band 4.1 at cell–cell contacts. Journal Of Cell Biology 2024, 223: e202311137. PMID: 39158698, PMCID: PMC11334333, DOI: 10.1083/jcb.202311137.Peer-Reviewed Original ResearchConceptsPlasma membraneNon-vesicular lipid transferSites of cell contactC-terminus motifsCell contact-dependent signalsContact-dependent signalingCell-cell contactER/PM junctionsTMEM24ER proteinsPM proteinsSynCAM 1Cell adhesion moleculesCellular functionsLipid transferC2CD2Phospholipid transportLipid transportCell contactProteinAdhesion moleculesCalcium homeostasisCellsFamily membersParalogsStructural bases for Na+-Cl− cotransporter inhibition by thiazide diuretic drugs and activation by kinases
Zhao Y, Schubert H, Blakely A, Forbush B, Smith M, Rinehart J, Cao E. Structural bases for Na+-Cl− cotransporter inhibition by thiazide diuretic drugs and activation by kinases. Nature Communications 2024, 15: 7006. PMID: 39143061, PMCID: PMC11324901, DOI: 10.1038/s41467-024-51381-y.Peer-Reviewed Original ResearchConceptsNa+-Cl- cotransporterFamilial hyperkalemic hypertensionRenal salt retentionThiazide diuretic drugsNa+-Cl-Cotransporter inhibitionNCC activitySalt reabsorptionDiuretic drugsBlood pressureBalanced electrolyteTreat hypertensionIon translocation pathwayIon translocationThiazideHypertensionSalt retentionOrthosteric siteCo-structureCarboxyl-terminal domainKinase cascadeEdemaChlorthalidoneCotransporterTranslocationIntestinal Nogo-B reduces GLP1 levels by binding to proglucagon on the endoplasmic reticulum to inhibit PCSK1 cleavage
Gong K, Xue C, Feng Z, Pan R, Wang M, Chen S, Chen Y, Guan Y, Dai L, Zhang S, Jiang L, Li L, Wang B, Yin Z, Ma L, Iwakiri Y, Tang J, Liao C, Chen H, Duan Y. Intestinal Nogo-B reduces GLP1 levels by binding to proglucagon on the endoplasmic reticulum to inhibit PCSK1 cleavage. Nature Communications 2024, 15: 6845. PMID: 39122737, PMCID: PMC11315690, DOI: 10.1038/s41467-024-51352-3.Peer-Reviewed Original ResearchConceptsEnteroendocrine cellsEndoplasmic reticulum (ER)-resident proteinGlucagon-like peptide 1Nogo-BEndoplasmic reticulumStimulate insulin secretionPotential therapeutic targetProglucagonGlucagon-like peptide 1 receptorInhibit glucagon secretionRegulatory processesIntestinal tractProglucagon fragmentInsulin secretionCleavageNogo-B knockoutTherapeutic targetPancreatic cellsPeptide 1Glucagon secretionCellsReticulonGolgiReticulon 4BInsulin resistanceDevelopment of a genetically encoded sensor for probing endogenous nociceptin opioid peptide release
Zhou X, Stine C, Prada P, Fusca D, Assoumou K, Dernic J, Bhat M, Achanta A, Johnson J, Pasqualini A, Jadhav S, Bauder C, Steuernagel L, Ravotto L, Benke D, Weber B, Suko A, Palmiter R, Stoeber M, Kloppenburg P, Brüning J, Bruchas M, Patriarchi T. Development of a genetically encoded sensor for probing endogenous nociceptin opioid peptide release. Nature Communications 2024, 15: 5353. PMID: 38918403, PMCID: PMC11199706, DOI: 10.1038/s41467-024-49712-0.Peer-Reviewed Original ResearchConceptsOpioid peptide releaseVentral tegmental areaAcute brain slicesN/OFQ actionsChemogenetic activationIn vivo studiesNociceptin/orphanin FQTegmental areaFibre photometryOpioid peptidesBrain slicesPharmacological profileGenetically encoded sensorIntracellular signal transducersReceptor ligandsPeptide releaseMammalian brainFunctional relevanceNeuronsBehavioral processesSignal transducerReleasePotential interactionsRegulatory functionsN/OFQUPF1 regulates mRNA stability by sensing poorly translated coding sequences
Musaev D, Abdelmessih M, Vejnar C, Yartseva V, Weiss L, Strayer E, Takacs C, Giraldez A. UPF1 regulates mRNA stability by sensing poorly translated coding sequences. Cell Reports 2024, 43: 114074. PMID: 38625794, PMCID: PMC11259039, DOI: 10.1016/j.celrep.2024.114074.Peer-Reviewed Original ResearchConceptsUpstream open reading framesOpen reading frameRegulate mRNA stabilityNonsense-mediated decayMRNA stabilityReading frameOpen reading frame lengthRegulate mRNA decayAU-rich elementsMicroRNA binding sitesCis-elementsTranslation initiationStop codonMRNA decayCodon optimizationUPF1Gene expressionBinding sitesCodonMRNAConvergent rolesHigher decay ratesMachine-learning analysisUTR
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