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#原始研究

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Oct 15Thu
  1. Mol Cell63

    STING engages PKR to drive lysosomal cell death in lung ischemia-reperfusion injury.

    Mitochondrial DNA released during lung ischemia-reperfusion injury activates the cGAS-STING pathway to trigger lysosomal cell death in mouse and rat models. In human lung epithelial cells, STING oligomerization drives autophosphorylation of PKR at serine 33, activating IκB kinase-NF-κB signaling independently of the canonical STING-TBK1 and PKR-eIF2α pathways, which induces LAMP3 transcription and lysosomal membrane permeabilization. Blockade of STING-PKR signaling attenuates epithelial lysosomal cell death and lung injury, identifying PKR as a non-canonical STING effector.

    Why it matters: Identifies PKR as a non-canonical STING effector driving lysosomal cell death, a potential target in lung ischemia-reperfusion injury.

  2. Cephalalgia41

    Alterations in the interstitial microenvironment across headache phases and clinical phenotypes in migraine: A multimodal diffusion MRI study.

    Multimodal diffusion MRI found no overall differences between migraine participants and healthy controls, but chronic migraine with medication-overuse headache showed reduced extracellular volume fraction and increased intracellular volume fraction versus controls, in the corpus callosum, anterior thalamic radiation, cingulum and optic radiations. Similar alterations appeared during headache. The findings suggest interstitial microenvironment changes tied to headache phase and disease burden rather than a stable trait.

  3. Nature76

    Artificial intelligence-enabled clinical phenotyping of human brown fat.

    Brown adipose tissue (BAT) presence is linked to lower prevalence of cardiovascular and psychiatric diseases across a cohort of 101,243 patients from a large cancer centre. Machine learning quantification of BAT activity in roughly 8,700 patients showed higher activity, especially in the axillary depot, correlates with lower odds of cardiometabolic diseases and healthier white fat distribution. Angiotensin receptor blocker use associated with BAT presence, and losartan increased brown adipocyte activity and whole-body energy expenditure, supporting drug repurposing to activate BAT in humans.

    Why it matters: AI phenotyping of 101,243 patients links brown fat to reduced cardiometabolic disease and identifies losartan as a candidate BAT activator.

  4. Nature77

    A microexon regulatory code reveals autism-linked genetic variation.

    An expanded map of neuronal microexons, built from extensive transcriptome profiling, adds hundreds of new microexons, including subtype-specific ones and others that trigger nonsense-mediated mRNA decay. A machine-learning sequence code predicts neuronally spliced microexons and identifies regulatory elements around them. Applied to autism, the code pinpoints rare splicing-altering variants, mostly in idiopathic individuals, that associate with autism status and converge on synaptic and other autism-linked genes.

    Why it matters: It links autism-associated genetic variation to a splicing code for neuronal microexons.

  5. Nature74

    Sexual dimorphism in epidermal stem cell dynamics.

    Intravital time-lapse imaging of lineage-labelled cells in mouse interfollicular epidermis supports a two-compartment model of epidermal homeostasis, with basal cells organized in a stem cell-transit-amplifying hierarchy. Female mice showed synchronized cell division, differentiation and delamination, linked to accelerated wound healing, while analyses of castrated mice showed male sex hormones promote stem cell differentiation and delamination. The work identifies sex-specific regulation of epidermal stem cell fate.

    Why it matters: It resolves a long-standing conflict over basal cell heterogeneity and reveals sex hormone control of epidermal stem cell fate.

  6. Nature73

    Targeted stimulation of motor cortex ensembles drives learned movements.

    Stimulating about 20 layer 2/3 motor cortex neurons whose activity precedes movement onset triggered lever-press-like movements in task-engaged mice and reproduced the learned population activity pattern. Trial-by-trial variability in the evoked activity and movements was predicted by the initial state of M1 before stimulation. Stimulating movement-following neurons, or stimulating in disengaged mice, failed, supporting a causal, active role for M1 in generating learned movements.

    Why it matters: It provides causal evidence that small defined M1 ensembles drive learned movements.

  7. JAMA59

    Fluid Therapy in Mechanically Ventilated Critically Ill Adult Patients.

    In 206 ICUs across 41 countries, fluid therapy for mechanically ventilated adults was driven mainly by maintenance and replacement fluids (31.9%) and creep fluids (30.9%), not resuscitation (16.0%). Among 2454 patients, median daily fluid input peaked at 3.0 L on day 1 after intubation, with balance near-neutral by day 3. Isotonic balanced crystalloids (48.9%) and saline (27.0%) dominated, and substantial between-site variation persisted after case-mix adjustment.

  8. biorxiv.org42

    Tobacco Carcinogen Induces Persistent DNA Damage and Homologous Recombination Dysregulation in Pancreatic Ductal Carcinogenesis

    The tobacco carcinogen NNK produces a biphasic DNA damage response in human pancreatic ductal epithelial cells: 5 days of exposure induced double-strand breaks with ATM-γH2AX activation and RAD51/BRCA2 recruitment, while 50 days caused persistent damage signaling, upregulation of HR genes (RAD51, BRCA1, BRCA2, FANCD2, PLK1), altered RAD51 localization, and chromosomal instability. In human PDAC tissue microarrays and TCGA-PAAD data, increased γH2AX correlated with tumor progression and poor overall survival, and elevated RAD51 with adverse outcomes, positioning γH2AX as a candidate prognostic biomarker in tobacco-associated PDAC.

  9. biorxiv.org49

    NIK stabilization reprograms the pancreas toward chronic pancreatitis and pancreatic lipomatosis

    Sustained stabilization of NF-κB-inducing kinase (NIK) in a pancreas-specific mouse model triggered fully penetrant remodeling, with acinar cell death by the end of the first week of age, acinar-to-ductal metaplasia, organ atrophy, and extensive adipose replacement. Deep learning on spatial transcriptomics showed progressive loss of acinar identity and identified GPA33 as a surface marker of ADMs. Relb deletion fully rescued the phenotype, placing RelB-dependent non-canonical NF-κB signaling upstream of chronic pancreatitis and pancreatic lipomatosis.

  10. doi.org55

    SARS-CoV-2 nucleocapsid protein hijacks host transcription by targeting eEF1A1

    SARS-CoV-2 nucleocapsid protein drives a conserved transcriptional program across variants, including Delta and Omicron, in human lung epithelial cells, activating interferon regulatory factors, immediate-early genes, and cytokines. Nucleocapsid recruits IRFs, AP-1, RNA polymerase II, and eEF1A1 to pro-inflammatory gene promoters. Blocking the N-eEF1A1 interaction with plitidepsin abolished complex formation and reversed host gene dysregulation, identifying a pan-variant therapeutic target.

  11. doi.org40

    Physiological Responses to Intermittent Environmental Heat Stress in Mice

    Intermittent heat stress in C57BL/6J mice (30-37°C, 3 h/day, 4 days/week, up to 4 weeks) produced a neuroendocrine stress response with 2-4-fold higher plasma corticosterone, >50% lower epinephrine, and ~10 mmHg lower systolic and diastolic blood pressure. Despite >30% depletion of circulating immune cells, leukocyte rolling and adhesion to vascular endothelium rose more than 3-fold, indicating endothelial activation that precedes cardiovascular dysfunction. Cardiac systolic function, arterial stiffness, plasma lipids, and organ injury markers were largely unaffected.

  12. doi.org51

    Structural and Mechanistic Insights Into GSDME Pore Formation and Functional Regulation

    Cryo-EM structures of gasdermin E pores, with oligomeric stoichiometries ranging from 23 to 29 protomers, expose how pore assembly works. Mutagenesis, liposome leakage assays and cancer-associated mutation analysis identified residues governing membrane binding, shallow membrane insertion and oligomerization via three interfaces, while molecular dynamics simulations showed anionic TMCL2 recruited by basic residues to aid membrane penetration. The work supports a stepwise, time-dependent mechanism of GSDME pore assembly.

  13. doi.org41

    Dynamic changes of claudin 18.2 expression after systemic therapy in gastric and esophagogastric junction cancer

    Claudin 18.2 (CLDN18.2) expression in advanced gastric/esophagogastric junction adenocarcinoma changes frequently during systemic therapy. In paired samples from 155 patients, positivity rose from 54 (34.84%) before treatment to 61 (39.35%) after (p < .001); overall, 131 patients (84.52%) showed altered expression. Conversion rates did not differ between chemotherapy alone and chemotherapy plus immunotherapy, supporting CLDN18.2 reassessment before targeted therapy.

  14. Nat Biotechnol69

    Mesenchymal thymic niche cells enable regeneration of the adult thymus and T cell immunity.

    A perivascular Postn+ mesenchymal subset of thymic stroma, identified by single-cell analysis of human and mouse tissue, proved to be a critical niche for T lymphopoiesis. Depleting these cells, which likely produce the chemokine Ccl19, blocks recruitment of T cell progenitors, and the subset declines with age and after hematopoietic stem cell transplant conditioning. Adoptively transferred Postn+ cells durably engraft the atrophic thymus, recruit early T progenitors, increase T cell neogenesis and improve T cell responses to vaccination; Ccl19-expressing mesenchymal populations give similar effects.

  15. Nat Biotechnol69

    Engineering bispecific exosome activators of T cells to target immune checkpoint inhibitor-resistant metastatic melanoma.

    An inhalable exosome system called BEAT co-displays PD-1 and FZD8 in a uniform 1:1 ratio to block PD-L1 and Wnt7b, overexpressed in immune checkpoint inhibitor-resistant melanoma. BEAT recruited and activated CD8+ T cells, reprogramming the tumor microenvironment and producing robust antitumor activity in mouse models of lung metastases, outperforming a linked dual antibody against PD-L1 and Wnt7b in vivo.

  16. Sci Adv53

    A "Progenitor Cell Ark" hydrogel system for intervertebral disc regeneration via mitochondrial targeting and mitophagy enhancement.

    A triple-layered hydrogel microsphere system called a Progenitor Cell Ark delivers nucleus pulposus progenitor cells (NPPCs) together with an SS31-modified Prussian blue nanozyme (SS31-UPN) that targets mitochondria to scavenge ROS and promote mitophagy. In vitro, SS31-UPN protected NPPCs from oxidative damage and restored mitochondrial function, and in severe IVDD rat models the Ark improved disc structure, promoted neo-tissue formation, and restored biomechanical function, outperforming cell or bioscaffold therapy alone.

  17. biorxiv.org40

    A Multi-Kinase Inhibitor Screen Identifies mTOR Signaling as a Vulnerability in Advanced Prostate Cancer.

    Loss of the receptor tyrosine kinase AXL is linked to treatment resistance, aggressive phenotypes, and shorter overall survival in prostate cancer. Screening isogenic CRISPR-generated AXL-knockout cells against 1,814 kinase inhibitors identified Torin-2, which showed an ~18-fold lower IC50 in AXL-knockout than AXL-wildtype cells. PRISM/DepMap analysis confirmed a selective vulnerability to PI3K/AKT/mTOR pathway inhibition, pointing to mTOR inhibition as a therapeutic strategy for AXL-deficient prostate cancer.

  18. nature.com62

    Educational intervention can rewire village social networks

    A health-education intervention in rural Honduran villages reshaped social networks, not just health-related connections but also friendships and financial ties. The finding comes from a randomized controlled trial and shows that an educational program can alter the underlying social fabric of a community, a layer of change usually unmeasured in such trials.

  19. nature.com81

    A microexon regulatory code reveals autism-linked genetic variation

    An expanded map of neuronal microexons and a machine learning model of microexon splicing reveal rare human genetic variation predicted to converge on a subset of microexons in genes linked to nervous system biology and neurodevelopmental disorders. Analysing 4,790 bulk RNA-seq samples and 47,380 single nuclei from human cortex, the authors detected 1,514 previously unannotated microexons, 292 of them differentially spliced between neural and non-neural cells. The work points to non-coding variants as a possible contributor to the roughly 85% of autism cases with no identified genetic cause.

    Why it matters: It offers a mechanistic explanation for much of the unexplained genetic aetiology of autism through non-coding microexon variation.

  20. nature.com80

    Sexual dimorphism in epidermal stem cell dynamics

    Long-term intravital imaging of ear skin epidermis shows the interfollicular epidermis is not maintained by a single equipotent compartment: basal cells pass through an intermediate transit-amplifying-like state with limited proliferative potential before differentiating. Tracking labelled clones over 5 months, combined with single-cell expression profiling and biophysical modelling, reveals stochastic but locally coordinated stem cell renewal. Sister-cell events show temporal coordination strongly enriched in female mice, and functional experiments tie this to sex hormone regulation of basal cell dynamics.

    Why it matters: Revises the model of epidermal stem cell maintenance and shows sex hormones directly shape basal cell fate decisions.

  21. nature.com74

    Intrinsic physicochemical activity at microplastic–water interfaces

    Commodity microplastics are not chemically inert at water interfaces: they spontaneously generate reactive oxygen species. This intrinsic physicochemical activity challenges the prevailing paradigm of plastic inertness and carries implications for human health and the environment. The work reframes microplastics as active chemical participants rather than passive contaminants.

    Why it matters: Overturns the assumption that commodity plastics are chemically inert in water, with health and environmental relevance.

  22. nature.com71

    Targeted stimulation of motor cortex ensembles drives learned movements

    Optogenetic stimulation of motor-cortex neuron ensembles generated learned neural patterns and movements, showing that precisely timed activity in the primary motor cortex can produce skilled motor output. The work demonstrates an active role for primary motor cortex in skilled motor control rather than passive relay of elsewhere-generated commands.

    Why it matters: Causal evidence that timed motor-cortex ensemble activity alone can produce learned movements.

  23. nature.com64

    Divergent genomic evolution in astrocytomas and oligodendrogliomas

    Astrocytomas and oligodendrogliomas develop treatment resistance through different genomic routes, longitudinal analyses of patient tumours show. Astrocytomas accumulate copy-number alterations and markers of chromosomal instability, whereas oligodendrogliomas acquire new driver mutations. The finding separates the two tumour types by evolutionary mechanism rather than by histology alone.

  24. nature.com81

    Capillary-selective vasodilation through myosin inhibition halts ischaemic cascades

    Myosin inhibition produces vasodilation that is selective for capillaries and halts the cascades that follow ischaemia, as reported in this work on microvascular obstruction. The approach targets the capillary level, where pericyte-mediated constriction has been linked to no-reflow after ischaemia in the brain, heart and kidney. No quantitative outcome data are reported here.

    Why it matters: It addresses capillary-level no-reflow, a mechanism implicated in stroke, myocardial infarction and kidney injury.

  25. nature.com63

    Elp1 is required for myeloid differentiation and brain repopulation

    A primary cultured haematopoietic stem and progenitor cell platform was used to analyse the molecular mechanisms of brain myeloid differentiation, and identified the elongation factor ELP1 as an important regulator of this process. ELP1 was shown to be required for myeloid differentiation and brain repopulation, pointing to a new molecular control point in the development of brain myeloid cells.

  26. nature.com83

    Engineered TYK2 dependence enables myeloid-selective IL-10 receptor agonism

    IL-10's therapeutic use is limited because its myeloid-suppressive and T-cell-activating effects cannot be separated. Using the JAK1 inhibitor VVD-118313 in bone-marrow-derived macrophages, the authors show that JAK1-JAK1 transphosphorylation only partially reduces IL-10-induced STAT3 phosphorylation, with TYK2-mediated transphosphorylation compensating; in TYK2-deficient BMDMs, VVD-118313 fully abrogated STAT3 phosphorylation and IL-10 function. In human monocytes, the TYK2 inhibitor zasocitinib similarly partially reduced IL-10-driven STAT3 phosphorylation, revealing differential TYK2 dependence that may enable myeloid-selective IL-10 receptor agonism.

    Why it matters: It maps a signalling route that could separate IL-10's anti-inflammatory benefit from its toxic T-cell activation.

  27. nature.com74

    Structural basis of ligand recognition and gating in mosquito IRs

    Cryo-EM structures of the IR8a-IR75k carboxylic acid receptor from the malaria mosquito Anopheles stephensi, captured in four states including apo, ligand-bound open, and nonanoic acid- and octanoic acid-bound forms, reveal how ligand specificity is set by alkyl chain length and carboxylate geometry. Ligand binding closes IR75k's bilobed ligand binding domain, and the change propagates through conserved mechanical linkers to dilate the pore, a mechanism corroborated by molecular dynamics simulations and electrophysiology. The work provides an atomic-resolution view of mosquito host detection and a basis for rational design of mosquito control strategies targeting host-seeking behavior.

    Why it matters: Atomic-level mechanism of mosquito host-seeking receptors opens a structure-based route to new mosquito control.

Oct 14Wed
  1. Cell76

    PTPRS mediates invasion of tetanus neurotoxin into the central nervous system.

    The receptor protein tyrosine phosphatase sigma (PTPRS) is the host receptor that carries tetanus neurotoxin into the central nervous system. Pull-down, mass spectrometry and a luciferase-based in vivo transport assay identified PTPRS as the retrograde transport receptor; global or motoneuron-specific PTPRS knockout abolished TeNT entry into the CNS in mice, and a PTPRS-binding-deficient TeNT mutant caused botulism-like flaccid paralysis. The finding exposes a targetable pathway for post-entry intervention and for drug delivery into the CNS.

    Why it matters: Identifies the long-sought host receptor mediating tetanus neurotoxin entry into the CNS.

  2. Mol Cell64

    Structural basis of directionality control in large serine integrases.

    Eight structures of SPβ integrase-DNA complexes, at resolutions down to 3.15 Å, reveal how directionality is controlled along the integrative and excisive pathways. Recombination-induced conformational changes and RDF-mediated repositioning of the coiled-coil subdomain determine which DNA site pairs form active synaptic complexes and which product complexes become conformationally locked against back reactions. The excision synaptic complex is fundamentally different from the integration one, providing a framework for engineering improved genome editing tools.

  3. Cell74

    Mechanisms of transcription control by distal enhancers from single-gene nanoscopy.

    Real-time single-gene nanoscopy with targeted perturbations shows that productive enhancer-promoter interactions are dynamic, occur within roughly 100 nm, and are coordinated with transcriptional bursts. Enhancers and promoters are often actively brought together by cohesin-mediated loop extrusion, a key determinant of burst frequency, and enhancers activate bursting by embedding promoters within clusters of general transcription factors. The work defines physical parameters and mechanisms of long-range gene activation.

    Why it matters: Directly visualizes how distal enhancers contact promoters and trigger transcriptional bursting.

  4. Mol Cell65

    A feedback mechanism of m6A via PARP1-mediated ADP ribosylation of METTL3/METTL14.

    The m6A reader IGF2BPs recruits PARP1 to m6A-modified RNAs and stimulates its activity, leading to ADP ribosylation of the m6A writer METTL3/METTL14, which impairs its RNA-binding capability and reduces m6A deposition in human cell lines. This "read-orchestrate-write" negative feedback loop expands the regulatory paradigm of m6A methylation beyond the writer/eraser/reader system. Combining PARP inhibitor therapy with inhibition of IGF2BP2 or METTL3 produced synergistic anti-tumor effects.

  5. Mol Cell62

    Reverse transcribed ssDNA derepresses translation of a retron antiviral protein.

    Type VI retrons defend bacteria against phage without producing detectable msDNA, and the mechanism is now defined in Retron-Vpa2 from V. parahaemolyticus. The system makes a structured hybrid RNA carrying both the reverse transcription template and a toxin coding sequence kept off by a riboregulator. On phage infection, msDNA accumulates, hybridizes to the riboregulator and enables RNase H cleavage, derepressing toxin translation.

  6. Cell75

    A high-dimensional population code in the bat motor cortex during natural dexterous flight.

    Motor cortex in freely flying bats uses a high-dimensional, sparse population code rather than wingbeat-dominated activity. Neurons showed mixed selectivity for flight kinematics and millisecond-scale entrainment to wingbeat phase, with successive wingbeats occupying distinct neural states despite bats executing accurate flights via precise individual wingbeat adjustments. This challenges prevailing views of motor cortical dynamics derived from constrained paradigms.

    Why it matters: It overturns expectations that motor cortex during rhythmic movement is dominated by the movement cycle.

  7. Mol Cell68

    Transposable element splicing reveals a tumor-enriched class of gene-independent transcripts.

    A pan-cancer analysis defines TEtrans, a splice-resolved class of transposable element-derived transcripts that are tumor-enriched and gene-independent. An endogenous retrovirus-derived TEtrans promotes colorectal cancer growth by enhancing topoisomerase I-mediated DNA relaxation, and a subset encodes shared tumor antigens that elicit cytotoxic T cell responses, with a murine TEtrans-like transcript mediating antigen-dependent tumor control in vivo. The work adds spliced TE transcripts to the roster of oncogenic drivers and actionable tumor antigens.

  8. JAMA51

    Clinicopathologic Evaluation of Amyloid Clearance in Alzheimer Disease.

    Extensive amyloid clearance after aducanumab tracked with less downstream Alzheimer pathology in a clinicopathologic case report of a man in his 50s with mild cognitive impairment carrying the p.R47H TREM2 variant, who received 30 doses (cumulative 280 mg/kg) over 4.5 years. At autopsy four years after his final dose, brain regions with low residual amyloid, preferentially at gyral crests, showed less tau and slower longitudinal atrophy on MRI (β = -0.50; P < .001), while regions of high amyloid in sulcal depths had tau levels similar to those of untreated controls.

  9. biorxiv.org40

    Early-onset spontaneous murine mammary tumors show increased lymphocyte representation and reduced MHC antigen presentation

    A wild-derived PWK/PhJ genetic background accelerates HER2/neu-driven mammary tumor onset and reshapes the tumor immune microenvironment. (BALBxPWK) F1 NeuT females developed tumors at 10 weeks versus 15 weeks in BALB NeuT mice (p < 0.0001), with more tumor-infiltrating T and B cells but lower expression of cytotoxicity genes Tox, Ltk, Nkg7, and Gzmb. Proteomics found coordinate down-regulation of Stat1, Tapbp, Parp9, and Dtx3l with MHC class I and II proteins, indicating that inherited background, not the oncogene alone, governs antigen presentation and immune recognition in these tumors.

  10. Nat Med69

    A health-system-scale, episode-resolved multimodal atlas of cancer cachexia.

    Longitudinal clinicogenomic data from 52,236 patients with cancer profiled by MSK-IMPACT (2010-2024) show that cachectic weight loss episodes cluster near disease progression, worsen outcomes across nearly all cancer types, and carry a consistent serologic signature of lower albumin and hemoglobin with higher liver enzymes. Tumor genotypes including TP53 mutation were linked to more frequent episode onset. A model predicting impending cachectic weight loss in lung, colorectal and prostate cancer was validated in an external Dana-Farber cohort of 5,785 patients.

    Why it matters: It shows routine clinicogenomic data can identify cachexia drivers and predict weight loss risk at health-system scale.

  11. doi.org42

    Acid-responsive nanoparticles with microneedles for anti‑inflammatory sonodynamic therapy of gouty arthritis

    A dissolving hyaluronic acid microneedle loaded with acid-responsive curcumin nanoparticles (Cur-PNPs@MN), paired with ultrasound, treated acute gouty arthritis in rats. The nanoparticles generated 1.47-fold more reactive oxygen species than curcumin aggregates and induced 29.9% apoptosis in M1 macrophages. In the rat model, joint swelling eased and IL-1β fell from 170.3 to 67.3 pg/mL, TNF-α from 20.8 to 5.9 pg/mL, and IL-6 from 140.9 to 48.2 pg/mL, matching conventional drugs.

  12. Sci Adv59

    Citron kinase activity controls alternative splicing events that drive prostate cancer growth.

    Citron (CIT) kinase drives prostate cancer growth by phosphorylating the RNA splicing regulator THRAP3, controlling its binding to pre-messenger RNA targets and producing transcripts that stimulate growth of prostate cancer cell lines, xenografts, patient-derived organoids, and PDX-derived organoids. An antisense oligonucleotide blocking THRAP3 recruitment to a CIT-dependent RNA binding site prevented production of these transcripts and inhibited growth of cell lines and PDX-derived organoids across prostate cancer stages and lineages, but not of benign cells. The work identifies CIT-mediated alternative splicing as a therapeutic strategy in treatment-resistant prostate cancer.

    Why it matters: It offers an indirect way to hit CIT kinase, for which no selective inhibitors exist, via a splicing antisense oligonucleotide.

Oct 13Tue
  1. Mol Cell63

    A CK2-β-TrCP kinase-E3 ubiquitin ligase cascade is a metabolic sensor regulating tryptophan 2,3-dioxygenase stability.

    Tryptophan binding shields human tryptophan 2,3-dioxygenase (TDO2) from degradation by a CK2-β-TrCP kinase-E3 ubiquitin ligase cascade that generates and recognizes phosphodegrons in the enzyme. Cryo-EM shows Trp's indole, amino and carboxylate groups order a flap over an exosite distal from the catalytic site, blocking adjacent phosphodegron formation; without Trp the flap is flexible, allowing phosphorylation-coupled ubiquitylation. This defines a mechanism in which tryptophan limits are sensed via TDO2 turnover to avert hypotryptophanemia.

    Why it matters: It defines a molecular mechanism by which an endogenous metabolite controls its own enzyme's degradation through the ubiquitin-proteasome system.

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