Biology subjects

Meng, M.

Publications and source records attributed to Meng, M..

At least 19 recordsLinked to original sources

bioRxiv2026

Endosperm secretion remodels the maternal seed coat

In flowering plants and mammals, maternal tissues must accommodate the growth of the offspring they enclose. The maternal seed coat expands around the developing embryo and endosperm. Endosperm pressure and hormonal signals coordinate seed-coat development1,2, but whether the endosperm directly promotes maternal cell elongation remains unclear. Here we show that the coenocytic Arabidopsis endosperm directly supplies cell-wall-loosening proteins to maternal seed-coat walls. The seed-size-regulating HAIKU-WRKY10 pathway activates an endosperm secretory programme enriched in cell-wall-associated proteins. These proteins spread through a shared extracellular domain across multiple inner seed-coat layers, revealing an extensive functional maternal-filial interface through which the endosperm reaches maternal cells it does not directly contact. Among these proteins, three expansins are necessary and sufficient for maternal cell elongation and seed growth. The endosperm therefore promotes its own growth by enabling expansion of the maternal tissues that enclose it. Paternal DNA methylation and maternal Polycomb activity jointly regulate this programme, with Polycomb also required for timely shutdown of expansin expression. These findings link parental epigenetic states to maternal tissue expansion through proteins supplied by the offspring. This cross-generational control of growth parallels epigenetically regulated signaling from mammalian extraembryonic tissues3, suggesting a shared strategy for adapting the maternal environment to offspring development.

plant biology↗

bioRxiv2026

The uplift of the Qinghai-Tibetan Plateau reshaped genome architecture and diversification of Asian torrent catfishes

Tectonic uplift and mountain building are major drivers of species diversification and adaptation, yet how they reshape genome architecture and promote evolutionary innovation remains poorly understood. Here, we generated multiple chromosome-level genomes for Asian torrent catfishes (Sisoridae) and performed phylogenomic and comparative genomic analyses. Our results support an Asian origin of Sisoridae and provide a refined phylogenetic topology for catfishes. Comparative analyses revealed extensive chromosomal rearrangements during sisorid evolution, indicating highly dynamic genome architectures. The timing of sisorid diversification overlaps with major phases of regional tectonic change, and analyses of phylogenetic discordance indicate heterogeneous contributions from incomplete lineage sorting and introgression. Elevational distribution was associated with variation in estimated molecular evolutionary rates, while exploratory scans identified lineage-specific candidates for selection and convergent evolution. Candidate coding and non-coding changes occur near genes with known roles in fin development, body patterning, and liver biology, but their effects on sisorid traits remain to be tested. Together, our results demonstrate how tectonic uplift reshaped genome architecture and diversification in Asian torrent catfishes and provide new insights into the genomic basis of adaptation in mountainous freshwater ecosystems.

evolutionary biology↗

bioRxiv2026

Inflammatory burning pain depends on a specific line of nociceptors

The development and persistence of burning pain and heat hyperalgesia following tissue injury and the subsequent inflammatory response, depend on the nuclear enzyme mitogen- and stress-activated kinase 1 (MSK1) expressed in a specific subset of transient receptor potential subfamily V member 1 (TRPV1)-expressing primary sensory neurons termed nociceptors, which are specialised for detecting harmful stimuli. Inflammation up-regulates and activates MSK1, and MSK1 governs TRPV1 expression in the MSK1 and TRPV1 co-expressing mouse and human nociceptors. Importantly, inhibition of inflammatory MSK1-mediated TRPV1 upregulation protects from heat hypersensitivity without affecting other relevant TRPV1 functions, such as the sensation of acute painful heat stimuli or the maintenance of the body core temperature. The newly discovered importance of the interaction between MSK1 and TRPV1 in a specific line of nociceptors provides mechanistic understanding of inflammatory pain and heat hyperalgesia pathogenesis.

neuroscience↗

bioRxiv2026

Interocular suppression weakens binocular disparity integration in the dorsal visual stream

A unified percept depends on the coordinated interplay of sensory integration and suppression, yet how this interaction is implemented across cortical representations remains unclear. Using binocular vision as a tractable model system, we combined fMRI with multivariate analyses to test how interocular suppression reshapes binocular disparity integration across human visual pathways. Local binocular rivalry weakened near-far disparity decoding, with disruption increasing along the dorsal pathway from V1 to V3A and intraparietal sulcus (IPS), but no reliable loss in ventral regions. In V3A, anticorrelated random-dot stereograms showed an inverted representational relationship relative to correlated stimuli, and this structure was abolished under suppression, indicating disrupted non-canonical disparity integration. Informational connectivity further revealed that suppression selectively weakened V3A-centered coordination while largely sparing coupling among early visual areas. Together, these findings identify higher-level dorsal regions as a key substrate for coordinating integrative and suppressive computations during unified percept formation.

neuroscience↗

bioRxiv2026

Transcription-specific synaptic plasticity mediates engram computations

Memory is encoded by sparse ensembles of neurons. While activity-dependent transcription and learning-induced synaptic plasticity are causally related to memory formation and recall, the link between the transcriptional regulation of synaptic plasticity and memory computations remains elusive. In particular, even though transcriptionally defined neuronal ensembles within a memory engram exhibit specific forms of synaptic plasticity and support distinct behavioral outputs, it is still unclear whether transcription-specific synaptic plasticity drives ensemble computations, rather than merely serving as a marker of ensemble identity. Here, we demonstrate that transcription-specific synaptic plasticity enables ensemble computations essential for learning-induced adaptive behaviors. In the mouse dentate gyrus (DG), we found that neuronal ensembles genetically defined by Fos-dependent transcription engage plasticity in feedforward excitatory synapses, whereas those defined by Npas4-dependent transcription engage plasticity in recurrent inhibitory synapses. We modeled spiking neural networks with transcription-specific synaptic plasticity and observed that Fos- and Npas4-dependent ensembles emerged following learning and stabilized with memory consolidation. Our computational model predicted that blocking Fos- or Npas4-dependent synaptic plasticity disrupts memory generalization and discrimination, respectively. By acutely deleting Fos or Npas4 in the DG to selectively block Fos- or Npas4-dependent synaptic plasticity, we conducted contextual fear conditioning experiments whose results supported our computational model's prediction. Our study provides causal evidence that specific transcriptional programs induced in distinct neuronal ensembles differentially engage synaptic plasticity and thereby regulate memory computations.

neuroscience↗

bioRxiv2026

Single-cell profiling reveals MMP7-associated epithelial transition and immune-stromal remodeling in esophageal carcinogenesis

The progression from reflux esophagitis (RE) to Barretts esophagus (BE) and esophageal adenocarcinoma (EAC) is a major route of inflammation-associated esophageal tumorigenesis, but the cellular transitions involved remain incompletely understood. We performed single-cell transcriptomic profiling of RE, BE, and EAC tissues and integrated public EAC datasets, yielding 51,283 cells across the RE-BE-EAC continuum. The analysis identified stage-associated epithelial and microenvironmental differences. Pseudotime analysis placed Basal epithelial cells along two differentiation branches, one toward mature epithelial states and the other through proliferative and gastric-type metaplastic states toward copy number alteration-bearing malignant epithelial cells. MMP7 increased along this malignant branch, was enriched in cancer-associated epithelial cells. Its knockdown reduced the proliferation and migration of OE19 and OE33 cells, supporting an association with proliferative and migratory phenotypes. In parallel, the microenvironment shifted toward immune suppression and stromal remodeling, with increased T-cell exhaustion, macrophage polarization toward tumor-associated states, and enrichment of CAF-like myofibroblasts. Ligand-receptor analysis further suggested an epithelial-centered communication network involving MDK-SDC2/LRP1/NCL interactions between malignant epithelial cells and fibroblast, T-cell, and myeloid compartments. These results identify MMP7-associated epithelial states and candidate MDK-related communication pathways for further longitudinal and functional validation.

cancer biology↗

bioRxiv2026

L-cysteine inhibited the growth of Vibrio parahaemolyticus via increasing the ROS level

The emergence of multidrug-resistant Vibrio parahaemolyticus poses a severe threat to mariculture sustainability, highlighting the urgent need for eco-friendly antimicrobial agents. In this study, we demonstrated that L-Cysteine (L-Cys) functions as an inhibitor of V. parahaemolyticus, with a minimum inhibitory concentration of 7.5 mM. Microscopic observation and viability assays revealed that L-Cys compromises bacterial membrane integrity, ultimately leading to cell death. Further investigation indicated that the antibacterial effect is primarily attributed to the intracellular production of hydrogen sulfide (H2S) generated by L-Cys metabolism. Transcriptomic and biochemical analyses showed that L-Cys induced metabolic reprogramming by suppressing fatty acid {beta}-oxidation, one-carbon metabolism, and antioxidant enzymes. This disruption of redox homeostasis results in accelerated accumulation of reactive oxygen species (ROS). In addition to its antibacterial effect, L-Cys also effectively reduced the virulence factor of bacterial motility. Finally, L-Cys demonstrated broad-spectrum antimicrobial activity against other pathogenic Vibrio species, including V. alginolyticus and V. anguillarum. Our findings suggest that L-Cys is a promising antimicrobial agent inducing ROS to mediate membrane disruption, with the advantages of cost-effectiveness and environmental safety for controlling vibriosis. ImportanceVibrio parahaemolyticus is a significant pathogen in aquaculture and a common cause of seafood-borne gastroenteritis worldwide. The increasing prevalence of antibiotic-resistant strains of this bacterium highlights the need for alternative control agents. This study shows that L-cysteine (L-Cys) inhibits the growth of V. parahaemolyticus. Our data indicate that L-Cys is metabolized to produce hydrogen sulfide, which contributes to the accumulation of ROS and disrupts bacterial membrane integrity. Additionally, L-Cys reduces bacterial motility and shows inhibitory effects against other Vibrio species. These findings suggest that L-Cys may represent a useful agent for managing Vibrio infections in aquaculture settings.

microbiology↗

bioRxiv2025

Systematic microcircuit reconfigurations underlie early experience-induced visual cortical plasticity

Experience-dependent reorganization of neuronal connections during a postnatal critical period (CP) is essential for the functional maturation of developing primary visual cortex (V1). However, the systematic reconfigurations across microcircuit synapses underlying this plasticity were poorly defined. Paired recording from excitatory pyramidal cells and other three major interneurons (INs) within layers 2/3 and 4 microcircuits in the developing mouse V1 monocular region, we find that monocular deprivation (MD) for one-day during the CP transiently reconfigures local excitatory synapses on inhibitory INs that specifically express parvalbumin (PV) or vasoactive intestinal peptide (VIP), whereas prolonged MD primarily strengthens inhibitory transmission from somatostatin (SST)-expressing INs to PV-INs and VIP-INs in both layers. A physiologically based microcircuit model suggests these coordinated synaptic changes in specific inhibitory neurons mediate differential MD-induced plasticity in visual responses across layer 2/3 neurons in vivo. Together, our findings define a systematic microcircuit basis for cortical critical-period plasticity. HighlightsO_LIInhibitory-to-inhibitory connectivity is conserved in cortical layer 2/3 and 4 circuits. C_LIO_LIEarly experience sequentially modifies excitatory and dis-inhibitory synapses in both layers. C_LIO_LISystematic microcircuit reconfigurations underlie plasticity of cortical visual responses. C_LIO_LIModeling suggests a pivotal role of disinhibitory microcircuits in mediating the plasticity. C_LI

neuroscience↗

bioRxiv2025

A BIOSECURITY AGENT FOR LIFECYCLE LLM BIOSECURITY ALIGNMENT

AO_SCPLOWBSTRACTC_SCPLOWLarge language models (LLMs) are increasingly integrated into biomedical re-search workflows-from literature triage and hypothesis generation to experimental design-yet this expanded utility also heightens dual-use concerns, including the potential misuse for guiding toxic compound synthesis. In response, this study shows a Biosecurity Agent that comprises four coordinated modes across the model lifecycle: dataset sanitization, preference alignment, runtime guardrails, and automated red teaming. For dataset sanitization (Mode 1), evaluation is conducted on CORD-19, a COVID-19 Open Research Dataset of coronavirus-related scholarly articles. We define three sanitization tiers-L1 (compact, high-precision), L2 (human-curated biosafety terms), and L3 (comprehensive union)-with removal rates rising from 0.46% to 70.40%, illustrating the safety-utility trade-off. For preference alignment (Mode 2), DPO with LoRA adapters internalizes refusals and safe completions, reducing end-to-end attack success rate (ASR) from 59.7% to 3.0%. At inference (Mode 3), runtime guardrails across L1-L3 show the expected security-usability trade-off: L2 achieves the best balance (F1 = 0.720, precision = 0.900, recall = 0.600, FPR = 0.067), while L3 offers stronger jailbreak resistance at the cost of higher false positives. Under continuous automated red-teaming (Mode 4), no successful jailbreaks are observed under the tested protocol. Taken together, our biosecurity agent offers an auditable, lifecycle-aligned framework that reduces attack success while preserving benign utility, providing safeguards for the use of LLMs in scientific research and setting a precedent for future agent-level security protections.

bioinformatics↗

bioRxiv2025

Population-specific brain charts reveal Chinese-Western differences in neurodevelopmental trajectories

Human brain charts provide unprecedented opportunities for decoding neurodevelopmental milestones and establishing clinical benchmarks for precision brain medicine 1-7. However, current lifespan brain charts are primarily derived from European and North American cohorts, with Asian populations severely underrepresented. Here, we present the first population-specific brain charts for China, developed through the Chinese Lifespan Brain Mapping Consortium (Phase I) using neuroimaging data from 43,037 participants (aged 0-100 years) across 384 sites nationwide. We establish the lifespan normative trajectories for 296 structural brain phenotypes, encompassing global, subcortical, and cortical measures. Cross-population comparisons with Western brain charts (based on data from 56,339 participants aged 0-100 years) reveal distinct neurodevelopmental patterns in the Chinese population, including prolonged cortical and subcortical maturation, accelerated cerebellar growth, and earlier development of sensorimotor regions relative to paralimbic regions. Crucially, these Chinese-specific charts outperform Western-derived models in predicting healthy brain phenotypes and detecting pathological deviations in Chinese clinical cohorts. These findings highlight the urgent need for diverse, population-representative brain charts to advance equitable precision neuroscience and improve clinical validity across populations.

neuroscience↗

bioRxiv2025

Flow cytometry-based isolation combined with ultra-sensitive proteomics of Salmonella-containing phagosomes reveals novel insights into host-pathogen interactions

Macrophages engulf pathogens into dynamic phagosomes, which many bacteria manipulate for survival. However, isolating pure pathogen-containing phagosomes remains challenging. Here, we developed a novel flow cytometry-based isolation and ultrasensitive proteomics approach to analyse phagosomal and bacterial proteomes from macrophages infected with wild-type (WT) Salmonella enterica serovar Typhimurium (STM) or a {Delta}phoP mutant at 30 min and 4 hrs post-infection. Our approach provides higher throughput, requires lower cell numbers and quantifies more proteins than previous techniques. Our data reveals key host-pathogen interactions, showing induction of PhoP-dependent virulence factors and novel putative proteins that shape STMs intracellular niche. Moreover, our data indicates that bacteria-containing phagosomes recruit mitochondrial membrane for production of reactive oxygen species. These findings provide new insights into Salmonellas manipulation of phagosomal maturation and intracellular niche formation.

microbiology↗

bioRxiv2025

VPS35/Retromer-dependent MT1-MMP regulation confers melanoma metastasis

Retromer is a conserved endosomal trafficking complex responsible for recycling transmembrane protein cargoes. Membrane-type I matrix metalloproteinase (MT1-MMP), a well-studied membrane-type metalloprotease, is highly expressed in metastatic melanomas. Previously, we reported that inducing MT1-MMP perinuclear localization and inhibiting MT1-MMP membrane localization significantly reduce melanoma metastasis. However, the regulation of MT1-MMP subcellular localization and recycling is still largely unknown. Here, we performed target gene shRNA screening and found that shRNA targeting the retromer complex subunit vacuolar protein sorting 35 (VPS35) inhibited MT1-MMP membrane localization and induced its perinuclear localization. We found that inhibiting VPS35/retromer decreased MT1-MMP recycling and increased MT1-MMP-lysosome localization, which significantly affected the stability of MT1-MMP. Furthermore, our results indicated that VPS35/retromer regulates the transcription of MT1-MMP through the activation of the IL6/STAT3 inflammatory signaling pathway. Tissue microarray analysis indicated that VPS35/retromer positively correlated with MT1-MMP levels and distant metastasis. Xenograft experiments showed that targeting VPS35/retromer significantly inhibited melanoma lung metastasis, which is dependent on MT1-MMP. Our results implicate the importance of VPS35/retromer in metastatic dissemination. Our study suggests that targeting the VPS35/retromer-MT1-MMP axis will contribute to inhibiting the metastasis of melanoma.

cancer biology↗

bioRxiv2024

The Assembly of Purple-red Spinach Provides Insight into the Mechanism of Betalain Biosynthesis

Purple-red spinach is a unique cultivar with rich in betalains, which has been used for food colorants and is beneficial for human health. In view of the lack of genomic inforamtion of purple-red spinach genome and promote the idetification of betalian gene, we presented the genome of purple-red spinach with Nanopore ultra-long and illumina sequencing platform. The contig N50 size was 2.2Mb and 99.33% contig sequence was anchored to the six chromosomes, totaling 878.83Mb. The purple-red genome constitues 74.15% repeat sequence and harbors 26020 protein-coding genes. We also comprehensively identified candidate genes in betalain biosynthesis pathway in spinach. Moreover, a combined transcriptomic and BSA analysis uncovered a key betalain gene, FUN_002594, which regulated the color and betalain content of leaf. Our data present a valuable resource for facilitating molecular breeding programs of spinach and shed novel light on unique attributes, as well as the modulation of betalain biosynthesis.

genomics↗

bioRxiv2024

A multiple Arc (mArc) tagging system to uncover the organizational principles of multiple memories

Engrams or memory traces are the neuronal ensembles that collectively store individual experiences. Genetic strategies based on immediate early genes (IEGs), such as Arc/Arg3.1, allow us to tag the ensembles active during memory encoding and compare them to those active during retrieval. However, these strategies only allow for the tagging of one neural ensemble. Here, we developed a multiple Arc (mArc) system that allows for the tagging of two Arc+ ensembles. We validated this system by investigating how context, time, and valence influence neuronal ensemble reactivation in the dentate gyrus (DG). We show that similar contextual and valenced experiences are encoded in overlapping DG ensembles. We also find that ensembles are modulated by time, where experiences closer in time are encoded in more similar ensembles. These results highlight the dynamic nature of DG ensembles and show that the mArc system provides a powerful approach for investigating multiple memories in the brain. HIGHLIGHTSO_LIThe mArc system allows for the tagging of two Arc+ ensembles in the same mouse C_LIO_LIDG ensembles labeled by the mArc system receive increased excitatory input C_LIO_LIContext, valence, and time influence DG ensemble reactivation C_LIO_LIDG neural ensembles are reactivated less with increasing time C_LI

neuroscience↗

bioRxiv2024

The EGF/EGFR-YAP1/TEAD2 axis-mediated BRAF inhibitor vemurafenib resistance upregulates STIM1 in melanoma

STIM1 is the endoplasmic reticulum (ER) Ca2+ sensor for store-operated entry (SOCE) and closely correlated to carcinogenesis and tumor progression. Previously we found that STIM1 is upregulated in melanoma cells resistant to the BRAF inhibitor vemurafenib, but the regulation mechanism is unknown. Here, we show that vemurafenib resistance upregulates STIM1 through an EGF/EGFR-YAP1/TEAD2 axis. Vemurafenib resistance can lead to the increase of EGF and EGFR levels to activate the EGFR signaling pathway. Reactivated EGFR signal promotes YAP1 nuclear localization to increase the expression of STIM1. Our finding not only demonstrates the mechanism by which vemurafenib resistance promotes STIM1 expression, but also provides combined targeting EGF/EGFR-YAP1/TEAD2-STIM1 to improve the therapeutic efficiency of BRAF inhibitor in melanoma patients.

cancer biology↗

bioRxiv2024

An opponent striatal circuit for distributional reinforcement learning

Machine learning research has achieved large performance gains on a wide range of tasks by expanding the learning target from mean rewards to entire probability distributions of rewards -- an approach known as distributional reinforcement learning (RL)1. The mesolimbic dopamine system is thought to underlie RL in the mammalian brain by updating a representation of mean value in the striatum2,3, but little is known about whether, where, and how neurons in this circuit encode information about higher-order moments of reward distributions4. To fill this gap, we used high-density probes (Neuropixels) to acutely record striatal activity from well-trained, water-restricted mice performing a classical conditioning task in which reward mean, reward variance, and stimulus identity were independently manipulated. In contrast to traditional RL accounts, we found robust evidence for abstract encoding of variance in the striatum. Remarkably, chronic ablation of dopamine inputs disorganized these distributional representations in the striatum without interfering with mean value coding. Two-photon calcium imaging and optogenetics revealed that the two major classes of striatal medium spiny neurons -- D1 and D2 MSNs -- contributed to this code by preferentially encoding the right and left tails of the reward distribution, respectively. We synthesize these findings into a new model of the striatum and mesolimbic dopamine that harnesses the opponency between D1 and D2 MSNs5-15 to reap the computational benefits of distributional RL.

neuroscience↗

bioRxiv2023

Integrated multi-omics approach reveals the role of SPEG in skeletal muscle biology including its relationship with myospryn complex

Autosomal-recessive mutations in SPEG (striated muscle preferentially expressed protein kinase) have been linked to centronuclear myopathy. Loss of SPEG is associated with defective triad formation, abnormal excitation-contraction coupling, and calcium mishandling in skeletal muscles. To elucidate the underlying molecular pathways, we have utilized multi-omics tools and analysis to obtain a comprehensive view of the complex biological processes. We identified that SPEG interacts with myospryn complex proteins (CMYA5, FSD2, RyR1), and SPEG deficiency results in myospryn complex abnormalities. In addition, transcriptional and protein profiles of SPEG-deficient muscle revealed defective mitochondrial function including aberrant accumulation of enlarged mitochondria on electron microscopy. Furthermore, SPEG regulates RyR1 phosphorylation at S2902, and its loss affects JPH2 phosphorylation at multiple sites. On analyzing the transcriptome, the most dysregulated pathways affected by SPEG deficiency included extracellular matrix-receptor interaction and peroxisome proliferator-activated receptors signaling, which may be due to defective triad and mitochondrial abnormalities. In summary, we have elucidated the critical role of SPEG in triad as it works closely with myospryn complex, phosphorylates JPH2 and RyR1, and demonstrated that its deficiency is associated with mitochondrial abnormalities. This study emphasizes the importance of using multi-omics techniques to comprehensively analyze the molecular anomalies of rare diseases. Synopsis O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=152 SRC="FIGDIR/small/538136v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@bc3cbborg.highwire.dtl.DTLVardef@37195dorg.highwire.dtl.DTLVardef@1624caeorg.highwire.dtl.DTLVardef@985a2c_HPS_FORMAT_FIGEXP M_FIG C_FIG We have previously linked mutations in SPEG (striated preferentially expressed protein) with a recessive form of centronuclear myopathy and/or dilated cardiomyopathy and have characterized a striated muscle-specific SPEG-deficient mouse model that recapitulates human disease with disruption of the triad structure and calcium homeostasis in skeletal muscles. In this study, we applied multi-omics approaches (interactomic, proteomic, phosphoproteomic, and transcriptomic analyses) in the skeletal muscles of SPEG-deficient mice to assess the underlying pathways associated with the pathological and molecular abnormalities. O_LISPEG interacts with myospryn complex proteins (CMYA5, FSD2, RyR1), and its deficiency results in myospryn complex abnormalities. C_LIO_LISPEG regulates RyR1 phosphorylation at S2902, and its loss affects JPH2 phosphorylation at multiple sites. C_LIO_LISPEG and SPEG{beta} have different interacting partners suggestive of differential function. C_LIO_LITranscriptome analysis indicates dysregulated pathways of ECM-receptor interaction and peroxisome proliferator-activated receptor signaling. C_LIO_LIMitochondrial defects on the transcriptome, proteome, and electron microscopy, may be a consequence of defective calcium signaling. C_LI

molecular biology↗

bioRxiv2022

IL-1β turnover by TRIP12 and AREL1 ubiquitin ligases and UBE2L3 limits inflammation

The cytokine interleukin-1{beta} (IL-1{beta}) has pivotal roles in antimicrobial immunity, but also incites inflammatory pathology. Bioactive IL-1{beta} is released following proteolytic maturation of the pro-IL-1{beta} precursor by caspase-1 inflammasomes. UBE2L3/UBCH7, a conserved ubiquitin conjugating enzyme, promotes pro-IL-1{beta} ubiquitylation and proteasomal disposal. However, UBE2L3 actions in vivo and ubiquitin ligases involved in this process are unknown. Here we report that deletion of Ube2l3 in mice markedly reduces pro-IL-1{beta} turnover in macrophages, leading to excessive mature IL-1{beta} production, neutrophilic inflammation and disease symptoms following inflammasome activation. A family-wide siRNA screen identified two ubiquitin ligases, TRIP12 and AREL1, which we show add K27-, K29- and K33- poly-ubiquitin chains on lysine residues in the pro domain and destabilise pro-IL-1{beta}. Mutation of ubiquitylation sites increased pro-IL-1{beta} stability, but did not affect proteolysis by caspase-1. The extent of mature IL-1{beta} production is therefore determined by precursor abundance, and UBE2L3, TRIP12 and AREL1 limit inflammation by shrinking the cellular pool of pro-IL-1{beta}. Our study has uncovered fundamental processes governing IL-1{beta} homeostasis and provided molecular insights that could be exploited to mitigate its adverse actions in disease.

immunology↗