Biology subjects

Fu, X.

Publications and source records attributed to Fu, X..

At least 145 records · Page 8Linked to original sources

bioRxiv2022

A Distinct Chromatin State Drives Therapeutic Resistance in Invasive Lobular Breast Cancer

Most invasive lobular breast cancers (ILC) are of the luminal A subtype and strongly hormone receptor positive. Yet, they are relatively resistant to tamoxifen and are associated with inferior long-term outcomes compared to invasive ductal cancers (IDC). In this study, we sought to gain mechanistic insights into these clinical findings that are not explained by the genetic landscape of ILC and to identify strategies to improve patient outcomes. Through a comprehensive analysis of the epigenome of ILC in pre-clinical models and clinical samples we found that compared to IDC, ILC has a distinct chromatin state that is linked to gained recruitment of FOXA1, a lineage-defining pioneer transcription factor. This results in an ILC-unique FOXA1-estrogen receptor (ER) axis that promotes the transcription of genes associated with tumor progression and poor outcomes. The ILC-unique FOXA1-ER axis leads to retained ER chromatin binding after tamoxifen treatment thereby facilitating tamoxifen resistance while remaining strongly dependent on ER signaling. Mechanistically, gained FOXA1 binding was associated with the auto-induction of FOXA1 in ILC through an ILC-unique FOXA1 binding site. Targeted silencing of this regulatory site resulted in the disruption of the feed-forward loop and growth inhibition in ILC. In summary, we show that ILC is characterized by a unique cell state and FOXA1-ER axis that dictate tumor progression and offer a novel mechanism of tamoxifen resistance. These results underscore the importance of conducting clinical trials dedicated to patients with ILC to optimize endocrine treatments in this breast cancer subtype.

cancer biology↗

bioRxiv2022

Chromatin-associated lncRNA Malat1 regulates Th17 effector program and promotes intestinal inflammation

Interleukin IL-17 cytokines are central regulators of mucosal homeostasis and disease. In mouse models of colonic tissue injury, IL-17A promotes epithelial barrier functions and restricts local inflammation. Here, we report that IL-17A production by the diverse T lymphocyte subsets is dynamically regulated at different stages of colitis pathogenesis. During the onset and peak of the disease, T{gamma}{delta}17 cells are the major IL-17A producers, while Th17 activity is temporally restricted by long non-coding RNA (lncRNA) Malat1. In response to IL-6 and TGF{beta} signaling, Malat1 is recruited to the Th17-specific cis-regulatory elements, CNS3 and CNS4, of the Il17a locus to fine-tune bivalent super-enhancer activities and repress local transcription. During the resolution phase of inflammation, Malat1 expression is down-regulated to enhance Th17 activities, allowing Th17 cells to emerge as the main producers of IL-17A in the colonic lamina propria. Genetic ablation of Malat1 potentiates IL-17A production in Th17 cells and improves disease outcomes in mouse models of colitis. These findings uncover a surprising role of a chromatin-associated lncRNA in regulating colonic Th17-specific responses to control the timing of inflammation resolution. Significance StatementT cells are critical modulators of mucosal barrier function and inflammation. The function of long-noncoding RNAs (lncRNAs) in T cells and their role in mucosal inflammation remain elusive. Here, we identify an essential role of the lncRNA Malat1 restricting transcription of the Il17a locus in Th17 cells encoding a cytokine implicated in epithelial barrier function post-injury. By controlling the activity of the bivalent super-enhancer at the Il17a locus, Malat1 regulates the timing of inflammation resolution in the intestine. The Malat1-Il17a pathway reveals new targets for combating mucosal diseases. Graphic Abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

immunology↗

bioRxiv2022

Zfp281 inhibits the pluripotent-to-totipotent state transition in mouse embryonic stem cells

The cell-fate transition between pluripotent and totipotent states determines embryonic development and the first cell-lineage segregation. However, limited by the scarcity of totipotent embryos, regulators on this transition remain largely elusive. A novel model to study the transition has been recently established, named the 2-cell-like (2C-like) model. The 2C-like cells are rare totipotent-like cells in the mouse embryonic stem cell (mESC) culture. Pluripotent mESCs can spontaneously transit into and out of the 2C-like state. We previously dissected the transcriptional roadmap of the transition. In this study, we revealed that Zfp281 is a novel regulator for the pluripotent-to-totipotent transition in mESCs. Zfp281 is a transcriptional factor involved in the cell-fate transition. Our study shows that Zfp281 represses transcripts upregulated during the 2C-like transition via Tet1 and consequentially inhibits mESCs from transiting into the 2C-like state. Interestingly, we found that the inhibitory effect of Zfp281 on the 2C-like transition leads to an impaired 2C-like-transition ability in primed-state mESCs. Altogether, our study reveals a novel mediator for the pluripotent-to-totipotent state transition in mESCs and provides insights into the dynamic transcriptional control of the transition.

cell biology↗

bioRxiv2022

Chromatin reprogramming and transcriptional regulation orchestrate embryogenesis in hexaploid wheat

Embryogenesis represents the beginning of life cycle, but our understanding of the regulatory circuitry in plants is far lagged to animals. Here, we draw a transcriptome trajectory and chromatin landscape profile during embryogenesis of most cultivated crop hexaploid wheat, highlighting large-scale chromatin reconfiguration and distinct proximal and distal transcriptional regulation in defining cell fate transition. Upon fertilization, H3K27ac and H3K4me3 resetting were correlated with maternal genome silence, while de novo building of chromatin accessibility activated zygotic genome. Global depletion of H3K27me3 in pre-embryo results in a permissive chromatin environment with gain-of-chromatin accessibility, allowing subsequent hierarchical cis- and trans-regulation network mediated by key factors, such as LEC1, MYB, ZHD, LEC2, governing embryo pattern formation. By contrast, H3K27me3 restoration coordinating with chromatin compaction in developmental genes attenuated totipotency and prohibited extensive organogenesis during embryo maturation. In addition, dynamic biased expression of homeolog triads and diverse expression profiles after polyploidization were observed. This is correlated with asymmetric transposon elements insertion in accessible proximal and distal regions. Thus, our study revealed a plant-specific chromatin reprogramming process in facilitating the hierarchical transcription regulation circuits mediated "inverse hourglass model" and unveiled epigenetic regulation of evolutionary divergence among different sub-genome in shaping embryogenesis in polyploidy wheat.

plant biology↗

bioRxiv2022

DelaySSAToolkit.jl: stochastic simulation of reaction systems with time delays in Julia

SummaryDelaySSAToolkit.jl is a Julia package for modelling reaction systems with non-Markovian dynamics, specifically those with time delays. These delays implicitly capture multiple intermediate reaction steps and hence serve as an effective model reduction technique for complex systems in biology, chemistry, ecology and genetics. The package implements a variety of exact formulations of the delay stochastic simulation algorithm. Contactxmfu@ecust.edu.cn, zcao@ecust.edu.cn, or ramon.grima@ed.ac.uk Availability and ImplementationThe source code and documentation of DelaySSAToolkit.jl are available at https://github.com/palmtree2013/DelaySSAToolkit.jl.

systems biology↗

bioRxiv2021

Human embryos arrest in a quiescent-like state characterized by metabolic and zygotic genome activation problems

Around 60% of in vitro fertilized (IVF) human embryos irreversibly arrest before compaction between the 3-8-cell stage, posing a significant clinical problem. The mechanisms behind this arrest are unclear. Here, we show that the arrested embryos enter a quiescent-like state, marked by cell cycle arrest, the downregulation of ribosomes and histones and downregulation of MYC and p53 activity. Mechanistically, the arrested embryos can be divided into three types. Type I embryos fail to complete the maternal-zygotic transition, and type II/III embryos have erroneously low levels of glycolysis and variable levels of oxidative phosphorylation. Treatment with resveratrol or nicotinamide riboside (NR) can partially rescue the arrested phenotype. The mechanism of reactivation involves the upregulation of SIRT1, and activation of glycolysis and fatty acid oxidation which forces the embryos out of a quiescent state. Overall, our data reveal how human embryo arrest can be overcome by modulating metabolic pathways.

developmental biology↗

bioRxiv2021

Interplay of adherens junctions and matrix proteolysis determines the invasive pattern and growth of squamous cell carcinoma

Cancers, such as squamous cell carcinoma, frequently invade as multicellular units. However, these invading units can be organized in a variety of ways, ranging from thin discontinuous strands to thick pushing collectives. Here we employ an integrated experimental and computational approach to identify the factors that determine the mode of collective cancer cell invasion. We find that matrix proteolysis is linked to the formation of wide strands, but has little effect on the maximum extent of invasion. Cell-cell junctions also favour wide strands, but our analysis also reveals a requirement for cell-cell junctions for efficient invasion in response to uniform directional cues. Unexpectedly, the ability to generate wide invasive strands is coupled to the ability to grow effectively when surrounded by ECM in 3D assays. Combinatorial perturbation of both matrix proteolysis and cell-cell adhesion demonstrates that the most aggressive cancer behaviour, both in terms of invasion and growth, is achieved at high levels of cell-cell adhesion and high levels of proteolysis. Contrary to expectation, cells with canonical mesenchymal traits - no cell-cell junctions and high proteolysis - exhibit reduced growth and lymph node metastasis. Thus, we conclude that the ability of squamous cell carcinoma cells to invade effectively is also linked to their ability to generate space for proliferation in confined contexts. These data provide an explanation for the apparent advantage of retaining cell-cell junctions in SCC.

cancer biology↗

bioRxiv2021

iEnhancer-CLA: Self-attention-based interpretable model for enhancers and their strength prediction

Enhancer is a class of non-coding DNA cis-acting elements that plays a crucial role in the development of eukaryotes for their transcription. Computational methods for predicting enhancers have been developed and achieve satisfactory performance. However, existing computational methods suffer from experience-based feature engineering and lack of interpretability, which not only limit the representation ability of the models to some extent, but also make it difficult to provide interpretable analysis of the model prediction findings.In this paper, we propose a novel deep-learning-based model, iEnhancer-CLA, for identifying enhancers and their strengths. Specifically, iEnhancer-CLA automatically learns sequence 1D features through multiscale convolutional neural networks (CNN), and employs a self-attention mechanism to represent global features formed by multiple elements (multibody effects). In particular, the model can provide an interpretable analysis of the enhancer motifs and key base signals by decoupling CNN modules and generating self-attention weights. To avoid the bias of setting hyperparameters manually, we construct Bayesian optimization methods to obtain model global optimization hyperparameters. The results demonstrate that our method outperforms existing predictors in terms of accuracy for identifying enhancers and their strengths. Importantly, our analyses found that the distribution of bases in enhancers is uneven and the base G contents are more enriched, while the distribution of bases in non-enhancers is relatively even. This result contributes to the improvement of prediction performance and thus facilitates revealing an in-depth understanding of the potential functional mechanisms of enhancers. Author summaryThe enhancers contain many subspecies and the accuracy of existing models is difficult to improve due to the small data set. Motivated by the need for accurate and efficient methods to predict enhancer types, we developed a self-attention deep learning model iEnhancer-CLA, the aim is to be able to distinguish effectively and quickly between subspecies of enhancers and whether they are enhancers or not. The model is able to learn sequence features effectively through the combination of multi-scale CNN blocks, BLSTM layers, and self-attention mechanisms, thus improving the accuracy of the model. Encouragingly, by decoupling the CNN layer it was found that the layer was effective in learning the motif of the sequences, which in combination with the self-attention weights could provide interpretability to the model. We further performed sequence analysis in conjunction with the model-generated weights and discovered differences in enhancer and non-enhancer sequence characteristics. This phenomenon can be a guide for the construction of subsequent models for identifying enhancer sequences.

bioinformatics↗

bioRxiv2021

The manipulation of spinal motor neuron axonal growth promotes spinal cord repair

The loss of motor function in patients with spinal cord injury (SCI) is primarily due to the severing of the corticospinal tract (CST). Spinal motor neurons are located in the anterior horn of the spinal cord, and as the lower neurons of the CST, they control voluntary movement. Furthermore, its intrinsic axonal growth ability is significantly stronger than that of cerebral cortex pyramid neurons, which are the upper CST neurons. Therefore, we established an axonal regeneration model of spinal motor neurons to investigate the feasibility of repairing SCI by promoting axonal regeneration of spinal motor neurons. We demonstrated that conditionally knocking out pten in mature spinal motor neurons drastically enhanced axonal regeneration in vivo, and the regenerating axons of the spinal motor neurons re-established synapses with other cells in the damaged spinal cord. Thus, this strategy may serve as a novel and effective treatment method for SCI.

neuroscience↗

bioRxiv2021

Accurate inference of stochastic gene expression from nascent transcript heterogeneity

Transcriptional rates are often estimated by fitting the distribution of mature mRNA numbers measured using smFISH (single molecule fluorescence in situ hybridization) with the distribution predicted by the telegraph model of gene expression, which defines two promoter states of activity and inactivity. However, fluctuations in mature mRNA numbers are strongly affected by processes downstream of transcription. In addition, the telegraph model assumes one gene copy, but in experiments cells may have two gene copies as cells replicate their genome during the cell cycle. Whilst it is often presumed that post-transcriptional noise and gene copy number variation affect transcriptional parameter estimation, the size of the error introduced remains unclear. To address this issue, here we measure both mature and nascent mRNA distributions of GAL10 in yeast cells using smFISH and classify each cell according to its cell cycle phase. We infer transcriptional parameters from mature and nascent mRNA distributions, with and without accounting for cell cycle phase and compare the results to live-cell transcription measurements of the same gene. We find that: (i) correcting for cell cycle dynamics decreases the promoter switching rates and the initiation rate, and increases the fraction of time spent in the active state, as well as the burst size; (ii) additional correction for post-transcriptional noise leads to further increases in the burst size and to a large reduction in the errors in parameter estimation. Furthermore, we outline how to correctly adjust for measurement noise in smFISH due to uncertainty in transcription site localisation when introns cannot be labelled. Simulations with parameters estimated from nascent smFISH data, which is corrected for cell cycle phases and measurement noise, leads to autocorrelation functions that agree with those obtained from live-cell imaging.

systems biology↗

bioRxiv2021

Genotyping of structural variation using PacBio high-fidelity sequencing

BackgroundStructural variations (SVs) pervade the genome and contribute substantially to the phenotypic diversity of species. However, most SVs were ineffectively assayed because of the complexity of plant genomes and the limitations of sequencing technologies. Recent advancement of third-generation sequencing technologies, particularly the PacBio high-fidelity (HiFi) sequencing, which generates both long and highly accurate reads, offers an unprecedented opportunity to characterize SVs and reveal their functionality. Since HiFi sequencing is new, it is crucial to evaluate HiFi reads in SV detection before applying the technology at scale. ResultsWe sequenced wheat genomes using HiFi, then conducted a comprehensive evaluation of SV detection using mainstream long-read aligners and SV callers. The results showed the accuracy of SV discovery depends more on aligners rather than callers. For aligners, pbmm2 and NGMLR provided the most accurate results while detecting deletion and insertion, respectively. Likewise, cuteSV and SVIM achieved the best performance across all SV callers. We demonstrated that the combination of the aligners and callers mentioned above is optimal for SV detection. Furthermore, we evaluated the impact of sequencing depth on the accuracy of SV detection. The results showed that low-coverage HiFi sequencing is capable of generating high-quality SV genotyping. ConclusionsThis study provides a robust benchmark of SV discovery with HiFi reads, showing the remarkable potential of long-read sequencing to investigate structural variations in plant genomes. The high accuracy SV discovery from low-coverage HiFi sequencing indicates that skim HiFi sequencing is an ideal approach to study structural variations at the population level.

bioinformatics↗

bioRxiv2021

ConTreeDP: A consensus method of tumor trees based on maximum directed partition support problem

Phylogenetic inference has become a crucial tool for interpreting cancer genomic data, but continuing advances in our understanding of somatic mutability in cancer, genomic technologies for profiling it, and the scale of data available have created a persistent need for new algorithms able to deal with these challenges. One particular need has been for new forms of consensus tree algorithms, which present special challenges in the cancer space for dealing with heterogeneous data, short evolutionary time scales, and rapid mutation by a wide variety of somatic mutability mechanisms. We develop a new consensus tree method for clonal phylogenetics, ConTreeDP, based on a formulation of the Maximum Directed Partition Support Consensus Tree (MDPSCT) problem. We demonstrate theoretically and empirically that our approach can efficiently and accurately compute clonal consensus trees from cancer genomic data. Availability: https://github.com/CMUSchwartzLab/ConTreeDP

bioinformatics↗

bioRxiv2021

The Synechocystis ORF slr0201 product is involved in succinate dehydrogenase-mediated cyclic electron transfer around PSI

The Synechocystis sp. PCC 6803 open reading frame (ORF) slr0201 was originally annotated as heterodisulfide reductase B subunit (HdrB). The slr0201 encodes a 301-amino acid hypothetical protein with the predicted amino acid sequence significantly homologous to not only the HdrB from methanogenic bacteria, but also some novel succinate dehydrogenase C subunit (SdhC) found in Archaea and Campylobacter. Genetic manipulation via knocking-out approach created a{Delta} slr0201 mutant showing a{Delta} sdhB-like phenotype that was characterized by impaired succinate-dependent DCPIP reduction activities, reduced SDH-mediated respiratory electron transports, lower cellular contents of succinate and fumarate, slower KCN-induced increases in Chl fluorescence yield in the dark, and weak state 2/strong state 1 transitions, being indicative of a more oxidized PQ pool. In addition, slower re-reductions of the photosystem (PS) I reaction center P700 upon light-off were also monitored in the{Delta} slr0201, indicating functional involvements of Slr0201 in cyclic electron transfer around PSI. Both photoautptrophical and photomixotrophical growth rates of the{Delta} slr0201 strain resembled to those of the wild type, but substantial growth deteriorations occurred when arginine ([~]25 mM) or other two urea-cycle relevant amino acids (citrulline and ornithine) were added, which were attributed to generations and accumulations of certain hazardous metabolites. Based on the{Delta} sdhB-resembling phenotype, in conjunction with its high sequence similarities to some archaeal SdhC, we proposed that the slr0201 encodes a SDH function-relevant protein and is most likely the SdhC, a membrane anchoring subunit, which, while being genetically distinct from those in traditional bacterial SDH, belongs to the C subunit of novel archaeal SDH.

plant biology↗

bioRxiv2021

Hydrogen sulfide improves the cold stress resistance through the CsARF5-CsDREB3 module in cucumber

Hydrogen sulfide (H2S) plays a crucial role in regulating cold tolerance. But the synergistic regulation of H2S and auxin in the plant response to cold stress has not been reported. In the study, we found that sodium hydrosulfide (NaHS, an H2S donor) treatment enhanced the cold tolerance of cucumber seedlings and increased the level of auxin. CsARF5, a cucumber auxin response factor (ARF) gene was isolated and its role in regulating H2S-mediated cold stress tolerance was described. Transgenic cucumber leaves overexpressing CsARF5 were obtained. Physiological analysis indicated that overexpression of CsARF5 enhanced the cold stress tolerance of cucumber and the regulation of the cold stress response by CsARF5 depends on H2S. In addition, molecular assays showed that CsARF5 modulated cold stress response by directly activating the expression of the dehydration-responsive element-binding (DREB)/C-repeat binding factor (CBF) gene CsDREB3, which was identified as a positive regulator of cold stress. Taken together, our results suggest that CsARF5 plays an important role in H2S-mediated cold stress in cucumber. These results shed light on the molecular mechanism by which H2S regulates cold stress response by mediating auxin signaling, and will provide insights for further studies on the molecular mechanism by which H2S regulates cold stress. HighlightAuxin signaling participates in H2S-mediated cold stress through the CsARF5-CsDREB3 module in cucumber.

physiology↗

bioRxiv2021

Edible fire buffers: mitigation of wildfire with multifunctional landscapes

Wildfires ravage lands in seasonally-dry regions, imposing high costs on infrastructure maintenance and human habitation at the wildland-urban interface (WUI). Current fire mitigation approaches present upfront costs with uncertain long-term payoffs. Instead, we show that a simple landscape intervention on human-managed wildlands - buffers of a low-flammability crop species such as banana irrigated using recycled water - can mitigate wildfires, produce food profitably, and provide additional ecosystem services. Recreating a recent, major fire in simulation, we find that a medium-sized banana buffer decreases fireline intensity by 96%, similar to prescribed burns and mechanical thinning combined, and delays the fire by 316 minutes, enabling safe and effective firefighting. We find that under climate change, despite worsened fires, banana buffers will still have a protective effect. We also find that banana buffers with average yield could produce a profit of $56k USD/hectare through fruit sales, in addition to fire mitigation and other benefits.

ecology↗

bioRxiv2021

Time Evolution of the Stroke Symptom-Herb Networks Based on TCM Prescriptions

Traditional Chinese Medicine (TCM) has its origins in distant antiquity and has piled up over a long time with much knowledge about diseases, especially stroke. Different combinations of symptom variables yield different combinations of herbs to form a myriad of prescriptions, and they have undergone repeated confirmation and are worthy objects of excavation and analysis. Herbal studies on stroke have developed from genomics to transcriptomics, proteomics and metabolomics, yet more thought is needed on putting time in a wider perspective of the symptoms and herbs for stroke in Chinese medicine. Due to this, we studied the dynamic structure of TCM prescriptions on stroke, using over 270 TCM prescription books containing 2231 prescriptions related to stroke recorded from 341 to 2000 CE. We labeled the functions of the prescriptions with the symptoms based on subject terms in MESH Neurologic Manifestations, then standardized the herbs in the prescriptions, and finally connected the co-occurring symptoms and herbs in the prescriptions to build an undirected complex network. The Stroke Symptom-Herb Networks (SSHNs) can be seen from its network characteristics that it is not a random network and has small-world characteristics. It has experienced two peaks in its nearly 1700-year history, during the Song dynasty, the Ming and Qing dynasties. From 600 years onwards, the core herb cluster has been initially formed. The comparison of sub-network similarities allowed us to identify several symptoms with similar herb clusters. We divided the community based on modularity, and by analyzing the community evolution, we found a more fixed historical evolutionary trend with Hemiplegia and Sialorrhea nodes and their associated symptom and herb nodes. In the time series analysis, we found many symptom-herb combinations that were consistently closely related to historic time depends on assessing the similarity between the symptoms and the herbs. The complex network provides a distinctive perspective for understanding the symptom-herb relationships embedded in TCM prescriptions in remote antiquity.

scientific communication and education↗

bioRxiv2021

Kindlin-2 preserves integrity of the articular cartilage to protect against osteoarthritis

Osteoarthritis (OA) is an aging-related degenerative joint disease, which has no cure partly due to limited understanding of its pathological mechanism(s). Here we report that the focal adhesion protein Kindlin-2, but not Kindlin-1 or -3, is highly expressed in articular chondrocytes of the hyaline cartilage, which is dramatically decreased in the degenerated articular cartilage of aged mice and patients with OA. Inducible deletion of Kindlin-2 in chondrocytes at adult stage leads to spontaneous OA and much severe OA lesions in the mice receiving the surgery of destabilization of the medial meniscus. Mechanistically, Kindlin-2 deficiency promotes mitochondrial oxidative stress and activates Stat3 in articular chondrocytes, leading to Runx2-mediated chondrocyte hypertrophic differentiation and catabolism. In vivo, systemic pharmacological blockade of Stat3 activation or genetic ablation of Stat3 in chondrocytes reverses aberrant accumulation of Runx2 and ECM-degrading enzymes and limits OA deteriorations caused by Kindlin-2 deficiency. Furthermore, genetic inactivation of Runx2 in chondrocytes reverses structural changes and OA lesions caused by Kindlin-2 deletion without down-regulating p-Stat3 in articular chondrocytes. Of translational significance, intraarticular injection of Kindlin-2-expressing adeno-associated virus decelerates progression of aging- and instability-induced knee joint OA in mice. Collectively, we identify a novel pathway comprising of Kindlin-2, Stat3 and Runx2 in articular chondrocytes responsible for maintaining integrity of the articular cartilage and define a potential therapeutic target for OA.

pathology↗

bioRxiv2021

E3 ubiquitin ligase SYVN1 is a key positive regulator for GSDMD-mediated pyroptosis

Gasdermin D (GSDMD) participates in activation of inflammasomes and pyroptosis. Meanwhile, ubiquitination strictly regulates inflammatory responses. However, how ubiquitination regulates Gasdermin D activity is not well understood. In this study, we show that pyroptosis triggered by Gasdermin D is regulated through ubiquitination. Specifically, SYVN1, an E3 ubiquitin ligase of gasdermin D, promotes GSDMD-mediated pyroptosis. SYVN1 deficiency inhibits pyroptosis and subsequent LDH release and PI uptake. SYVN1 directly interacts with GSDMD, and mediates K27-linked polyubiquitination of GSDMD on K203 and K204 residues, promoting GSDMD-induced pyroptotic cell death. Thus, our findings revealed the essential role of SYVN1 in GSDMD-mediated pyroptosis. Overall, GSDMD ubiquitination is a potential therapeutic module for inflammatory diseases.

immunology↗