Biology subjects

Meng, Z.

Publications and source records attributed to Meng, Z..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

Towards a species search engine: KISSE offers a rigorous statistical framework for bone collagen tandem mass spectrometry data

DNA and bone collagen are two key sources of resilient molecular markers used to identify species from their remains. Collagen is more stable than DNA, and thus it is preferred for ancient and degraded samples. Current mass spectrometry-based collagen sequencing approaches are empirical and lack a rigorous statistical framework. Based on the well-developed approaches to protein identification in shotgun proteomics, we introduce a first approximation of the species search engine (SSE). Our SSE named KISSE is based on a species-specific library of collagenous peptides that uses both peptide sequences and their relative abundances. The developed statistical model can identify the species and the probability of correct identification, as well as determine the likelihood of the analyzed species not being in the library. We discuss the advantages and limitations of the proposed approach and the possibility of extending it to other tissues.

zoology↗

bioRxiv2025

Meiotic cohesion requires Sirt1 and preserving its activity in aging oocytes reduces missegregation

Chromosome segregation errors in human oocytes increase dramatically as women age and premature loss of meiotic cohesion is one factor that contributes to a higher incidence of segregation errors in older oocytes. Here we show that cohesion maintenance during meiotic prophase in Drosophila oocytes requires the NAD+-dependent deacetylase, Sirt1. Knockdown of Sirt1 during meiotic prophase causes premature loss of arm cohesion and chromosome segregation errors. We have previously demonstrated that when Drosophila oocytes arrest and age in diplotene, segregation errors increase significantly. By quantifying acetylation of the Sirt1 substrate H4K16 on oocytes chromosomes, we find that Sirt1 deacetylase activity declines markedly during aging. However, if females are fed the Sirt1 activator SRT1720 as their oocytes age, the H4K16ac signal on oocyte DNA remains low in aged oocytes, consistent with preservation of Sirt1 activity during aging. Strikingly, age-dependent segregation errors are significantly reduced if mothers are fed SRT1720 while their oocytes age. Our data suggest that maintaining Sirt1 activity in aging oocytes may provide a viable therapeutic strategy to decrease age-dependent segregation errors.

cell biology↗

bioRxiv2024

A Label-free Nanowell-based Impedance Sensor for Ten-minute SARS-CoV-2 Detection

This work explores label-free biosensing as an effective method for biomolecular analysis, ensuring the preservation of native conformation and biological activity. The focus is on a novel electronic biosensing platform utilizing micro-fabricated nanowell-based impedance sensors, offering rapid, point-of-care diagnosis for SARS-CoV-2 (COVID-19) detection. The nanowell sensor, constructed on a silica substrate through a series of microfabrication processes including deposition, patterning, and etching, features a 5x5 well array functionalized with antibodies. Real-time impedance changes within the nanowell array enable diagnostic results within ten minutes using small sample volumes (<5 {micro}L). The research includes assays for SARS-CoV-2 spike proteins in Phosphate-buffered saline (PBS) and artificial saliva buffers to mimic real human SARS-CoV-2 samples, covering a wide range of concentrations. The sensor exhibits a detection limit of 0.2 ng/mL (1.5 pM) for spike proteins. Middle East Respiratory Syndrome (MERS-CoV) spike proteins are differentiated from SARS-CoV-2 spike proteins, demonstrating specificity. TOC Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/627986v1_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@1a9f2a7org.highwire.dtl.DTLVardef@79d5acorg.highwire.dtl.DTLVardef@bb1bc1org.highwire.dtl.DTLVardef@1b5098_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2024

scCompass: An integrated cross-species scRNA-seq database for AI-ready

Emerging single-cell sequencing technology has generated large amounts of data, allowing analysis of cellular dynamics and gene regulation at the single-cell resolution. Advances in artificial intelligence enhance life sciences research by delivering critical insights and optimizing data analysis processes. However, inconsistent data processing quality and standards remain to be a major challenge. Here we propose scCompass, which provides a data quality solution to build a large-scale, cross-species and model-friendly single-cell data collection. By applying standardized data pre-processing, scCompass integrates and curates transcriptomic data from 13 species and nearly 105 million single cells. Using this extensive dataset, we are able to archieve stable expression genes (SEGs) and organ-specific expression genes (OSGs) in human and mouse. We provide different scalable datasets that can be easily adapted for AI model training and the pretrained checkpoints with state-of-the-art (SOTA) single-cell foundataion models. In summary, the AI-readiness of scCompass, which combined with user-friendly data sharing, visualization and online analysis, greatly simplifies data access and exploitation for researchers in single cell biology(http://www.bdbe.cn/kun).

bioinformatics↗

bioRxiv2024

One-Pot Time-Induced Proteome Integral Solubility Alteration (OPTI-PISA) assay for automated and sensitive drug target identification

Proteome Integral Solubility Alteration (PISA) assay is widely used for identifying drug targets, but it is labour-intensive and time-consuming, and requires a substantial amount of biological sample. Aiming at enabling automation and greatly reducing the sample amount, we developed One-Pot Time-Induced (OPTI)-PISA. Here we demonstrate OPTI-PISA performance on identifying targets of multiple drugs in cell lysate and scaling down the sample amount to sub-microgram levels, making PISA method suitable for NanoProteomics.

biochemistry↗

bioRxiv2024

ThermoTargetMiner as a proteome integral solubility alteration target database for prospective drugs against lung cancer

Knowledge of the targets of therapeutic compounds is vital for understanding their action mechanisms and side effects, but such valuable data is seldom available. The multiple complementary techniques needed for comprehensive target characterization must combine data reliability with sufficient analysis throughput. Here, we leveraged the Proteome Integral Solubility Alteration (PISA) assay to characterize the targets of 67 approved and experimental compounds against two main lung cancer subtypes, which is now provided through the website https://thermotargetminer.serve.scilifelab.se/app/thermotargetminer. Novel target candidates (pro-targets) were found for 77% of the tested molecules. Comparison of the protein solubility shifts in lysate vs. living cells highlighted the targets directly interacting with the compounds. We verified that the drug PEITC exerts cytotoxicity through the inhibition of a pro-target PAFAH1B. As PISA is now joining the arsenal of fast and reliable target characterization techniques, the presented database, ThermoTargetMiner, will become a useful resource in lung cancer research.

biochemistry↗

bioRxiv2024

Climate adaptation in P. trichocarpa: key adaptive loci identified for stomata and leaf traits

Identifying the genetic basis of traits underlying climate adaptation remains a key goal for predicting species responses to climate change, enabling the elucidation of gene targets for future climate-resilient crops. Here, we measured 14 leaf and stomatal traits under control (well-watered) and drought conditions, subsampling a diversity collection of over 1,300 Populus trichocarpa genotypes, a potential biofuel feedstock crop. Stomatal traits were correlated with the climate of origin for genotypes, such that those originating from environments subject to water deficit tended to have smaller stomata, but with higher density. Stomatal traits were also correlated with leaf morphology, with larger leaves having larger stomata and lower stomatal density mirrored in correlations to climate of origin. The direction of plastic responses - reduced stomatal size under drought - mirrors the correlations seen among genotypes with respect to the aridity of environmental origin. Genome-Wide Association Studies (GWAS) identified loci underlying trait diversity, including candidates contributing to stomatal size. We used climate of origin to predict stomatal size in genotypes with unknown trait values and found that these predicted phenotypes confirmed empirically measured allele effects. Finally, we found evidence that future climates may select for alleles contributing to decreased stomatal size, with the strength of selection depending on the availability of moisture. These findings reveal adaptive variation in stomatal and physiological traits along with underlying genetic loci, with implications for future selection and breeding - providing insights into the responses to future climate change. HighlightResearch on Populus trichocarpa reveals adaptation of physiological and stomatal traits linked to drought tolerance, with genotypes from arid regions exhibiting smaller stomata, offering insights for climate change adaptation and sustainable biofuel production.

plant biology↗

bioRxiv2024

Cell-Graph Compass: Modeling Single Cells with Graph Structure Foundation Model

Inspired by the advancements in pre-trained Large Language Models, there has been a surge of studies in the Life Sciences focusing on constructing foundation models with large scale single-cell RNA-seq data. These studies typically involve pre-training a transformer model on large-scale single-cell sequencing data, followed by fine-tuning for a variety of downstream tasks, achieving notable performance. However, these models all share a common short-coming: to utilize the transformer architecture, originally designed for textual data, they artificially impose a sequential structure on genes within cells, simplifying the complex interactions between genes. Furthermore, they focus solely on transcriptomic data, neglecting other relevant biological information. To address these issues, here we introduce Cell-Graph Compass (CGC), the first foundational model that leverages graph structures to model single cells and describes cells from multiple perspectives, including transcriptional profiles, gene text summaries, transcription factor regulatory networks, gene co-expression patterns, and gene positional relationships. By incorporating self-attention mechanisms, we pretrained the model on 50 million human single-cell sequencing data, resulting in a robust digital representation of cells. Extensive downstream experiments demonstrate that our approach can capture meaningful biological knowledge and achieve superior results in various problem scenarios, achieving the state-of-the-art (SOTA).

bioinformatics↗

bioRxiv2024

Recognition of RNA secondary structures with a programmable peptide nucleic acid-based platform

RNA secondary structures comprise double-stranded (ds) and single-stranded (ss) regions. Antisense peptide nucleic acids (asPNAs) enable the targeting of ssRNAs and weakly formed dsRNAs. Nucleobase-modified dsRNA-binding PNAs (dbPNAs) allow for targeting of relatively stable dsRNAs. A programmable RNA structure-specific targeting strategy is needed for simultaneous recognition of dsRNAs and ssRNAs. Here, we report on combining dbPNAs and asPNAs (designated as daPNAs) for the targeting of dsRNA-ssRNA junctions. Our binding and modeling data suggest that combining traditional asPNA (with a 4-letter code: T, C, A, and G) and dbPNA (with a 4-letter code: T or s2U, L, Q, and E) scaffolds facilitates RNA structure-specific tight binding (nM to M) under physiologically-relevant conditions. We further applied our daPNAs in substrate specific inhibition of Dicer acting on pre-miR-198 in a cell-free assay and regulating ribosomal frameshifting induced by model hairpins in both cell-free and cell culture assays. daPNAs would be a useful platform for developing chemical probes and therapeutic ligands targeting RNA. HighlightO_LIWe demonstrated that sequence- and structure-specific targeting of RNA can be facilitated by nucleobase-modified dsRNA-binding PNAs (dbPNAs) platform in combination with antisense PNAs (asPNAs). We name the novel PNAs as daPNAs. C_LIO_LIdaPNAs can be used in a programmable way for targeting RNAs by formation of a short triplex next to a short duplex at a dsRNA-ssRNA junction. C_LIO_LIWe applied our daPNAs in substrate specific inhibition of Dicer acting on pre-miR-198 in a cell-free assay and regulating ribosomal frameshifting induced by model hairpins in both cell-free and cell culture assays. C_LIO_LIThe daPNAs platform would serve as useful junction-specific molecular glues for the targeting of many biologically important RNA structures in transcriptomes. C_LI

biochemistry↗

bioRxiv2024

Super Enhancer-driven LncRNA UNC5B-AS1 Inhibits Inflammatory Phenotypic Transition in Smooth Muscle Cells via Lactylation Modification

BackgroundThe phenotypic transition of pulmonary artery smooth muscle cells (PASMCs) is a central pathological alteration in pulmonary artery remodeling that contributes to pulmonary hypertension (PH). The specific role of long noncoding RNAs (lncRNAs), especially super enhancer (SE)-driven lncRNAs, in the phenotypic transformation of PASMCs induced by hypoxia remains unclear. The objective of this study is to determine the mechanistic role of the super enhancer-driven LncRNA UNC5B-AS1 in phenotypic transformation of PASMCs and hypoxia-induced vascular remodeling. MethodsThe lncRNA UNC5B-AS1 regulated by super-enhancers was identified in hypoxic human PASMCs through RNA sequencing and H3K27ac ChIP sequencing. Overexpression of lncRNA UNC5B-AS1 in human PASMCs was performed to elucidate its role in the pathogenesis of PH. A conserved functional fragment of lncRNA UNC5B-AS1 was used for the treatment of mouse PH. ResultsIn PASMCs, we have identified a SE-driven lncRNA called UNC5B-AS1 that regulates phenotype transition. It is transcriptionally activated by the transcription factor FOXP3. We demonstrate that UNC5B-AS1, as a molecular scaffold in mitochondria, stabilizes the interaction between LRPPRC, which is rich in leucine, and oxidative respiratory chain complex IV. This complex regulates the lactylation modification level of upstream promoter regions of inflammatory genes IL-1{beta}, IL-6, and TNF- by influencing the glycolytic pathway in PASMCs under hypoxic conditions, ultimately affecting the inflammatory phenotype transition of PASMCs. ConclusionsOur findings identify the SE-driven lncRNA UNC5B-AS1 as a novel regulatory factor in hypoxia-induced phenotypic switch of PASMCs, and suggest that overexpression of UNC5B-AS1 may represent a promising therapeutic strategy for PH. HighlightsThe long non-coding RNA UNC5B-AS1, regulated by super-enhancers (SE), is downregulated in hypoxic PASMCs, and regulates PASMC phenotype transition through glycolysis. The super-enhancer region of lncRNA UNC5B-AS1 recruits the transcription factor FOXP3 to its promoter region, forming a chromatin loop to regulate its expression. The lncRNA UNC5B-AS1 acts as a molecular scaffold stabilizing the interaction between LRPPRC and mitochondrial complex IV. The lactate generated by glycolysis activation induces lactylation modification of histones at the IL-1{beta}, IL-6, and TNF- promoters, leading to the inflammatory phenotype transition of PASMCs. Overexpression of lncRNA UNC5B-AS1 conserved fragment reversed SuHx-induced PH in mice. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=121 SRC="FIGDIR/small/593065v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@864576org.highwire.dtl.DTLVardef@13a5fe4org.highwire.dtl.DTLVardef@16d7884org.highwire.dtl.DTLVardef@35d50_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2024

Regulatory Functional Landscape of the HMX1 Gene for Normal Ear Development

Enhancers, through the combinatorial action of transcription factors (TFs), dictate both the spatial specificity and the levels of gene expression, and their aberrations can result in diseases. The association between HMX1 and its downstream enhancer with ear deformities has been previously documented. However, the pathogenic variations and molecular mechanisms underlying the bilateral constricted ear (BCE) malformations remain unclear. This study identifies a copy number variation (CNV) encompassing three enhancers that induces BCE. These enhancers, collectively termed the positional identity hierarchical enhancer cluster (PI-HEC), co-regulate spatiotemporal expression of the HMX1 gene in a coordinated and synergistic mode, each displaying unique activity-location-structure characteristics. A thorough exploration of this regulatory locus reveals that specific motif clusters within the PI-HEC variably modulate its activity and specificity, with the high mobility group (HMG) box combined with Coordinator and homeodomain (HD)-TFs notably influencing them respectively. Our findings based on various types of mouse models, reveal that both aberrant Hmx1 expression in the fibroblasts of the basal pinna, originating from neural crest cells, and ectopic expression in the distal pinna structures contribute to the abnormal development of the outer ear, including the cartilage, muscle, and epidermis tissues. This study deepens our understanding of mammalian ear morphogenesis and sheds light on the complexity of gene expression regulation by enhancers and specific sequence motifs.

developmental biology↗

bioRxiv2024

Gel-Assisted Proteome Position Integral Shift (GAPPIS) Assay Returns Molecular Weight to Shotgun Proteomics and Identifies Novel Caspase 3 Substrates

Here we present a high-throughput virtual top-down proteomics approach that restores the molecular weight (MW) information in shotgun proteomics, and demonstrate its utility in studying proteolytic events in programmed cell death. With Gel-Assisted Proteome Position Integral Shift (GAPPIS), we quantified over 7000 proteins in staurosporine-induced apoptotic HeLa cells and identified 84 proteins exhibiting in a statistically significant manner at least two of the following features: 1) a negative MW shift; 2) an elevated ratio in a pair of a semi-tryptic and tryptic peptide, 3) a negative shift in the standard deviation of MW estimated for different peptides, and 4) a negative shift in skewness of the same data. Of these proteins, 58 molecules were novel caspase 3 substrates. Further analysis identified the preferred cleavage sites consistent with the known caspase cleavages after the DXXD motif. As a powerful tool for high-throughput MW analysis simultaneously with the conventional expression analysis, GAPPIS assay can prove useful in studying a broad range of biological processes involving proteolytic events.

biochemistry↗

bioRxiv2024

Do light eaters live shorter lives? The case of ultralight Caenorhabditis elegans

The idea that ingesting heavy stable isotopes can increase longevity emerged shortly after the discovery of deuterium in the early 1930s and has been extensively tested since then on animals. Here we present the first experimental evidence for the opposite. Growing C. elegans on bacteria E. coli that are in turn fed on a diet depleted of heavy isotopes of C, H, N and O produced ultralight worms that grow and mature faster but have a shorter lifespan. Based on the differences in expression and solubility of proteins, we established an aging pseudo-time scale. Notably, the newly born ultralight worms appear to be significantly "younger" than their normal counterparts, while at day 10 they are significantly "older". Pathway analysis revealed involvement of mitochondria; analysis of reactive oxygen species (ROS) confirmed significant ROS overproduction in ultralight worms that increases further with age. These findings provide a new modality of affecting the lifespan in this important animal model of human diseases and aging.

biochemistry↗

bioRxiv2024

RNA Splicing Junction Landscape Reveals Abundant Tumor-Specific Transcripts in Human Cancer

RNA splicing is a critical process governing gene expression and transcriptomic diversity. Despite its importance, a detailed examination of transcript variation at the splicing junction level remains scarce. Here, we perform a thorough analysis of RNA splicing junctions in 34,775 samples across multiple sample types. We identified 29,051 tumor-specific transcripts (TSTs) in pan-cancer, with a majority of these TSTs being unannotated. Our findings show that TSTs are positively correlated with tumor stemness and linked to unfavorable outcomes in cancer patients. Additionally, TSTs display mutual exclusivity with somatic mutations and are overrepresented in transposable element-derived transcripts possessing oncogenic functions. Importantly, TSTs can generate neoepitopes that bind to MHC class I molecules for immunotherapy. Moreover, TSTs can be detected in blood extracellular vesicles from cancer patients. Our results shed light on the intricacies of RNA splicing and offer promising avenues for cancer diagnosis and therapy. In briefThis study thoroughly analyzed RNA splicing junctions in 34,775 samples and identified 29,051 tumor-specific transcripts (TSTs), which may serve as novel cancer driver genes, neoantigens, and circulating biomarkers. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=153 SRC="FIGDIR/small/579246v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@7e1db2org.highwire.dtl.DTLVardef@1cfbe81org.highwire.dtl.DTLVardef@1e427e1org.highwire.dtl.DTLVardef@1f655f5_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2023

Brief change in dopamine activity during consolidation impairs long-term memory via sleep disruption

Sleep disturbances are associated with poor long-term memory (LTM) formation, yet the underlying cell types and neural circuits involved have not been fully decoded. Dopamine neurons (DANs) are involved in memory processing at multiple stages. Here, using both male and female flies, Drosophila melanogaster, we show that, during the first few hours of memory consolidation, disruption of basal activity of a small subset of protocerebral anterior medial DANs (PAM-DANs), by either brief activation or inhibition of the two dorsal posterior medial (DPM) neurons, impairs 24 h LTM. Interestingly, these brief changes in activity using female flies result in sleep loss and fragmentation, especially at night. Importantly, pharmacological rescue of sleep after manipulation restores LTM. A specific subset of PAM-DANs (PAM-1) that synapse onto DPM neurons specify the microcircuit that links sleep and memory. MBON-1 also contributes to the integration of sleep and memory by acting as an additional parallel circuit. PAM-DANs, including PAM-1, form functional synapses onto DPM mainly via two dopamine receptor subtypes. Dop1R1 primarily mediates the link between sleep and memory. This PAM-1 to DPM microcircuit exhibits a synchronized, transient, post-training change in activity during the critical memory consolidation window, suggesting an effect of this microcircuit on maintaining the sleep necessary for LTM consolidation. Our results provide a new molecular and circuit basis for the complex relationship between sleep and memory.

neuroscience↗

bioRxiv2023

Interplay of RAP2 GTPase and the cytoskeleton in Hippo pathway regulation

The Hippo signaling is instrumental in regulating organ size, regeneration, and carcinogenesis. The cytoskeleton emerges as a primary Hippo signaling modulator. Its structural alterations in response to environmental and intrinsic stimuli control Hippo kinase cascade activity. However, the precise mechanisms underlying the cytoskeleton regulation of Hippo signaling are not fully understood. RAP2 GTPase is known to mediate the mechanoresponses of Hippo signaling via activating the core Hippo kinases LATS1/2 through MAP4Ks and MST1/2. Here we show the pivotal role of the reciprocal regulation between RAP2 GTPase and the cytoskeleton in Hippo signaling. RAP2 deletion undermines the responses of the Hippo pathway to external cues tied to RhoA GTPase inhibition and actin cytoskeleton remodeling, such as energy stress and serum deprivtion. Notably, RhoA inhibitors and actin disruptors fail to activate LATS1/2 effectively in RAP2-deficient cells. RNA sequencing highlighted differential regulation of both actin and microtubule networks by RAP2 gene deletion. Consistently, Taxol, a microtubule-stabilizing agent, was less effective in activating LATS1/2 and inhibiting cell growth in RAP2 and MAP4K4/6/7 knockout cells. In summary, our findings position RAP2 as a central integrator of cytoskeletal signals for Hippo signaling, which offers new avenues for understanding Hippo regulation and therapeutic interventions in Hippo-impaired cancers.

cell biology↗

bioRxiv2023

GeneCompass: Deciphering Universal Gene Regulatory Mechanisms with Knowledge-Informed Cross-Species Foundation Model

Deciphering the universal gene regulatory mechanisms in diverse organisms holds great potential to advance our knowledge of fundamental life process and facilitate research on clinical applications. However, the traditional research paradigm primarily focuses on individual model organisms, resulting in limited collection and integration of complex features on various cell types across species. Recent breakthroughs in single-cell sequencing and advancements in deep learning techniques present an unprecedented opportunity to tackle this challenge. In this study, we developed GeneCompass, the first knowledge-informed, cross-species foundation model pre-trained on an extensive dataset of over 120 million single-cell transcriptomes from human and mouse. During pre-training, GeneCompass effectively integrates four types of biological prior knowledge to enhance the understanding of gene regulatory mechanisms in a self-supervised manner. Fine-tuning towards multiple downstream tasks, GeneCompass outperforms competing state-of-the-art models in multiple tasks on single species and unlocks new realms of cross-species biological investigation. Overall, GeneCompass marks a milestone in advancing knowledge of universal gene regulatory mechanisms and accelerating the discovery of key cell fate regulators and candidate targets for drug development.

bioinformatics↗

bioRxiv2023

Hippo Signaling Modulates Mechano-inflammatory Responses of Chondrocytes

Knee osteoarthritis (KOA) is a degenerative disease resulting from mechanical overload, where direct physical impacts on chondrocytes play a crucial role in disease development by inducing inflammation and extracellular matrix degradation. However, the signaling cascades that sense these physical impacts and induce the pathogenic transcriptional programs of KOA remain to be defined, which hinders the identification of novel therapeutic approaches. Recent studies have implicated a crucial role of Hippo signaling in osteoarthritis. Since Hippo signaling senses mechanical cues, we aimed to determine its role in chondrocyte responses to mechanical overload. Here we show that mechanical loading induces the expression of inflammatory and matrix-degrading genes by activating the nuclear factor-kappaB (NF{kappa}B) pathway in a Hippo-dependent manner. Applying mechanical compressional force to 3-dimensional cultured chondrocytes activated NF{kappa}B and induced the expression of NF{kappa}B target genes for inflammation and matrix degradation (i.e., IL1{beta} and ADAMTS4). Interestingly, deleting the Hippo pathway effector YAP or activating YAP by deleting core Hippo kinases LATS1/2 blocked the NF{kappa}B pathway activation induced by mechanical loading. Consistently, treatment with a LATS1/2 kinase inhibitor abolished the upregulation of IL1{beta} and ADAMTS4 caused by mechanical loading. Mechanistically, mechanical loading activates Protein Kinase C (PKC), which activates NF{kappa}B p65 by phosphorylating its Serine 536. Furthermore, the mechano-activation of both PKC and NF{kappa}B p65 is blocked in LATS1/2 or YAP knockout cells, indicating that the Hippo pathway is required by this mechanoregulation. Additionally, the mechanical loading-induced phosphorylation of NF{kappa}B p65 at Ser536 is blocked by the LATS1/2 inhibitor Lats-In-1 or the PKC inhibitor AEB-071. Our study suggests that the interplay of the Hippo signaling and PKC controls NF{kappa}B-mediated inflammation and matrix degradation in response to mechanical loading. Chemical inhibitors targeting Hippo signaling or PKC can prevent the mechanoresponses of chondrocytes associated with inflammation and matrix degradation, providing a novel therapeutic strategy for KOA.

cell biology↗