Biology subjects

Yu, X.

Publications and source records attributed to Yu, X..

At least 325 records · Page 18Linked to original sources

bioRxiv2022

Conserved allosteric inhibition mechanism in SLC1 transporters

Excitatory Amino Acid Transporter 1 (EAAT1) is a plasma-membrane glutamate transporter belonging to the SLC1 family of solute carriers. It plays a key role in neurotransmitter transport and contributes to the regulation of the extracellular glutamate concentration in the mammalian brain. The structure of EAAT1 was determined using cryo-EM, in complex with UCPH-101, a highly potent and non-competitive inhibitor of EAAT1. Alanine Serine Cysteine Transporter 2 (ASCT2) is a neutral amino acid transporter, which regulates pools of amino acids such as glutamine, serine and alanine between intracellular and extracellular compartments in a Na+ dependent manner. ASCT2 also belongs to the SLC1 family and shares 58% sequence similarity with EAAT1. However, allosteric modulation of ASCT2 via non-competitive inhibitors is unknown. Here we explore the UCPH-101 inhibitory mechanisms of EAAT1 and ASCT2 by using rapid kinetic experiments. Our results show that UCPH-101 slows substrate translocation rather than substrate or Na+ binding, confirming a non-competitive inhibitory mechanism, but only partially inhibits wild-type ASCT2 with relatively low affinity. Guided by computational modeling using ligand docking and molecular dynamics (MD) simulations, we selected two residues involved in UCPH-101/EAAT1 interaction, which were mutated in ASCT2 (F136Y, I237M, F136Y/I237M) in the corresponding positions. We show that in the F136Y/I237M double mutant transporter, 100% of the inhibitory effect of UCPH-101 on anion current could be restored, and the apparent affinity was increased (Ki = 9.3 M), much closer to the EAAT1 value of 0.6 M. Finally, we identify a novel non-competitive ASCT2 inhibitor, identified through virtual screening and experimental testing against the allosteric site, further supporting its localization. Together, these data indicate that the mechanism of allosteric modulation is conserved between EAAT1 and ASCT2. Due to the difference in binding site residues between ASCT2 and EAAT1, these results raise the possibility that more potent, and potentially selective inhibitors can be designed that target the ASCT2 allosteric binding site.

biophysics↗

bioRxiv2022

Microbiota-stimulated Interleukin-22 regulates brain neurons and protects against stress-induced anxiety

Psychological stress and its sequelae are a major public health problem. While the immune system has been implicated in the development of stress-related disorders, how the immune signals modulate neural responses to stress is poorly understood. Contrary to our expectations, we found that the immune cytokine Interleukin (IL)-22 is the key mediator of an immune-to-brain pathway that diminishes, rather than amplifies, stress-induced anxiety. We showed that stress induced TH17 differentiation and IL-22 production in the intestine following barrier dysfunction and microbiota stimulation. IL-22 then directly signaled to septal neurons in the brain to mitigate anxiety-like behavior. Accordingly, mice treated with exogenous IL-22 showed resilience to chronic stress-induced anxiety disorders. Our study thus reveals a previously-unappreciated immune-to-brain axis that defends against psychological stress, suggesting a potential intervention strategy for stress-related mental diseases.

immunology↗

bioRxiv2022

Structures of human Malic Enzyme 3

Malic enzymes (ME1, ME2, and ME3) are involved in cellular energy regulation, redox homeostasis, and biosynthetic processes, through the production of pyruvate and reducing agent NAD(P)H. Recent studies have implicated the third and least well-characterized isoform, mitochondrial NADP+-dependent malic enzyme 3 (ME3), as a therapeutic target for pancreatic cancers. Here, we utilized an integrated structure approach to capture the structures of ME3 in various ligand binding states. ME3 exists as a stable tetramer and its dynamic Domain C is critical for activity. Catalytic assay results reveal that ME3 is a non-allosteric enzyme and does not require modulators for activity while structural analysis suggests that the inner stability of ME3 domain A relative to ME2 disables allostery in ME3. With structural information available for all three malic enzymes, the foundation has been laid to understand the structural and biochemical differences of these enzymes and could aid in the development of specific malic enzyme small molecule drugs.

molecular biology↗

bioRxiv2022

A cryptic transactivation domain of EZH2 binds AR and AR's splice variant promoting oncogene activation and tumorous transformation

Enhancer of Zeste Homolog 2 (EZH2) and androgen receptor (AR) are crucial chromatin regulators involved in the development and/or progression of prostate tumor, including advanced castration-resistant prostate cancer (CRPC). To sustain prostate tumorigenicity, EZH2 establishes noncanonical biochemical interaction with AR for mediating oncogene activation, in addition to its canonical role as a transcriptional repressor and enzymatic subunit of Polycomb Repressive Complex 2 (PRC2). However, the molecular basis underlying non-canonical activities of EZH2 in prostate cancer remains elusive and therapeutic strategies for targeting EZH2:AR-mediated oncogene activation activities are also lacking. Here, we report that a cryptic transactivation domain of EZH2 (EZH2TAD) binds both AR and AR spliced variant 7 (AR-V7, an AR variant enriched in CRPC), mediating assembly and/or recruitment of transactivation-related machineries at genomic sites that lack PRC2 binding. Such noncanonical targets of EZH2:AR/AR-V7:(co)activators are enriched for the clinically-relevant oncogenes. We also show that EZH2TAD is required for the chromatin recruitment of EZH2, for EZH2-mediated oncogene activation, and for CRPC growth in vitro and in vivo. To completely block EZH2s multifaceted oncogenic activities in prostate cancer, we employed MS177, a recently developed proteolysis targeting chimera (PROTAC) of EZH2. Strikingly, MS177 achieved on-target depletion of both EZH2s canonical (EZH2:PRC2) and noncanonical (EZH2TAD:AR/AR-V7:coactivators) complexes in prostate tumor, eliciting much more potent antitumor effects than the catalytic inhibitors of EZH2. Overall, this study reports previously unappreciated requirements of EZH2TAD for mediating EZH2s noncanonical (co)activator recruitment and gene-activation functions in prostate tumor and suggests EZH2-targeting PROTACs as potentially attractive therapeutics for the treatment of aggressive prostate tumors that rely on the circuits wired by EZH2 and AR.

cancer biology↗

bioRxiv2022

Apicosome: newly identified cell-type-specific organelle in mouse cochlear and vestibular hair cells

Cochlear and vestibular hair cells in the inner ear are highly specialized sensory receptors for sound waves and acceleration of body movements; these cells can perform their specialized functions because of their distinctive morphology and some unique organelles that they harbor. Here, we report a serendipitous identification in the mouse of a hair-cell-specific organelle, which we name "apicosome." The apicosome was recognized by anti-FLRT1 antibodies but contains no FLRT1, and the organelle presents several distinctive characteristics: (1) the apicosome typically appears as a single entity ([~]500 nm in diameter), but occasionally as two entities, in hair cells; (2) it first appears in the subapical region at the neural side at embryonic day (E) 17-18 in cochlear hair cells, subsequently descends to the perinuclear region during the first postnatal week, and completely disappears around postnatal day (P) 10; (3) in vestibular hair cells, it can be detected in the subapical region of neonatal (P3) cells and persists in adult hair cells although it becomes smaller and more distant from the subapical region; (4) the timing of apicosome translocation and disappearance during development is correlated in kinocilium maintenance; (5) the organelle is potentially associated with microtubules; and (6) the appearance of the apicosome is irregular in supernumerary hair cells and this is likely linked to anomalous lateral inhibition. Thus, our study identifies a previously undescribed organelle in sensory hair cells and lays the foundation for further characterization of this specialized structure potentially linked to hair-cell development and morphogenesis.

neuroscience↗

bioRxiv2022

A maximum-type microbial differential abundance test with application to high-dimensional microbiome data analyses

AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSBackgroundC_ST_ABSHigh-throughput metagenomic sequencing technologies have shown prominent advantages over traditional pathogen detection methods, bringing great potential in clinical pathogen diagnosis and treatment of infection diseases. Yet, how to accurately detect the difference of microbiome profiles between treatment or disease conditions remains computationally challenging. ResultsIn this study, we propose a novel test for identifying the difference between two high-dimensional microbiome abundance data matrices based on the centred log-ratio transformation of the microbiome compositions. The test p-value can be calculated directly with a closed-form solution from the derived asymptotic null distribution. We also investigate the asymptotic statistical power against sparse alternatives which are typically encountered in microbiome studies. The proposed Maximum-type test is Equal-Covariance-Assumption-Free (MECAF), making it widely applicable to studies that compare microbiome compositions between conditions. Our simulation studies demonstrated that the proposed MECAF test achieves desirable power than competing methods while having the type I error rate well controlled under various scenarios. The usefulness of the proposed test is further illustrated with two real microbiome data analyses. The source code of the proposed method is freely available at https://github.com/JiyuanHu. ConclusionsMECAF is a flexible differential abundance test and achieves statistical efficiency in analyzing high-throughput microbiome data. The proposed new method will allow us to efficiently discover shifts of microbiome abundances between disease and treatment conditions, broadening our understanding of the disease and ultimately improving clinical diagnosis and treatment.

bioinformatics↗

bioRxiv2022

Structural basis of interdomain communication in PPARγ

The nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR{gamma}) regulates transcription via two activation function (AF) regulatory domains: a ligand-dependent AF-2 coregulator interaction surface within the C-terminal ligand-binding domain (LBD), and an N-terminal disordered AF-1 domain (NTD or A/B region) that functions through poorly understood structural mechanisms. Here, we show the PPAR{gamma} AF-1 contains an evolutionary conserved Trp-Pro motif that undergoes cis/trans isomerization, populating two long-lived conformations that participate in intradomain AF-1 and interdomain interactions including two surfaces in the C-terminal LBD ({beta}-sheet and the AF-2 surface), which are predicted in AlphaFold 3 models but not AlphaFold 2. NMR and chemical crosslinking mass spectrometry show that interdomain interactions occur for soluble isolated AF-1 and LBD proteins, as well as in full-length PPAR{gamma} in a phase separated state. Mutation of the region containing the Trp-Pro motif, which abrogates cis/trans isomerization of this region, impacts LBD interaction and reduces basal PPAR{gamma}-mediated transcription and agonist-dependent activation of PPAR{gamma}. Our findings provide structural insight into published in vitro and cellular studies that reported interdomain functional communication between the PPAR{gamma} AF-1 and LBD suggesting some of these effects may be mediated via AF-1/LBD interactions.

biochemistry↗

bioRxiv2022

CTPC, a combined transcriptome dataset of prostate cancer cell lines

Cell lines are the most used model system in cancer research. The transcriptomic data of established prostate cancer (PCa) cell lines help researchers to explore the differential gene expression across the different PCa cell lines and develop hypothesis. Through large scale datamining, we established a curated Combined Transcriptome dataset of PCa Cell lines (CTPC) which contains the transcriptomic data of 1840 samples of seven commonly used PCa cell lines including LNCaP, C4-2, VCaP, 22Rv1, PC3, DU145, and NCI-H660. The CTPC dataset provides an opportunity for researchers to not only compare gene expression across different PCa cell lines but also retrieve the experiment information and associate the differential gene expression with meta data such as gene manipulation and drug treatment information. Additionally, based on the CTPC dataset, we built a platform for users to visualize the data (https://pcatools.shinyapps.io/CTPC_V2/). It is our hope that the combined CTPC dataset and the user-friendly platform are of great service to the PCa research community.

cancer biology↗

bioRxiv2022

POT-3 preferentially binds the terminal DNA-repeat on the telomeric G-overhang

Eukaryotic chromosomes typically end in 3 telomeric overhangs. The safeguarding of telomeric single-stranded DNA overhangs is carried out by factors related to the Protection of Telomeres 1 (POT1) protein in humans. Of the three POT1-like proteins in C. elegans, POT-3 was the only member thought to not play a role at telomeres. Here, we provide evidence that POT-3 is a bona fide telomere-binding protein. Using a new loss-of-function mutant, we show that the absence of POT-3 causes telomere lengthening and increased levels of telomeric C-circles. We find that POT-3 directly binds the telomeric G-strand in vitro and map its minimal DNA binding site to the six-nucleotide motif, GCTTAG. We further show that the closely related POT-2 protein binds the same motif, but that POT-3 shows higher sequence selectivity. Crucially, in contrast to POT-2, POT-3 prefers binding sites immediately adjacent to the 3 end of DNA. These differences are significant as genetic analyses reveal that pot-2 and pot-3 do not function redundantly with each other in vivo. Our work highlights the rapid evolution and specialisation of telomere binding proteins and places POT-3 in a unique position to influence activities that control telomere length.

molecular biology↗

bioRxiv2022

Structures of perforin-2 in solution and on a membrane reveal mechanisms for pore formation

Perforin-2 (PFN2, MPEG1) is a key pore-forming protein in mammalian innate immunity restricting intracellular bacteria proliferation. It forms a membrane-bound pre-pore complex that converts to a pore-forming structure upon acidification; but its mechanism of conformational transition has been debated. Here we used cryo-electron microscopy, tomography and subtomogram averaging to determine structures of PFN2 in pre-pore and pore conformations in isolation and bound to liposomes. In isolation and upon acidification, the pre-assembled complete pre-pore rings convert to pores in both flat ring and twisted conformations. The twisted pore structure suggests an intermediate or alternative state to the flat conformation, and a capacity to distort the underlying membrane during membrane insertion. On membranes, in situ assembled PFN2 pre-pores display various degrees of completeness; whereas PFN2 pores are mainly incomplete arc structures that follow the same subunit packing arrangements as found in isolation. Both assemblies on membranes use their P2 {beta}-hairpin for binding to the lipid membrane surface. These structural snapshots in different states reveal a molecular mechanism for PFN2 pre-pore to pore transition on a targeted membrane.

biophysics↗

bioRxiv2022

Anaerobic degradation of acid red 73 by obligately aerobic Aspergillus tabacinus LZ-M though a self-redox mechanism

Fungi are potential biological resources for refractory organics degradation, but their anaerobic degradation of azo dyes are rarely reported. In this study, a fungus Aspergillus tabacinus LZ-M was isolated grown aerobically and degraded acid red 73 (AR73) with a decolorization rate of 90.28% in 5 days at 400 mg/L of concentration anaerobically. Metabolic pathway showed that AR73 was reduced into 2-hydroxynaphthalene and aniline then mineralized into CO2. The anaerobic self-redox process revealed electrons generated in carbon oxidation and transferred to -C-N= and -N=N, resulting in complete mineralization of AR73 in strain LZ-M. Data of transcriptome analysis showed that the benzene compounds produced from AR73 by declorizing reductase entered the catechol pathway and glycolysis process to mineralize. Enzymes involved in aromatics degradation, glycolysis processes, cytochrome C and quinone oxidoreductases were up-regulate, but the key reductase responsible to cleave AR73 to phenylhydrazine was not found. A novel enzyme Ord95 containing a glutamate S-transferase domain was identified in the unknown genes as a reductase which cleaving -C-N= in AR73 using NADH as electron donor, and three arginines key active sites. These observations reveal a new degradation mechanism of AR73 in strain LZ-M which would be potential candidate for treatment of azo dyes wastewater. Graphical abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

microbiology↗

bioRxiv2022

Eudicot primary cell wall glucomannan is related in synthesis, structure and function to xyloglucan

The functional differences between plant cell wall hemicelluloses such as glucomannan, xylan and xyloglucan (XyG) remain unclear. These polysaccharides influence assembly and properties of the wall, perhaps by interacting with cellulose to affect the deposition and bundling of the fibrils. As the most abundant hemicellulose, XyG is considered important in eudicot primary cell walls (PCWs), but plants devoid of XyG show relatively mild phenotypes. We report here that a patterned {beta}-galactoglucomannan ({beta}-GGM) is widespread in PCW of eudicots and shows remarkable similarities to XyG. The sugar linkages forming the backbone and side chains of {beta}-GGM are analogous to those that make up XyG, and moreover, these linkages are formed by glycosyltransferases from the same CAZy families. Solid-state NMR indicated that {beta}-GGM shows low mobility in the cell wall, consistent with interaction with cellulose. Although Arabidopsis {beta}-GGM synthesis mutants show no obvious growth defects, genetic crosses between {beta}-GGM and XyG mutants produce exacerbated phenotypes compared to XyG mutants. These findings demonstrate a related role of these two similar but distinct classes of hemicelluloses in PCWs. This work will provide new avenues to study the roles of both {beta}-GGM and XyG in PCWs. One sentence summaryPatterned {beta}-GGM resembles xyloglucan in structure, biosynthesis and function.

plant biology↗

bioRxiv2022

Suppression of tumor/host intrinsic CMTM6 drives anti-tumor cytotoxicity in a PD-L1 independent manner

CKLF-like MARVEL transmembrane domain-containing 6 (CMTM6) has been identified as a regulator of membranal programmed death ligand 1 (PD-L1) stability and a factor associated with malignancy progression, but the effects and mechanisms of CMTM6 on tumor growth, as well as its potential for therapy, are still largely unknown. Here, we show that tumor CMTM6 increased with progression in both clinical patients and mice. Ablation of CMTM6 resulted in significant retardation of human and murine tumor growth dependent on T-lymphocyte immunity. Tumor CMTM6 suppression broke resistance to immune checkpoint inhibitors and remodeled the tumor immune microenvironment, as specific antitumor cytotoxicity was enhanced and contributed primarily to tumor inhibition. Further, without the PD-1/PD-L1 axis, CMTM6 suppression still significantly dampened tumor growth dependent on cytotoxic cells. Notably, we identified that CMTM6 was widely expressed on immune cells. T-cell CMTM6 increased with sustained immune activation and intratumoral immune exhaustion and affected the T-cell-intrinsic PD-L1 levels. Host CMTM6 knockout significantly restrained tumor growth dependent on CD8+ T-cells, and similarly, not entirely dependent on PD-L1. Thus, we developed and evaluated the antitumor efficacy of CMTM6-targeting adeno-associated virus (AAV), which effectively mobilized antitumor immunity and could be combined with various antitumor drugs. Our findings reveal that both tumor and host CMTM6 are deeply involved in tumor immunity with or without the PD-1/PD-L1 axis and that gene therapy targeting CMTM6 is a promising strategy for cancer immunotherapy. One Sentence SummaryEven in the absence of the PD-1/PD-L1 axis, tumor or host CMTM6 deficiency can mediate cytotoxicity-dependent anti-tumor immune responses, allowing CMTM6 to be a novel target for scAAV-mediated oncoimmunology gene therapy and combination treatment.

immunology↗

bioRxiv2022

Lola-I is a developmentally regulated promoter pioneer factor

While enhancers are often regulated at the level of accessibility by pioneer factors, promoters tend to be constitutively accessible and poised for activation by paused Pol II -- thus are often not considered as sites of developmental regulation. Here we show that the accessibility of promoters and the acquisition of paused Pol II can be subject to developmental regulation by pioneer factors. We show that Lola-I, a Drosophila zinc finger transcription factor, is ubiquitously expressed at the end of embryogenesis and causes its target promoters to become accessible and acquire paused Pol II throughout the embryo. This promoter transition is required but not sufficient for tissue-specific target gene expression. Lola-I mediates this function by binding to the edges of the promoter nucleosomes, which leads to their depletion, similar to the action of pioneer factors at enhancers. These results uncover a level of regulation for promoters that is normally found at enhancers, providing further evidence that promoters and enhancers display unexpectedly similar characteristics.

genomics↗

bioRxiv2022

Rare Monoclonal Antibody Discovery Based on Indirect Competitive Screening of Single Hapten-specific Rabbit Antibody Secreting Cell

Rare antibody that is able to tolerate physio-chemical factors is preferred and highly demanded in diagnosis and therapy. Rabbit monoclonal antibodies (RmAbs) are distinguished owing to their high affinity and stability. However, the efficiency and availability of traditional methods for RmAb discovery are limited, especially for small molecules. Here, we present an indirect competitive screening method in nanowells, named CSMN, for single rabbit antibody secreting cells (ASCs) selection with 20.6 h and proposed an efficient platform for RmAb production against small molecule with 5.8 days for the first time. Chloramphenicol (CAP) as an antibacterial agent has the great threats for public health. We applied the CSMN to select CAP-specific ASCs and produced one high affinity RmAb, surprisingly showing extremely halophilic properties with an IC50 of 0.08 ng mL-1 in saturated salt solution which has as yet not been shown by other antibodies. Molecular dynamic simulation showed that the negatively charged surface improved the stability of the RmAb structure with additional disulfide bonds compared with mouse antibody. Moreover, the reduced solvent accessible surface area of the binding pocket increased the interactions of RmAb with CAP in a saturated salt solution. Furthermore, the RmAb was used to develop an immunoassay for the detection of CAP in real biological samples with simple pretreatment, shorter assay time, and higher sensitivity. The results demonstrated that the practical and efficient CSMN is suitable for rare RmAb discovery against small molecules.

biochemistry↗

bioRxiv2022

Identification of two bZIP transcription factors that regulate development of pavement and trichome cells in Arabidopsis thaliana by single-cell RNA-sequencing

Epidermal cells are the main avenue for signal and material exchange between plants and the environment. Leaf epidermal cells primarily include pavement cells (PCs), guard cells, and trichomes cells (TCs), which differentiate from protodermal cells or meristemoids. The development and distribution of different epidermal cells are tightly regulated by a complex transcriptional regulatory network mediated by phytohormones, including jasmonic acid (JA), and transcription factors. Understanding how the fate of leaf epidermal cells is determined, however, is still largely unknown due to the diversity of cell types and the complexity of its regulation. Here, we characterized the transcriptional profiles of epidermal cells in 3-day-old true leaves of Arabidopsis thaliana using single-cell RNA-sequencing. We identified two genes encoding BASIC LEUCINE-ZIPPER (bZIP) transcription factors, namely the bZIP25 and bZIP53, which are highly expressed in PCs and early-stage meristemoid cells. Densities of PCs and TCs were found to increase and decrease, respectively, in bzip25 and bzip53 mutants, compared with wild-type plants. This trend was more pronounced in the presence of JA, suggesting that these transcription factors regulate the development of TCs and PCs in response to JA. IN A NUTSHELLO_ST_ABSBackgroundC_ST_ABSLeaf epidermal cells, comprised of trichome cells (TCs), guard cells (GCs), and pavement cells (PCs), are responsible for exchanging materials and information between plants and the surrounding aerial environment. Many genes have been identified in Arabidopsis thaliana and confirmed to be involved in the initiation and differentiation of TCs and PCs. The fate determination of TCs and PCs is tightly regulated by positive and negative regulators at the cellular level. The precise underlying molecular mechanisms responsible for the fate determination of TCs and PCs, however, are still unclear at this time. QuestionWhat are the transcriptomic profiles of different leaf epidermal cell types? Can we dissect the genes that are specifically expressed in certain epidermal cell types? What kinds of transcription factors are involved in regulating the fate determination of TCs and PCs? FindingsWe performed single cell RNA-seq to investigate the transcriptomic profiles of different leaf epidermal cell types and identified differentially expressed genes in each cell type. We found that genes that are involved in jasmonic acid signaling are highly expressed in early-stage meristemoid (EM) cells which can act as the precursor of PCs and perhaps of TCs. To investigate the regulatory mechanisms underlying EM development, we identified the transcription factors (TFs) in EM cells and found that two bZIP TF genes, bZIP25 and bZIP53, are highly expressed in EMs. Further analyses of these two genes using both loss-of-function and gain-of-function approaches indicated that bZIP25 and bZIP53 are functionally involved in promoting trichome formation but inhibit pavement cell development in response to jasmonic acid. Next stepsBesides of bZIP25 and bZIP53, we also identified other key genes, for example FES1B, in leaf epidermal cells. Our next step will be to explore the regulation of other key genes involved in the fate determination of different cell types in leaf epidermis.

plant biology↗

bioRxiv2022

Convergence of immune escape strategies highlights plasticity of SARS-CoV-2 spike

The SARS-CoV-2 spike protein is the target of neutralizing antibodies and the immunogen used in all currently approved vaccines. The global spread of the virus has resulted in emergence of lineages which are of concern for the effectiveness of immunotherapies and vaccines based on the early Wuhan isolate. Here we describe two SARS-CoV-2 isolates with large deletions in the N-terminal domain (NTD) of the spike. Cryo-EM structural analysis showed that the deletions result in complete reshaping of the antigenic surface of the NTD supersite. The remodeling of the NTD affects binding of all tested NTD-specific antibodies in and outside of the NTD supersite for both spike variants. A unique escape mechanism with high antigenic impact observed in the {Delta}N135 variant was based on the loss of the Cys15-Cys136 disulfide due to the P9L-mediated shift of the signal peptide cleavage site and deletion of residues 136-144. Although the observed large loop and disulfide deletions are rare, similar modifications became independently established in several other lineages, highlighting the possibility of a general escape mechanism via the NTD supersite. The observed plasticity of the NTD foreshadows its broad potential for immune escape with the continued spread of SARS-CoV-2.

molecular biology↗

bioRxiv2022

WDR5 promotes breast cancer growth and metastasis via KMT2-independent translation regulation

Metastatic breast cancer remains a major cause of cancer related deaths in women and there are few effective therapies against this advanced disease. Emerging evidence suggests that key steps of tumor progression and metastasis are controlled by reversible epigenetic mechanisms. Using an in vivo genetic screen, we identified WDR5 as an actionable epigenetic regulator that is required for metastatic progression in models of triple-negative breast cancer. We found that knockdown of WDR5 in breast cancer cells independently impaired their tumorigenic as well as metastatic capabilities. Mechanistically, WDR5 promotes cell growth by increasing ribosomal gene expression and translation efficiency in a KMT2-independent manner. Consistently, pharmacological inhibition or degradation of WDR5 impedes cellular translation rate and the clonogenic ability of breast cancer cells. Furthermore, combination of WDR5-targeting with mTOR inhibitors leads to potent suppression of translation and proliferation of breast cancer cells. These results reveal novel therapeutic strategies to treat metastatic breast cancer.

cancer biology↗