Biology subjects

Yang, X.-L.

Publications and source records attributed to Yang, X.-L..

14 recordsLinked to original sources

bioRxiv2025

Human SerRS/SIRT2 complex structure reveals cross regulation between translation and NAD+ metabolism

Life at the cellular level depends on effective coordination between diverse processes. Here we uncover a novel cross-regulation between metabolism and translation through a 3.2 [A] cryo-EM structure of human cytosolic seryl-tRNA synthetase (SerRS) bound to sirtuin-2 (SIRT2), an NAD+-dependent deacetylase. This interaction, naturally triggered by the NAD+ metabolite ADP-ribose (ADPR), resembles substrate binding and block SIRT2s active site. Interestingly, SerRS acetylation is not required for this interaction. SIRT2 binding sterically and allosterically impedes tRNA binding to SerRS, lowering charged tRNASer level and protein synthesis activity. Key interaction residues in both proteins emerged simultaneously in vertebrates, suggesting co-evolution for cross-regulation. Given ADPRs accumulation under stress, the ADPR-induced SerRS/SIRT2 interaction likely serves as a cell-protective response.

molecular biology↗

bioRxiv2025

WHEP Domain of Glycyl-tRNA Synthetase Regulates Neuropilin 1 Binding and Vascular Permeability

AbstractAminoacyl-tRNA synthetases (aaRSs) charge tRNAs with their cognate amino acids, ensuring accurate translation of the genetic code from mRNA to protein. During eukaryotic evolution, aaRSs acquired additional domains with unclear functions, including the WHEP domain, a two-helix bundle found in several eukaryotic aaRSs such as glycyl-tRNA synthetase (GlyRS, encoded by GARS1). We generated Gars1{Delta}WHEP mutant mice lacking exon 2, which disrupts most of the WHEP domain. Homozygous Gars1{Delta}WHEP/{Delta}WHEP mice exhibited late embryonic or neonatal lethality, with delayed lung development, characterized by reduced airway dilation (inflatability), and increased vascular leakage. Disruption of the WHEP domain did not impair tRNA aminoacylation but inhibited the free release of GlyRS from cells. Instead, GlyRS{Delta}WHEP was found in the membrane fractions and showed a stronger interaction with the extracellular region of neuropilin 1 (Nrp1) receptor compared to full-length GlyRS. This aberrant interaction enhanced Nrp1s endocytic activity and significantly reduced the localization of the Nrp1 interactor VE-cadherin at the adherens junctions of endothelial cells. A heterozygous knockout of Nrp1 in the Gars1 {Delta}WHEP/{Delta}WHEP mice partially rescued body weight and vascular permeability defects. This study establishes a physiological role for the GlyRS WHEP domain in lung development and its regulation of GlyRS-Nrp1 interaction and vascular permeability.

molecular biology↗

bioRxiv2024

AARS Online: a collaborative database on the structure, function, and evolution of the aminoacyl-tRNA synthetases

The aminoacyl-tRNA synthetases (aaRS) are a large group of enzymes that implement the genetic code in all known biological systems. They attach amino acids to their cognate tRNAs, moonlight in various non-translational activities, and are linked to many genetic disorders. The aaRS have a subtle ontology characterized by structural and functional idiosyncrasies that vary from organism to organism, and protein to protein. Across the tree of life, the twenty-two coded amino acids are handled by sixteen evolutionary Families of Class I aaRS and twenty-one Families of Class II aaRS. We introduce AARS Online, an interactive Wikipedia-like tool curated by an international consortium of field experts. This platform systematizes existing knowledge about the aaRS by showcasing a taxonomically diverse selection of aaRS sequences and structures. Through its graphical user interface, AARS Online facilitates a seamless exploration between protein sequence and structure, providing a friendly introduction to the material for non-experts and a useful resource for experts. Curated multiple sequence alignments can be extracted for downstream analyses. Accessible at www.aars.online, AARS Online is a free resource to delve into the world of the aaRS.

biochemistry↗

bioRxiv2024

Fish CDK2 recruits Dtx4 to degrade TBK1 through ubiquitination in the antiviral response

Although the classical biological protein cell cycle protein kinase CDK2 has been extensively studied in higher vertebrates, its function in lower vertebrates beyond the regulation of mitosis remains unknown. In this study, we report a distinct mechanism whereby IFN expression is negatively regulated in fish by CDK2. After infection with the spring viremia of carp virus (SVCV), fish CDK2 expression significantly increased in tissues and cells. Moreover, antiviral resistance was improved in cdk2-/- homozygotes, and the antiviral cytokine interferon (IFN) expression was significantly higher. At the cellular level, CDK2 overexpression reduced IFN expression, while cdk2 knockdown increased the ability of cells to produce IFN. Subsequently, it was discovered that fish CDK2 binds and degrades TBK1, resulting in reduced IFN. CDK2 increases the K48-linked ubiquitination of TBK1, causing its degradation, while E3 ubiquitin ligase Dtx4 was found to be involved in this process following the significant enhancement of TBK1 K48-linked ubiquitination. Protein mass spectrometry and immunoblot analysis confirmed that the K567 site on TBK1 is essential for CDK2 to engage with Dtx4 and degrade TBK1; thus, after mutating the K567 site, K48-linked ubiquitination of TBK1 was not enhanced by Dtx4, and TBK1 was not degraded by CDK2. Our data demonstrate that fish CDK2 recruits the E3 ubiquitin ligase Dtx4 to target the K567 site of TBK1 and promote its degradation. These results suggest that CDK2 in lower vertebrates is implicated in a specialized role for antiviral innate immunity.

immunology↗

bioRxiv2023

Boosting BDNF in muscle rescues impaired in vivo axonal transport in a mouse model of DI-CMTC peripheral neuropathy

Charcot-Marie-Tooth disease (CMT) is a genetic peripheral neuropathy caused by mutations in many functionally diverse genes. The aminoacyl-tRNA synthetase (ARS) enzymes, which transfer amino acids to partner tRNAs for protein synthesis, represent the largest protein family genetically linked to CMT aetiology, suggesting pathomechanistic commonalities. Dominant intermediate CMT type C (DI-CMTC) is caused by YARS1 mutations driving a toxic gain-of-function in the encoded tyrosyl-tRNA synthetase (TyrRS), which is mediated by exposure of consensus neomorphic surfaces through conformational changes of the mutant protein. In this study, we first showed that human DI-CMTC-causing TyrRSE196K mis-interacts with the extracellular domain of the BDNF receptor TrkB, an aberrant association we have previously characterised for several mutant glycyl-tRNA synthetases linked to CMT type 2D (CMT2D). We then performed temporal neuromuscular assessments of YarsE196K mice modelling DI-CMT. We determined that YarsE196K homozygotes display a selective, age-dependent impairment in in vivo axonal transport of neurotrophin-containing signalling endosomes, phenocopying CMT2D mice. This impairment is replicated by injection of recombinant TyrRSE196K, but not TyrRSWT, into muscles of wild-type mice. Augmenting BDNF in DI-CMTC muscles, through injection of recombinant protein or muscle-specific gene therapy, resulted in complete axonal transport correction. Therefore, this work identifies a non-cell autonomous pathomechanism common to ARS-related neuropathies, and highlights the potential of boosting BDNF levels in muscles as a therapeutic strategy.

neuroscience↗

bioRxiv2021

Identification of a novel lineage bat SARS-related coronaviruses that use bat ACE2 receptor

Severe respiratory disease coronavirus-2 (SARS-CoV-2) causes the most devastating disease, COVID-19, of the recent century. One of the unsolved scientific questions around SARS-CoV-2 is the animal origin of this virus. Bats and pangolins are recognized as the most probable reservoir hosts that harbor the highly similar SARS-CoV-2 related viruses (SARSr-CoV-2). Here, we report the identification of a novel lineage of SARSr-CoVs, including RaTG15 and seven other viruses, from bats at the same location where we found RaTG13 in 2015. Although RaTG15 and the related viruses share 97.2% amino acid sequence identities to SARS-CoV-2 in the conserved ORF1b region, but only show less than 77.6% to all known SARSr-CoVs in genome level, thus forms a distinct lineage in the Sarbecovirus phylogenetic tree. We then found that RaTG15 receptor binding domain (RBD) can bind to and use Rhinolophus affinis bat ACE2 (RaACE2) but not human ACE2 as entry receptor, although which contains a short deletion and has different key residues responsible for ACE2 binding. In addition, we show that none of the known viruses in bat SARSr-CoV-2 lineage or the novel lineage discovered so far use human ACE2 efficiently compared to SARSr-CoV-2 from pangolin or some of the SARSr-CoV-1 lineage viruses. Collectively, we suggest more systematic and longitudinal work in bats to prevent future spillover events caused by SARSr-CoVs or to better understand the origin of SARS-CoV-2.

microbiology↗

bioRxiv2020

Spontaneous depolarization-induced action potentials of ON-starburst amacrine cells during cholinergic and glutamatergic retinal waves

Correlated spontaneous activity in the developing retina (termed "retinal waves") plays an instructive role in refining neural circuits of the visual system. Depolarizing (ON) and hyperpolarizing (OFF) starburst amacrine cells (SACs) initiate and propagate cholinergic retinal waves. Where cholinergic retinal waves stop, SACs are thought to be driven by glutamatergic retinal waves initiated by ON-bipolar cells. However, the properties and function of cholinergic and glutamatergic waves in ON- and OFF-SACs still remain poorly understood. As expected, we found that both SAC subtypes exhibited spontaneous rhythmic depolarization during cholinergic and glutamatergic waves. Interestingly, ON-SACs had wave-induced action potentials (APs) in an age-dependent manner, but OFF-SACs did not. We further found that the number of APs in ON-SACs was correlated with the amplitude of Ca2+ transients of either ON- or OFF-SACs during cholinergic retinal waves. These results advance the understanding of the cellular mechanisms underlying correlated spontaneous activity in the developing retina.

neuroscience↗

bioRxiv2020

Nucleus translocation of tRNA synthetase mediates late integrated stress response

Various stress conditions are signaled through phosphorylation of translation initiation factor eIF2 to inhibit global translation while selectively activating transcription factor ATF4 to aid cell survival and recovery. However, this integrated stress response is acute and cannot resolve lasting stress. Here we report that TyrRS, a member of the aminoacyl-tRNA synthetase family capable of responding to diverse stress factors through cytosol-nucleus translocation and activating stress-response genes, also inhibits global translation, however at a later stage than eIF2/ATF4 and mTOR responses. Excluding TyrRS from the nucleus over-activates protein synthesis and increases apoptosis in cells under prolonged oxidative stress. Nuclear TyrRS transcriptionally represses translation genes by recruiting TRIM28 and/or NuRD complex. We propose TyrRS, possibly along with other family members, can sense a variety of stress signals through intrinsic properties of this enzyme and its strategically located nuclear localization signal and integrate them by nucleus-translocation to effect protective responses against prolonged stress.

molecular biology↗

bioRxiv2020

Discovery of a novel coronavirus associated with the recent pneumonia outbreak in humans and its potential bat origin

Since the SARS outbreak 18 years ago, a large number of severe acute respiratory syndrome related coronaviruses (SARSr-CoV) have been discovered in their natural reservoir host, bats1-4. Previous studies indicated that some of those bat SARSr-CoVs have the potential to infect humans5-7. Here we report the identification and characterization of a novel coronavirus (nCoV-2019) which caused an epidemic of acute respiratory syndrome in humans, in Wuhan, China. The epidemic, started from December 12th, 2019, has caused 198 laboratory confirmed infections with three fatal cases by January 20th, 2020. Full-length genome sequences were obtained from five patients at the early stage of the outbreak. They are almost identical to each other and share 79.5% sequence identify to SARS-CoV. Furthermore, it was found that nCoV-2019 is 96% identical at the whole genome level to a bat coronavirus. The pairwise protein sequence analysis of seven conserved non-structural proteins show that this virus belongs to the species of SARSr-CoV. The nCoV-2019 virus was then isolated from the bronchoalveolar lavage fluid of a critically ill patient, which can be neutralized by sera from several patients. Importantly, we have confirmed that this novel CoV uses the same cell entry receptor, ACE2, as SARS-CoV.

microbiology↗

bioRxiv2020

SMRT sequencing yields the chromosome-scale reference genome of tea tree, Camellia sinensis var. sinensis

Tea is the oldest and most popular nonalcoholic beverage consumed in the world. It provides abundant secondary metabolites that account for its diverse flavors and health benefits. Here we present the first high-quality chromosome-length reference genome of C. sinensis var. sinensis using long read single-molecule real time (SMRT) sequencing and Hi-C technologies to anchor the [~]2.85-Gb genome assembly into 15 pseudo-chromosomes with a scaffold N50 length of [~]195.68 Mb. We annotated at least 2.17 Gb ([~]74.13%) of repetitive sequences and high-confidence prediction of 40,812 protein-coding genes in the [~]2.92-Gb genome assembly. This accurately assembled genome allows us to comprehensively annotate functionally important gene families such as those involved in the biosynthesis of catechins, theanine and caffeine. The contiguous genome assembly provides the first view of the repetitive landscape allowing us to accurately characterize retrotransposon diversity. The large tea tree genome is dominated by a handful of Ty3-gypsy long terminal repeat (LTR) retrotransposon families that recently expanded to high copy numbers. We uncover the latest bursts of numerous non-autonomous LTR retrotransposons that may interfere with the propagation of autonomous retroelements. This reference genome sequence will largely facilitate the improvement of agronomically important traits relevant to the tea quality and production.

genomics↗

bioRxiv2019

A lipid code-dependent phosphoswitch directs PIN-mediated auxin efflux in Arabidopsis development

Directional intercellular transport of the phytohormone auxin mediated by PIN FORMED (PIN) efflux carriers plays essential roles in both coordinating patterning processes and integrating multiple external cues by rapidly redirecting auxin fluxes. Multilevel regulations of PIN activity under internal and external cues are complicated; however, the underlying molecular mechanism remains elusive. Here we demonstrate that 3-Phosphoinositide-Dependent Protein Kinase1 (PDK1), which is conserved in plants and mammals, functions as a molecular hub integrating the upstream lipid signalling and the downstream substrate activity through phosphorylation. Genetic analysis uncovers that loss-of-function Arabidopsis mutant pdk1.1 pdk1.2 exhibits a plethora of abnormalities in organogenesis and growth, due to the defective PIN-dependent auxin transport. Further cellular and biochemical analyses reveal that PDK1 phosphorylates D6 Protein Kinase to facilitate its activity towards PIN proteins. Our studies establish a lipid-dependent phosphorylation cascade connecting membrane composition-based cellular signalling with plant growth and patterning by regulating morphogenetic auxin fluxes.

plant biology↗

bioRxiv2019

Genome-wide association study of appendicular lean mass in UK Biobank cohort

Lean body mass (LBM), an important physiological measure, has a strong genetic determination. To clarify its genetic basis, a large-scale genome-wide association study (GWAS) of appendicular lean mass (ALM) was conducted in 450,580 UK Biobank subjects. A total of 717 variants (p<5x10-9) from 561 loci were identified, which were replicated across genders (achieving p<5x10-5 in both genders). The identified variants explained ~11% phenotypic variance, accounting for one quarter of the total ~40% GWAS-attributable heritability. The identified variants were enriched in gene sets related to musculoskeletal and connective tissue development. Of interest are several genes, including ADAMTS3, PAM, SMAD3 and MEF2C, that either contain multiple significant variants or serve as the hub genes of the associated gene sets. Polygenic score prediction based on the associated variants was able to distinguish subjects of high from low ALM. Overall, our results offered significant findings on the genetic basis of lean mass through an extraordinarily large sample GWAS. The findings are important to not only lean mass per se but also other complex diseases, such as type 2 diabetes and fracture, as our Mendelian randomization analysis showed that ALM is a protective factor for these two diseases.

genetics↗

bioRxiv2018

Network analysis of lymphocyte nucleus staining image

Background: A complex network has been studied and applied in various disciplines. As network analysis and image processing are based on matrices, this research analysed the changes in the chromatin image of lymphocyte nuclei in peripheral blood of humans using a network motif and static features (static parameters), so as to complete image classification with network method.\n\nMethods: Image processing technology was used to establish a chromatin image network of a cell nucleus; Network analysis tool Pajek was used to display the special motif of an isolated structural hole with different symmetric line values; afterwards, the frequency of occurrence of this structural hole in patients with nasopharyngeal carcinoma and AIDS, and healthy people was computed. Then by applying the network static features as variables, the chromatin images of stained lymphocytes from the three groups of people were classified and recognised by using an extreme learning machine (ELM).\n\nResults: The frequency of occurrence of the isolated structural hole with different symmetric line values was adopted to distinguish the structures of the chromatins of peripheral blood lymphocytes in patients with nasopharyngeal carcinoma and AIDS, and healthy people. Similarly, The static features of the chromatin image network of a cell nucleus were applied to classify and recognise the morphological and structural changes in chromatins for peripheral blood lymphocytes in the three groups of people.\n\nConclusion: The surface chemical and physical characteristics, as well as the polymerisation link status of biomacromolecules such as DNA, RNA, and protein in the lymphocyte nucleus change under certain pathological conditions. The change influences the combination of small molecular staining materials and any associated biomacromolecules. Therefore, various macroscopic and microscopic changes were found in the chromatin images of the cell nucleus. The microscopic changes include the variations of the extent of staining of chromatin in the nuclei, coarseness and direction of the texture therein, the size of stained conglomerations, etc. These changes contribute to the differences in chromatin image networks among the same type of cells across the three groups. Based on this, the model can be used to classify and reorganise certain diseases. The results prove that using complex network to analyse the chromatin structure of a cell nucleus is of significance.

bioinformatics↗

bioRxiv2017

Investigating on relationship between effective quantum efficiency and irradiance

AbstractModels describing the relationship between effective quantum efficiency of PS II ({Phi}PSII) and irradiance (I) are routinely used to determine how irradiance influences effective quantum efficiency and photosynthetic electron transport rate (ETR). However, with no single model one can accurately describe the relationship between{Phi} PSII and I, and explain the interdependence between{Phi} PSII and biophysical properties of photosynthetic pigments, especially in plants growing under low level irradiances. Basing on the mechanistic model of photosynthetic electron transport rate we have developed the model of the relationship between{Phi} PSII and I. The new model reveals that{Phi} PSII increases with photochemistry (kP) and heat dissipation (kD). Furthermore, the values of key parameters calculated using the new model were compared with the values calculated with two other empirical models. The new model was perfectly fitted to the light-response curves of{Phi} PSII. The key calculated photosynthetic parameters: maximum{Phi} PSII, maximum ETR and their corresponding saturation irradiance were close to the measured values. In addition, our model associates{Phi} PSII with intrinsic features of photosynthetic pigments. We concluded that{Phi} PSII decreased with increasing I due to the decrease in the effective absorption cross-section of photosynthetic pigments molecules.\n\nHighlightA model of the relationship between effective quantum efficiency of PS II ({Phi}PSII) and irradiance (I) has been developed. Using this new model it was found that{Phi} PSII decreased with increasing I due to the decrease in the effective absorption cross-section of photosynthetic pigments molecules.\n\nAbbreviations

plant biology↗