Biology subjects

Sui, X.

Publications and source records attributed to Sui, X..

29 records · Page 2Linked to original sources

bioRxiv2022

Global proteome metastability response in isogenic animals to missense mutations and polyglutamine expansions in aging

The conformational stability of the proteome has tremendous implications for the health of the cell and its capacity to determine longevity or susceptibility to age-associated degenerative diseases. For humans, this question of proteome conformational stability has the additional complexity from non-synonymous mutations in thousands of protein coding genes challenging the capacity of the proteostasis network to properly fold, transport, assemble and degrade proteins. Here, we quantify the proteome-wide capacity to such challenges using the isogenic organism Caenorhabditis elegans by examining the dynamics of global proteome conformational stability in animals expressing different temperature-sensitive (ts) proteins or short polyglutamine (polyQ) expansions in the context of biological aging. Using limited proteolysis of native extracts together with tandem mass tag-based quantitative proteomics, we identify proteins that become metastable under these conditions and monitor the effects on proteome solubility and abundance. Expression of different mutant proteins in the same tissue identifies hundreds to a thousand proteins that become metastable affecting multiple compartments and processes in a cell autonomous and non-autonomous manner. Comparison of the network of metastable proteins, however, reveals only a small number of common proteins. The most dramatic effects on global proteome dynamics occur in aging with one-third of the proteome undergoing conformational changes in early adulthood. These age-dependent metastable proteins overlap substantially with ts proteins and polyQ; moreover, expression of polyQ accelerates the aging phenotype. Together, these results reveal that the proteome responds to misfolding one-at-a-time to generate a metastable sub-proteome network with features of a fingerprint for which aging is the dominant determinant of proteome metastability.

biochemistry↗

bioRxiv2022

The structure, catalytic mechanism, and inhibitor identification of phosphatidylinositol remodeling MBOAT7

Cells remodel glycerophospholipid acyl chains via the Lands cycle to adjust membrane properties. Membrane-bound O-acyltransferase (MBOAT) 7 acylates lyso-phosphatidylinositol (lyso-PI) with arachidonyl-CoA. MBOAT7 mutations cause brain developmental disorders, and reduced expression is linked to fatty liver disease. Further, increased MBOAT7 expression is linked to hepatocellular and renal cancers. The mechanistic basis of MBOAT7 catalysis and substrate selectivity are unknown. Here, we report the structure and a model for the catalytic mechanism of human MBOAT7. Arachidonyl-CoA and lyso-PI access the catalytic center through a twisted tunnel from the cytosol and lumenal sides, respectively. N-Terminal residues on the ER lumenal side determine phospholipid headgroup selectivity: swapping them between MBOATs 1, 5, and 7 converts enzyme specificity for different lyso-phospholipids. Finally, the MBOAT7 structure and virtual screening enabled identification of small-molecule inhibitors that may serve as lead compounds for pharmacologic development.

biochemistry↗

bioRxiv2021

Text Mining Drug-Protein Interactions using an Ensemble of BERT, Sentence BERT and T5 models

In this work, we trained an ensemble model for predicting drug-protein interactions within a sentence based on only its semantics. Our ensembled model was built using three separate models: 1) a classification model using a fine-tuned BERT model; 2) a fine-tuned sentence BERT model that embeds every sentence into a vector; and 3) another classification model using a fine-tuned T5 model. In all models, we further improved performance using data augmentation. For model 2, we predicted the label of a sentence using k-nearest neighbors with its embedded vector. We also explored ways to ensemble these 3 models: a) we used the majority vote method to ensemble these 3 models; and b) based on the HDBSCAN clustering algorithm, we trained another ensemble model using features from all the models to make decisions. Our best model achieved an F-1 score of 0.753 on the BioCreative VII Track 1 test dataset.

bioinformatics↗

bioRxiv2021

Seipin forms a flexible cage at lipid droplet formation sites

Lipid droplets (LDs) form in the endoplasmic reticulum by phase separation of neutral lipids. This process is facilitated by the seipin protein complex, which consists of a ring of seipin monomers, with yet unclear function. Here, we report a structure of yeast seipin based on cryo-electron microscopy and structural modeling data. Seipin forms a decameric, cage-like structure with the lumenal domains forming a stable ring at the cage floor and transmembrane segments forming the cage sides and top. The transmembrane segments interact with adjacent monomers in two distinct, alternating conformations. These conformations result from changes in switch regions, located between the lumenal domains and the transmembrane segments, that are required for seipin function. Our data suggest a model for LD formation in which a closed seipin cage enables TG phase separation and subsequently switches to an open conformation to allow LD growth and budding.

molecular biology↗

bioRxiv2020

The PRC2-dependent epigenetic reprograming of the bladder epithelium exacerbates urinary tract infections

Mucosal imprint sensitizes recurrent urinary tract infections (UTIs), a significant health and quality of life burden worldwide, which are associated with heightened inflammatory host response, severe basal cell hyperplasia and impaired superficial cell differentiation. Here, we show that bladder infections induce expression of Ezh2, the methyltransferase of polycomb repressor complex 2 (PRC2)-dependent epigenetic gene silencing program. In mouse models of UTIs, urothelium-specific inactivation of PRC2 reduces the urine bacteria burden. The mutants exhibit a blunted inflammatory response likely due to the diminished activity of NF-{kappa}B signaling pathway. PRC2 inactivation also improves urothelial differentiation and attenuates basal cell hyperplasia phenotype. Moreover, the Ezh2-specific small molecule inhibitors markedly improve disease outcomes of bladder superinfection and chronic cystitis. Taken together, these findings suggest that the UTI-induced epigenetic reprograming in the bladder urothelium likely contributes to the mucosal imprint, and further suggest that targeting PRC2 methyltransferase offers a non-antibiotic strategy to mitigate UTIs.

immunology↗

bioRxiv2020

Neural encoding of socially adjusted value during competitive and hazardous foraging

In group foraging organisms, optimizing the conflicting demands of competitive food loss and safety is critical. We demonstrate that humans select competition avoidant and risk diluting strategies during foraging depending on socially adjusted value. We formulate a mathematically grounded quantification of socially adjusted value in foraging environments and show using multivariate fMRI analyses that socially adjusted value is encoded by mid-cingulate and ventromedial prefrontal cortices, regions that integrate value and action signals.

neuroscience↗

bioRxiv2020

Unravel the Mystery of NIC1-locus on Nicotine Biosynthesis Regulation in Tobacco

ABSTRACTBackground Nicotine biosynthesis is mainly regulated by jasmonate (JA) signaling cascade in Nicotiana tabacum. As an allotetraploid species, the regulation of nicotine biosynthesis has been genetically verified via two unlinked NIC loci (named as NIC1 and NIC2) which are possibly originated from its two ancestral diploids. Previously, a N. tomentosiformis originated ethylene response factor (ERF) gene cluster was identified as the NIC2-locus which has been demonstrated positively regulates nicotine accumulation in N. tabacum.Results Here, we describe the genetic mapping of NIC1-locus, the major nicotine regulatory locus, by using a NIC1-locus segregating population through bulked segregant analysis. We identified two linkage marker TM23004 and TM22038 were delimited the NIC1-locus within a ~34.3-Mb genomic region at pseudochromosome 07 of tobacco genome. Genomic scan within this region revealed a NIC2-like locus ERF gene cluster exist in. To verify this ERF gene cluster is the genetically called “NIC1-locus”, different functional experiments based on most of the ERFs in regulating nicotine biosynthesis and their influences on alkaloid accumulations have been carried out. Collinearity analysis showed that NIC1-locus ERF genes are originated from N. sylvestris and exclusively expressed in root tissues. In addition, transcriptomic results indicate that NIC1-locus ERF genes are coexpressed with the NIC2-locus ERF genes and other nicotine biosynthetic genes and regulators after JA induction. Furthermore, the suppressed expression of four ERFs of the NIC1-locus genes corresponding with decreased NtPMT and NtQPT expression in NtMYC2-RNAi lines indicates the selected NIC1-locus ERFs function in downstream of NtMYC2 in the JA signaling cascades. In the meanwhile, the alkaloid levels are also determined by the amplitude of the four ERF gene expressions in both wild type and LA mutant. Additionally, in vitro binding assays, transient activation assays, and ectopic expression in transgenic plants demonstrate that these ERF genes are able to bind the GCC-box elements residing in the step-limiting gene promoters (such as NtPMT2, NtQPT2) and functional redundant but quantitatively transactivate nicotine biosynthetic gene expression. For nic1-locus mutation, two different sizes of deletions (nic1-S and nic1-B) were identified which occurred at the surrounding regions of the NIC1-locus gene cluster, which might disrupt, to some extent, chromosomal microenvironment and change gene expression around the deletion regions (including NIC1-locus ERFs), resulting in the decreased expression levels of NIC1-locus ERFs (such as NtERF199) and reduced alkaloid accumulation in the nic1-locus mutant.Conclusions Our findings not only provide insight in to the mechanism of the NIC1-locus ERFs in the regulatory network of nicotine biosynthesis, but also unraveled the theoretical basis of the nic1-locus mutation in low nicotine mutant. These functional verified NIC1-locus ERF genes can be further used as potential target(s) for ethyl methanesulfonate-based mutagenesis to manipulate nicotine level in tobacco variety in tobacco breeding program.Competing Interest StatementThe authors have declared no competing interest.AbbreviationsA622a PIP family oxidoredutase for nicotine precursors condensationODCornithine decarboxylaseADCarginine decarboxylasePMTputrescine N-methyltransferaseMPON-methylputrescine oxidaseAOaspartate oxidaseQSquinolinic acid synthaseQPTqunolinic acid phosphoribosyl transferaseSPDSspermidine synthaseSAMSS-adenosylmethionine synthaseSAMDCS-adenosylmethione decarboxylasePCRPolymerase chain reactionRNA-seqRNA SequencingRPKMReads Per Kilobase per Million mapped readsSSRsimple sequence repeatqRT-PCRQuantitative real-time PCRCRchromosome rearrangementCNVcopy number variantView Full Text

plant biology↗

bioRxiv2020

The Role of the Medial Prefrontal Cortex in Spatial Margin of Safety Calculations

Humans, like many other animals, pre-empt danger by moving to locations that maximize their success at escaping future threats. We test the idea that spatial margin of safety (MOS) decisions, a form of pre-emptive avoidance, results in participants placing themselves closer to safer locations when facing more unpredictable threats. Using multivariate pattern analysis on fMRI data collected while subjects engaged in MOS decisions with varying attack location predictability, we show that while the hippocampus encodes MOS decisions across all types of threat, a vmPFC anterior-posterior gradient tracked threat predictability. The posterior vmPFC encoded for more unpredictable threat and showed functional coupling with the amygdala and hippocampus. Conversely, the anterior vmPFC was more active for the more predictable attacks and showed coupling with the striatum. Our findings suggest that when pre-empting danger, the anterior vmPFC may provide a safety signal, possibly via predictable positive outcomes, while the posterior vmPFC drives prospective danger signals.

neuroscience↗

bioRxiv2019

Arabidopsis CPR5 regulates ethylene signaling via interacting with ETR1 N-terminus and controlling mRNAs nucleocytoplasmic transport

ETR1 is the major ethylene receptor in Arabidopsis thaliana. Previous studies showed that RTE1 and CPR5 can bind to ETR1 and play regulatory roles in ethylene signaling. RTE1 has been suggested to promote ETR1 signal transduction by influencing the conformation of ETR1, but little is known about the mechanism of CPR5 on the regulation of ETR1 signaling. In this study, we showed that both CPR5 and RTE1 could interact with the N-terminal transmembrane domains of ETR1, and CPR5 needs at least three transmembrane domains of ETR1 while RTE1 needs only two for the binding. As CPR5 has also been shown to be localized in the nuclear membrane and might act as a nucleoporin, we analyzed the effects of CPR5 on the nucleocytoplasmic transport of ethylene-related mRNAs using poly(A)-mRNA in situ hybridization and real-time quantitative PCR (qPCR), and the results indicated that CPR5 could selectively regulate the nucleocytoplasmic transport of mRNAs in ethylene signaling pathway. In contrast, the nucleoporin mutants (nup160, nup96-1 and nup96-2) dramatically accumulated all the examined mRNAs in the nucleus. In conclusion, the present study provides evidence demonstrating that CPR5 regulates ethylene signaling through interacting with the ETR1 receptor and controlling the mRNAs nucleocytoplasmic transport in ethylene signaling pathway. Key messageThis study reveals that CPR5 is involved in the regulation of ethylene signaling via two different ways: interacting with the N-terminal domains of ERT1 and controlling the nucleocytoplasmic transport of mRNAs in ethylene signaling pathway.

plant biology↗

bioRxiv2019

Widespread remodelling of proteome solubility in response to different protein homeostasis stresses

The accumulation of protein deposits in neurodegenerative diseases involves the presence of a metastable subproteome vulnerable to aggregation. To investigate this subproteome and the mechanisms that regulates it, we measured the proteome solubility of the Neuro2a cell line under protein homeostasis stresses induced by Huntington Disease proteotoxicity; Hsp70, Hsp90, proteasome and ER-mediated folding inhibition; and oxidative stress. We found one-quarter of the proteome extensively changed solubility. Remarkably, almost all the increases in insolubility were counteracted by increases in solubility of other proteins. Each stress directed a highly specific pattern of change, which reflected the remodelling of protein complexes involved in adaptation to perturbation, most notably stress granule proteins, which responded differently to different stresses. These results indicate that the robustness of protein homeostasis relies on the absence of proteins highly vulnerable to aggregation and on large changes in aggregation state of regulatory mechanisms that restore protein solubility upon specific perturbations.

biochemistry↗

bioRxiv2018

Cryo-electron microscopy structure of the lipid droplet-formation protein seipin

Sui et al. report the cryo-EM structure of the conserved luminal domain of the lipid droplet (LD)-formation protein seipin. The structure reveals key features of this domain and suggest a new model for seipins role in LD formation.\n\nMetabolic energy is stored in cells primarily as triacylglycerols in lipid droplets (LDs), and LD dysregulation leads to metabolic diseases. The formation of monolayer-bound LDs from the endoplasmic reticulum (ER) bilayer is poorly understood, but the ER protein seipin is essential to this process. Here, we report a cryo-electron microscopy structure and functional characterization of D. melanogaster seipin. The structure reveals a ring-shaped dodecamer, with the luminal domain of each monomer resolved at [~]4.0 [A]. Each luminal domain monomer exhibits two distinctive features: a hydrophobic helix positioned towards the ER bilayer, and a {beta}-sandwich domain that has structural similarity with lipid-binding proteins. This structure, and our functional testing in cells, suggest a model in which seipin oligomers initially detect forming LDs in the ER via hydrophobic helices and subsequently act as membrane anchors to enable lipid transfer and LD growth.

cell biology↗