Biology subjects

Lan, J.

Publications and source records attributed to Lan, J..

At least 37 records · Page 2Linked to original sources

bioRxiv2021

Serine/arginine-rich splicing factor 7 plays oncogenic roles through specific regulation of m6A RNA modification

Serine/Arginine-Rich Splicing Factor 7 (SRSF7), which is previously recognized as a splicing factor, has been revealed to play oncogenic roles in multiple cancers. However, the mechanisms underlying its oncogenic roles have not been well addressed. Here, based on N6-methyladenosine (m6A) co-methylation network analysis across diverse cell lines, we found SRSF7 positively correlated with glioblastoma cell-specific m6A methylation. We then proved SRSF7 is a novel m6A regulator that specifically facilitates the m6A methylation near its binding sites on the mRNAs involved in cell proliferation and migration through recruiting methyltransferase complex. Moreover, SRSF7 promotes the proliferation and migration of glioblastoma cells largely dependent on the m6A methyltransferase. The two single-nucleotide m6A sites on PBK are regulated by SRSF7 and partially mediate the effects of SRSF7 on glioblastoma cells through recognition by IGF2BP2. Together, our discovery revealed a novel role of SRSF7 in regulating m6A and timely confirmed the existence and functional importance of RNA binding protein (RBP) mediated specific regulation of m6A.

molecular biology↗

bioRxiv2021

Circadian patterns of energy metabolism are only partially reconstituted in gnotobiotic mice

The capacity of the intestinal microbiota to degrade otherwise indigestible diet components is known to greatly improve the recovery of energy from food. This has led to the hypothesis that increased digestive efficiency may underlie the contribution of the microbiome to obesity. OligoMM12-colonized gnotobiotic mice have a consistently higher fat-mass than germ-free or fully colonized counterparts. We therefore investigated their food intake, digestion efficiency, energy expenditure and respiratory quotient using a novel isolator-housed metabolic cage system which allows long-term measurements without contamination risk. This demonstrated that microbiota- released calories are perfectly balanced by decreased food intake in fully colonized versus gnotobiotic OligoMM12 and germ-free mice fed a standard chow diet, i.e., microbiota-released calories can in fact be well-integrated into appetite control. We also observed no significant difference in energy expenditure per gram lean mass between the different microbiota groups, suggesting that cumulative very small differences in energy balance, or altered energy storage must underlie fat accumulation in OligoMM12 mice. Consistent with altered energy storage, major differences were observed in the type of respiratory substrates used in metabolism over the circadian cycle: in germ-free mice the respiratory exchange ratio was consistently lower than that of fully colonized mice at all times of day, indicative of more reliance on fat and less on glucose metabolism. Intriguingly the RER of OligoMM12-colonized gnotobiotic mice phenocopied fully colonized mice during the dark (active/eating) phase but phenocopied germ-free mice during the light (fasting/resting) phase. Further, OligoMM12-colonized mice showed a germ-free-like drop in liver glycogen storage during the light cycle and both liver and plasma metabolomes of OligoMM12 mice clustered closely with germ-free mice. This implies the existence of microbiota functions that are required to maintain normal host metabolism during the resting/fasting phase of circadian cycle, and which are absent in the OligoMM12 consortium.

microbiology↗

bioRxiv2021

Characterization of SARS-CoV-2 variants B.1.617.1 (Kappa), B.1.617.2 (Delta) and B.1.618 on cell entry, host range, and sensitivity to convalescent plasma and ACE2 decoy receptor

Recently, highly transmissible SARS-CoV-2 variants B.1.617.1 (Kappa), B.1.617.2 (Delta) and B.1.618 were identified in India with mutations within the spike proteins. The spike protein of Kappa contains four mutations E154K, L452R, E484Q and P681R, and Delta contains L452R, T478K and P681R, while B.1.618 spike harbors mutations {Delta}145-146 and E484K. However, it remains unknown whether these variants have altered in their entry efficiency, host tropism, and sensitivity to neutralizing antibodies as well as entry inhibitors. In this study, we found that Kappa, Delta or B.1.618 spike uses human ACE2 with no or slightly increased efficiency, while gains a significantly increased binding affinity with mouse, marmoset and koala ACE2 orthologs, which exhibits limited binding with WT spike. Furthermore, the P618R mutation leads to enhanced spike cleavage, which could facilitate viral entry. In addition, Kappa, Delta and B.1.618 exhibits a reduced sensitivity to neutralization by convalescent sera owning to the mutation of E484Q, T478K, {Delta}145-146 or E484K, but remains sensitive to entry inhibitors-ACE2-lg decoy receptor. Collectively, our study revealed that enhanced human and mouse ACE2 receptor engagement, increased spike cleavage and reduced sensitivity to neutralization antibodies of Kappa, Delta and B.1.618 may contribute to the rapid spread of these variants and expanded host range. Furthermore, our result also highlighted that ACE2-lg could be developed as broad-spectrum antiviral strategy against SARS-CoV-2 variants.

microbiology↗

bioRxiv2021

Mutation Y453F in the spike protein of SARS-CoV-2 enhances interaction with the mink ACE2 receptor for host adaption

COVID-19 patients transmitted SARS-CoV-2 to minks in the Netherlands in April 2020. Subsequently, the mink-associated virus (miSARS-CoV-2) spilled back over into humans. Genetic sequences of the miSARS-CoV-2 identified a new genetic variant known as "Cluster 5" that contained mutations in the spike protein. However, the functional properties of these "Cluster 5" mutations have not been well established. In this study, we found that the Y453F mutation located in the RBD domain of miSARS-CoV-2 is an adaptive mutation that enhances binding to mink ACE2 and other orthologs of Mustela species without compromising, and even enhancing, its ability to utilize human ACE2 as a receptor for entry. Structural analysis suggested that despite the similarity in the overall binding mode of SARS-CoV-2 RBD to human and mink ACE2, Y34 of mink ACE2 was better suited to interact with a Phe rather than a Tyr at position 453 of the viral RBD due to less steric clash and tighter hydrophobic-driven interaction. Additionally, the Y453F spike exhibited resistance to convalescent serum, posing a risk for vaccine development. Thus, our study suggests that since the initial transmission from humans, SARS-CoV-2 evolved to adapt to the mink host, leading to widespread circulation among minks while still retaining its ability to efficiently utilize human ACE2 for entry, thus allowing for transmission of the miSARS-CoV-2 back into humans. These findings underscore the importance of active surveillance of SARS-CoV-2 evolution in Mustela species and other susceptible hosts in order to prevent future outbreaks.

microbiology↗

bioRxiv2021

Susceptibilities of human ACE2 genetic variants in coronavirus infection

The COVID-19 pandemic, caused by SARS-CoV-2, has resulted in more than 1603 million cases worldwide and 3.4 million deaths (as of May 2021), with varying incidences and death rates among regions/ethnicities. Human genetic variation can affect disease progression and outcome, but little is known about genetic risk factors for SARS-CoV-2 infection. The coronaviruses SARS-CoV, SARS-CoV-2 and HCoV-NL63 all utilize the human protein angiotensin-converting enzyme 2 (ACE2) as the receptor to enter cells. We hypothesized that the genetic variability in ACE2 may contribute to the variable clinical outcomes of COVID-19. To test this hypothesis, we first conducted an in silico investigation of single-nucleotide polymorphisms (SNPs) in the coding region of ACE2 gene. We then applied an integrated approach of genetics, biochemistry and virology to explore the capacity of select ACE2 variants to bind coronavirus spike protein and mediate viral entry. We identified the ACE2 D355N variant that restricts the spike protein-ACE2 interaction and consequently limits infection both in vitro and in vivo. In conclusion, ACE2 polymorphisms could modulate susceptibility to SARS-CoV-2, which may lead to variable disease severity.

microbiology↗

bioRxiv2021

Reduced graphene oxide membrane as supporting film for high-resolution cryo-EM

Although single-particle cryogenic electron microscopy (cryo-EM) has been applied extensively for elucidating many crucial biological mechanisms at the molecular level, this technique still faces critical challenges, the major one of which is to prepare the high-quality cryo-EM specimen. Aiming to achieve a more reproducible and efficient cryo-EM specimen preparation, novel supporting films including graphene-based two-dimensional materials have been explored in recent years. Here we report a robust and simple method to fabricate EM grids coated with single- or few-layer reduced graphene oxide (RGO) membrane in large batch for high-resolution cryo-EM structural determination. The RGO membrane has decreased interlayer space and enhanced electrical conductivity in comparison to regular graphene oxide (GO) membrane. Moreover, we found that the RGO supporting film exhibited nice particle-absorption ability, thus avoiding the air-water interface problem. More importantly, we found that the RGO supporting film is particularly useful in cryo-EM reconstruction of sub-100 kDa biomolecules at near-atomic resolution, as exemplified by the study of RBD-ACE2 complex and other small protein molecules. We envision that the RGO membranes can be used as a robust graphene-based supporting film in cryo-EM specimen preparation.

biophysics↗

bioRxiv2021

Spike mutations in SARS-CoV-2 variants confer resistance to antibody neutralization

New SARS-CoV-2 variants continue to emerge from the current global pandemic, some of which can replicate faster and with greater transmissibility and pathogenicity. In particular, UK501Y.V1 identified in UK, SA501Y.V2 in South Africa, and BR501Y.V3 in Brazil are raising serious concerns as they spread quickly and contain spike protein mutations that may facilitate escape from current antibody therapies and vaccine protection. Here, we constructed a panel of 28 SARS-CoV-2 pseudoviruses bearing single or combined mutations found in the spike protein of these three variants, as well as additional nine mutations that within or close by the major antigenic sites in the spike protein identified in the GISAID database. These pseudoviruses were tested against a panel of monoclonal antibodies (mAbs), including some approved for emergency use to treat SARS-CoV-2 infection, and convalescent patient plasma collected early in the pandemic. SA501Y.V2 pseudovirus was the most resistant, in magnitude and breadth, against mAbs and convalescent plasma, followed by BR501Y.V3, and then UK501Y.V1. This resistance hierarchy corresponds with Y144del and 242-244del mutations in the N-terminal domain as well as K417N/T, E484K and N501Y mutations in the receptor binding domain (RBD). Crystal structural analysis of RBD carrying triple K417N-E484K-N501Y mutations found in SA501Y.V2 bound with mAb P2C-1F11 revealed a molecular basis for antibody neutralization and escape. SA501Y.V2 and BR501Y.V3 also acquired substantial ability to use mouse and mink ACE2 for entry. Taken together, our results clearly demonstrate major antigenic shifts and potentially broadening the host range of SA501Y.V2 and BR501Y.V3, which pose serious challenges to our current antibody therapies and vaccine protection.

immunology↗

bioRxiv2020

Machine Learning-based Biomarkers Identification and Validation from Toxicogenomics - Bridging to Regulatory Relevant Phenotypic Endpoints

High-throughput in vitro assays and AOP-based approach is promising for the assessment of health and ecotoxicological risks from exposure to pollutants and their mixtures. However, one of the major challenges in realization and implementations of the Tox21 vision is the urgent need to establish quantitative link between in-vitro assay molecular endpoint and in-vivo phenotypic toxicity endpoint. Here, we demonstrated that, using time series toxicomics in-vitro assay along with machine learning-based feature selection (MRMR) and classification method (SVM), an "optimal" number of biomarkers with minimum redundancy can be identified for prediction of phenotypic endpoints with good accuracy. We included two case studies for in-vivo carcinogenicity and Ames genotoxicity prediction with 20 selected chemicals including model genotoxic chemicals and negative controls, respectively, using an in-vitro toxicogenomic assay that captures real-time proteomic response data of 38 GFP-fused proteins of S. cerevisiae strains covering biomarkers indicative of all known DNA damage and repair pathways in yeast. The results suggested that, employing the adverse outcome pathway (AOP) concept, molecular endpoints based on a relatively small number of properly selected biomarker-ensemble involved in the conserved DNA-damage and repair pathways among eukaryotes, were able to predict both in-vivo carcinogenicity in rats and Ames genotoxicity endpoints. The specific biomarkers identified are different for the two different phenotypic genotoxicity assays. The top-ranked five biomarkers for the in-vivo carcinogenicity prediction mainly focused on double strand break repair and DNA recombination, whereas the selected top-ranked biomarkers for Ames genotoxicity prediction are associated with base- and nucleotide-excision repair. Current toxicomics approach still mostly rely on large number of redundant markers without pre-selection or ranking, therefore, selection of relevant biomarkers with minimal redundancy would reduce the number of markers to be monitored and reduce the cost, time, and complexity of the toxicity screening and risk monitoring. The method developed in this study will help to fill in the knowledge gap in phenotypic anchoring and predictive toxicology, and contribute to the progress in the implementation of tox 21 vision for environmental and health applications. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/423486v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@11bc876org.highwire.dtl.DTLVardef@105ebc2org.highwire.dtl.DTLVardef@1b91a63org.highwire.dtl.DTLVardef@1738486_HPS_FORMAT_FIGEXP M_FIG TOC Art C_FIG

pharmacology and toxicology↗

bioRxiv2020

Characterization and structural basis of a lethal mouse-adapted SARS-CoV-2

The ongoing SARS-CoV-2 pandemic has brought an urgent need for animal models to study the pathogenicity of the virus. Herein, we generated and characterized a novel mouse-adapted SARS-CoV-2 strain, named MASCp36, that causes severe acute respiratory symptoms and mortality in standard laboratory mice. Particularly, this model exhibits age and gender related skewed distribution of mortality akin to severe COVID-19, and the 50% lethal dose (LD50) of MASCp36 was 58 PFU in 9-month-old, male BALB/c mice. Deep sequencing identified three amino acid substitutions, N501Y, Q493H, and K417N, subsequently emerged at the receptor binding domain (RBD) of MASCp36, during in vivo passaging. All three mutations in RBD significantly enhanced the binding affinity to its endogenous receptor, mouse ACE2 (mACE2). Cryo-electron microscopy (cryo-EM) analysis of human ACE2 (hACE2) or mACE2 in complex with the RBD of MASCp36 at 3.1 to 3.7 angstrom resolution elucidates molecular basis for the receptor-binding switch driven by specific amino acid substitutions. Interestingly, N501Y and Q493H enhanced the binding affinity to human ACE2 (hACE2); while triple mutations N501Y/Q493H/K417N decreased affinity to hACE2, thus led to the reduced infectivity of MASCp36 to human cells. Our study not only provides a robust platform for studying the pathogenesis of severe COVID-19 and rapid evaluation of coutermeasures against SARS-CoV-2, but also unveils the molecular mechanism for the rapid adaption and evolution of SARS-CoV-2 in human and animals. One sentence summaryA mouse adapted SARS-CoV-2 strain that harbored specific amino acid substitutions in the RBD of S protein showed 100% mortality in aged, male BALB/c mice.

microbiology↗

bioRxiv2020

Bat and pangolin coronavirus spike glycoprotein structures provide insights into SARS-CoV-2 evolution

In recognizing the host cellular receptor and mediating fusion of virus and cell membranes, the spike (S) glycoprotein of coronaviruses is the most critical viral protein for cross-species transmission and infection. Here we determined the cryo-EM structures of the spikes from bat (RaTG13) and pangolin (PCoV_GX) coronaviruses, which are closely related to SARS-CoV-2. All three receptor-binding domains (RBDs) of these two spike trimers are in the "down" conformation, indicating they are more prone to adopt this receptor-binding inactive state. However, we found that the PCoV_GX, but not the RaTG13, spike is comparable to the SARS-CoV-2 spike in binding the human ACE2 receptor and supporting pseudovirus cell entry. Through structure and sequence comparisons, we identified critical residues in the RBD that underlie the different activities of the RaTG13 and PCoV_GX/SARS-CoV-2 spikes and propose that N-linked glycans serve as conformational control elements of the RBD. These results collectively indicate that strong RBD-ACE2 binding and efficient RBD conformational sampling are required for the evolution of SARS-CoV-2 to gain highly efficient infection.

biophysics↗

bioRxiv2020

Comparative analysis reveals the species-specific genetic determinants of ACE2 required for SARS-CoV-2 entry

Coronavirus interaction with its viral receptor is a primary genetic determinant of host range and tissue tropism. SARS-CoV-2 utilizes ACE2 as the receptor to enter host cell in a species-specific manner. We and others have previously shown that ACE2 orthologs from New World monkey, koala and mouse cannot interact with SARS-CoV-2 to mediate viral entry, and this defect can be restored by humanization of the restrictive residues in New World monkey ACE2. To better understand the genetic determinants behind the ability of ACE2 orthologs to support viral entry, we compared koala and mouse ACE2 sequences with that of human and identified the key residues in koala and mouse ACE2 that restrict viral receptor activity. Humanization of these critical residues rendered both koala and mouse ACE2 capable of binding the spike protein and facilitating viral entry. The single mutation that allowed for mouse ACE2 to serve as a viral receptor provides a potential avenue for the development of SARS-CoV-2 mouse model.

microbiology↗

bioRxiv2020

A functional chromogen gene C from wild rice is involved in a different anthocyanin biosynthesis pathway in indica and japonica

Accumulation of anthocyanin is a desirable trait to be selected in rice domestication, but the molecular mechanism of anthocyanin biosynthesis in rice remains largely unknown. In this study, a novel allele of chromogen gene C, OrC1, from Oryza rufipongon was cloned and identified as a determinant regulator of anthocyanin biosynthesis. Although OrC1 functions in purple apiculus, leaf sheath and stigma in indica background, it only promotes purple apiculus in japonica. Transcriptome analysis revealed that OrC1 regulates flavonoid biosynthesis pathway and activates a few bHLH and WD40 genes of ternary MYB-bHLH-WD40 complex in indica. Differentially expressed genes and metabolites were found in the indica and japonica backgrounds, indicating that OrC1 activated the anthocyanin biosynthetic genes OsCHI, OsF3H, OsANS, OsINS and OsANR and produced six metabolites independently. Artificial selection and domestication of C1 gene in rice occurred on the coding region in the two subspecies independently. Our results reveal the regulatory system and domestication of C1, provide new insights into MYB transcript factor involved in anthocyanin biosynthesis, and show the potential of engineering anthocyanin biosynthesis in rice. Author summaryAccumulation of anthocyanin is a selection trait in rice domestication, whereas the mechanisms regulating the anthocyanin biosynthetic pathway in rice remain unresolved. Here, a novel allele of chromogen gene C from wild rice (Oryza rufipongon) was identified as a determinant regulator of anthocyanin biosynthesis. A key question is to what extent the involvement of the C1 gene can explain coloration variability of cultivated rice, where anthocyanin accumulation has been eliminated by artificial selection. Our results reveal the functional chromogen gene C from wild rice causes different coloration phenotypes, regulates various anthocyanin biosynthetic genes and produces different metabolites in indica and japonica. Artificial selection and domestication of the C1 gene in rice only occurs within the coding region of the two subspecies independently.

plant biology↗

bioRxiv2020

Minimizing ion competition boosts volatile metabolome analysis by secondary electrospray ionization orbitrap mass spectrometry

Secondary electrospray ionization high-resolution mass spectrometry (SESI-HR-MS) is an emerging technique for the detection of volatile metabolites. However, sensitivity and reproducibility of SESI-HRMS have limited its applications in untargeted metabolomics profiling. Ion suppression in the SESI source has been considered to be the main cause. Here, we show that besides ion suppression, ion competition in the C-trap of Orbitrap instruments is another important factor that influences sensitivity and reproducibility of SESI-MS. Instead of acquiring the full mass-to-charge ratio (m/z) range, acquisition of consecutive m/z windows to minimize the ion competition effect allows the detection of more features. m/z window ranges are optimized to fill the C-trap either with an equal number of features or an equal cumulative intensity per window. Considering a balance between maximizing scanning speed and minimizing ion competition, splitting the m/z = 50-500 range into 4 windows is selected for measuring human breath and bacterial culture samples on SESI-Orbitrap MS, corresponding to a duty cycle of 2.3 s at a resolution of 140000. In a small cohort of human subjects, the proposed splitting into 4 windows allows three times more features to be detected compared to the classical full m/z range method.

systems biology↗

bioRxiv2020

Potent synthetic nanobodies against SARS-CoV-2 and molecular basis for neutralization

SARS-CoV-2, the causative agent of COVID-191, recognizes host cells by attaching its receptor-binding domain (RBD) to the host receptor ACE22-7. Neutralizing antibodies that block RBD-ACE2 interaction have been a major focus for therapeutic development8-18. Llama-derived single-domain antibodies (nanobodies, [~]15 kDa) offer advantages including ease of production and possibility for direct delivery to the lungs by nebulization19, which are attractive features for bio-drugs against the global respiratory disease. Here, we generated 99 synthetic nanobodies (sybodies) by in vitro selection using three libraries. The best sybody, MR3 bound to RBD with high affinity (KD = 1.0 nM) and showed high neutralization activity against SARS-CoV-2 pseudoviruses (IC50 = 0.40 g mL-1). Structural, biochemical, and biological characterization of sybodies suggest a common neutralizing mechanism, in which the RBD-ACE2 interaction is competitively inhibited by sybodies. Various forms of sybodies with improved potency were generated by structure-based design, biparatopic construction, and divalent engineering. Among these, a divalent MR3 conjugated with the albumin-binding domain for prolonged half-life displayed highest potency (IC50 = 12 ng mL-1) and protected mice from live SARS-CoV-2 challenge. Our results pave the way to the development of therapeutic nanobodies against COVID-19 and present a strategy for rapid responses for future outbreaks.

biochemistry↗

bioRxiv2020

Potent human neutralizing antibodies elicited by SARS-CoV-2 infection

The pandemic caused by emerging coronavirus SARS-CoV-2 presents a serious global public health emergency in urgent need of prophylactic and therapeutic interventions. SARS-CoV-2 cellular entry depends on binding between the viral Spike protein receptor-binding domain (RBD) and the angiotensin converting enzyme 2 (ACE2) target cell receptor. Here, we report on the isolation and characterization of 206 RBD-specific monoclonal antibodies (mAbs) derived from single B cells of eight SARS-CoV-2 infected individuals. These mAbs come from diverse families of antibody heavy and light chains without apparent enrichment for particular families in the repertoire. In samples from one patient selected for further analyses, we found coexistence of germline and germline divergent clones. Both clone types demonstrated impressive binding and neutralizing activity against pseudovirus and live SARS-CoV-2. However, the antibody neutralizing potency is determined by competition with ACE2 receptor for RBD binding. Surprisingly, none of the SARS-CoV-2 antibodies nor the infected plasma cross-reacted with RBDs from either SARS-CoV or MERS-CoV although substantial plasma cross-reactivity to the trimeric Spike proteins from SARS-CoV and MERS-CoV was found. These results suggest that antibody response to RBDs is viral species-specific while that cross-recognition target regions outside the RBD. The specificity and neutralizing characteristics of this plasma cross-reactivity requires further investigation. Nevertheless, the diverse and potent neutralizing antibodies identified here are promising candidates for prophylactic and therapeutic SARS-CoV-2 interventions.

immunology↗

bioRxiv2020

Optimized sgRNA design by deep learning to balance the off-target effects and on-target activity of CRISPR/Cas9

The CRISPR/Cas9 system derived from bacteria especially Streptococcus pyogenes (SpyCas9) is currently considered as the most advanced tool used for numerous areas of biological study in which it is useful to target or modify specific DNA sequences. However, low on-target cleavage efficiency and off-target effects impede its wide application. Several different sgRNA design tools for SpyCas9 by using various algorithms have been developed, including linear regression model, support vector machine (SVM) model and convolutional neuron network model. While the deep insight into the sgRNA features contributing for both on-target activity and off-target still remains to be determined. Here, with public large-scale CRISPR screen data, we evaluated contribution of different features influence sgRNA activity and off-target effects, and developed models for sgRNA off-target evaluation and on-target activity prediction. In addition, we combined both activity and off-target prediction models and packaged them as an online sgRNA design tool, OPT-sgRNA.

bioinformatics↗

bioRxiv2020

Crystal structure of the 2019-nCoV spike receptor-binding domain bound with the ACE2 receptor

A novel and highly pathogenic coronavirus (2019-nCoV) has caused an outbreak in Wuhan city, Hubei province of China since December 2019, and soon spread nationwide and spilled over to other countries around the world. To better understand the initial step of infection at atomic-level, we determined the crystal structure of the 2019-nCoV spike receptor-binding domain (RBD) bound with the cell receptor ACE2 at 2.45 [A] resolution. The overall ACE2-binding mode of the 2019-nCoV RBD is nearly identical to that of the SARS-CoV RBD, which also utilizes ACE2 as the cell receptor. Structural analysis identified residues in 2019-nCoV RBD critical for ACE2 binding, and majority of which are either highly conserved or shared similar side chain properties with those in the SARS-CoV RBD. Such similarity in structure and sequence strongly argue for a convergent evolution between 2019-nCoV and SARS-CoV RBD for improved binding to ACE2 despite of being segregated in different genetic lineages in the betacoronavirus genus. The epitopes of two SARS-CoV antibodies targeting the RBD are also analyzed with the 2019-nCoV RBD, providing insights into future identification of cross-reactive antibodies.

biophysics↗

bioRxiv2019

Mitochondrial translation and dynamics synergistically extend lifespan in C. elegans through HLH-30

Mitochondrial form and function, such as translation, are closely interlinked in homeostasis and aging. Inhibiting mitochondrial translation is known to increase lifespan in C. elegans, which is accompanied by a fragmented mitochondrial network. However, the causality between mitochondrial translation and morphology in longevity remains uncharacterized. Here, we show in C. elegans that disrupting mitochondrial network homeostasis by either blocking fission or fusion synergizes with the reduced mitochondrial translation to substantially prolong lifespan and stimulate stress response such as the mitochondrial unfolded protein response, UPRMT. Conversely, immobilizing the mitochondrial network through a simultaneous abrogation of fission and fusion reverses the lifespan increase induced by mitochondrial translation inhibition. Furthermore, we find that the synergistic effect of inhibiting both mitochondrial translation and dynamics on lifespan, despite stimulating UPRMT, does not require it. Instead, this lifespan-extending synergy is exclusively dependent on the lysosome biogenesis and autophagy transcription factor HLH-30/TFEB. Altogether, our study reveals the mechanistic connections between mitochondrial translation and dynamics in regulating longevity. SUMMARYMitochondrial form and function are intimately intertwined. Liu et al. find the synergistic effect of inhibiting both mitochondrial translation and dynamics on lifespan. This synergy is dependent on the induction of lysosome biogenesis through the nuclear localization of HLH-30.

cell biology↗