Biology subjects

Cao, M.

Publications and source records attributed to Cao, M..

At least 55 records · Page 3Linked to original sources

bioRxiv2023

Mapping the shared and unique structural asymmetry abnormalities of young children with autism and developmental delay/intellectual disability with normative models and their multimodal cascade

To understand the neural mechanism of autism spectrum disorder (ASD) concurrent with developmental delay/intellectual disability (DD/ID), it is essential to comprehensively take genetic, brain, and behavioural measurements as a whole and focus on subjects at early age. However, such research is still lacking. Here, using the sMRI data of 1030 children under 8 years old, we employed developmental normative models to explore the atypical development of gray matter volume (GMV) asymmetry in individuals with ASD without DD/ID, ASD with DD/ID and DD/ID, and their associations with neurophysiological measures and transcription profiles. By computing the individual deviations from typical controls, we observed an ASD-specific abnormal GMV laterality pattern that was more rightwards in the inferior parietal cortex and precentral cortex and noted abnormal within-group heterogeneity in the temporal pole. Specifically, ASD with DD/ID children exhibited more regional abnormalities; ASD without DD/ID children showed higher within-group variability; while children with DD/ID showed no significant abnormalities. However, there were no significant differences among the three groups. The GMV laterality of ASD without DD/ID children was associated with ASD symptoms, whereas that of ASD with DD/ID children was associated with both ASD symptoms and verbal IQ. Last, the GMV laterality of the ASD with DD/ID, ASD without DD/ID, and DD/ID groups was associated with shared and unique gene expression profiles, but the associations of the latter two groups with intellectual genes showed opposite effects. Our findings illustrated the atypical development of regional structural lateralization in autistic children, which is associated with upstream genes and downstream behavioural performance. The differences and similarity between ASD and DD/ID additionally improve our standing to the neural mechanism of neurodevelopmental disorders comorbidity.

neuroscience↗

bioRxiv2023

Strong cascading impacts of micropollutants on planktonic food web in urban river

Urban rivers rely on intricate multitrophic interactions in food webs, which are vital for ecological functions. Human-induced pollutant discharge, notably micropollutants, poses a threat to these interactions. To study the impact of micropollutants on the microbial food web, we sampled downstream areas of the Jiulong Rivers north tributary (lower urbanization, [~]25% built land) and west tributary (higher urbanization, [~]65% built land) for eleven consecutive days in both dry and wet seasons in Fujian, China. We constructed a conceptualized planktonic food web model by employing DNA metabarcoding targeting bacteria, micro-eukaryotes (algae and protozoa), and microzooplankton. Our results revealed that the more urbanized west tributary exhibited significantly higher micropollutant concentrations. Structural equation modeling (SEM) incorporating micropollutants and all food web elements indicated a significantly stronger impact of micropollutants on the planktonic food web in the west tributary than in the north tributary. Micropollutants exhibited both direct and indirect (cascade) effects on high trophic levels (protozoa and microzooplankton), with algal communities mediating the cascade effects instead of bacterial communities, likely due to the increased eutrophication in the urbanized tributary. Overall, our study underscores the potential ecological disruptions caused by micropollutants in shaping planktonic food web interactions in urban rivers. SynopsisUrban rivers face ecological threats from micropollutants. This study shows elevated micropollutants significantly affected the planktonic food webs. Algal, rather than bacterial, food web pathway mediated micropollutants cascading effects on high trophic levels, emphasizing micropollutant-induced disruptions in urban rivers.

ecology↗

bioRxiv2023

Dynamics of Brain Lateralization and Genetic Underpinnings during Chinese Natural Speech Processing: Preferential Occurrence of Logic-Related Patterns in Males and Emotion-Related Patterns in Females

Though language is considered unique to humans with left dominant lateralization in the brain, the dynamic nature of the interplay between hemispheres during language processing remains largely unknown. Here, we investigated whole-brain functional dynamic lateralization patterns during Chinese language processing and potential sex disparities using functional MRI data of 20 subjects listening to narrative stories in a 7T MRI scanner. Our findings revealed two distinct dynamic lateralization states, with regions of the language system consistently showing the left lateralization but reversed lateralization for other regions. These two states, characterized by higher-level functioning regions exhibiting left- or right-lateralization, corresponded to the processing of rational and emotional contents, respectively. We observed pronounced inclinations towards the former state in males and the latter state in females, especially during the processing of rational contents. Finally, genetic analyses revealed that the sex differences in lateralization states were potentially influenced by sex hormones.

neuroscience↗

bioRxiv2023

CRISPR-Cas9 genome editing in Steinernema entomopathogenic nematodes

Molecular tool development in traditionally non-tractable animals opens new avenues to study gene functions in the relevant ecological context. Entomopathogenic nematodes (EPN) Steinernema and their symbiotic bacteria of Xenorhabdus spp are a valuable experimental system in the laboratory and are applicable in the field to promote agricultural productivity. The infective juvenile (IJ) stage of the nematode packages mutualistic symbiotic bacteria in the intestinal pocket and invades insects that are agricultural pests. The lack of consistent and heritable genetics tools in EPN targeted mutagenesis severely restricted the study of molecular mechanisms underlying both parasitic and mutualistic interactions. Here, I report a protocol for CRISPR-Cas9 based genome-editing that is successful in two EPN species, S. carpocapsae and S. hermaphroditum. I adapted a gonadal microinjection technique in S. carpocapsae, which created on-target modifications of a homologue Sc-dpy-10 (cuticular collagen) by homology-directed repair. A similar delivery approach was used to introduce various alleles in S. hermaphroditum including Sh-dpy-10 and Sh-unc-22 (a muscle gene), resulting in visible and heritable phenotypes of dumpy and twitching, respectively. Using conditionally dominant alleles of Sh-unc-22 as a co-CRISPR marker, I successfully modified a second locus encoding Sh-Daf-22 (a homologue of human sterol carrier protein SCPx), predicted to function as a core enzyme in the biosynthesis of nematode pheromone that is required for IJ development. As a proof of concept, Sh-daf-22 null mutant showed IJ developmental defects in vivo (in insecta). This research demonstrates that Steinernema spp are highly tractable for targeted mutagenesis and has great potential in the study of gene functions under controlled laboratory conditions within the relevant context of its ecological niche.

genetics↗

bioRxiv2023

Abnormal white matter development during early childhood in autism and developmental disability

The abnormal maturation of white matter microstructure in autism spectrum disorder (ASD) compared with typical developing (TD) and developmental delay/intellectual disorder (DD/ID) during early childhood and their associations with clinical implications remain unclear. Here, we characterized spatial and temporal patterns of white matter development in 364 children (including ASD, DD/ID and TD) under 8 years old using neurite orientation dispersion and density imaging. Using neurite density index (NDI), we consistently detected three white matter clusters across all the groups through clustering analysis, indicating the conserved spatial layout in atypical development. Further, three developmental stages with successively lower growth rates were identified in ASD, similar to those in TD but delayed overall. Meanwhile, DD/ID children showed the slowest growth rates and lacked staging features. Finally, for ASD children, the NDI was correlated with cognitive impairments at the fast developmental stage but associated with social deficits during the moderate-to-slow stage.

neuroscience↗

bioRxiv2023

In vivo expansion of gene-targeted hepatocytes through transient inhibition of an essential gene

Homology Directed Repair (HDR)-based genome editing is an approach that could permanently correct a broad range of genetic diseases. However, its utility is limited by inefficient and imprecise DNA repair mechanisms in terminally differentiated tissues. Here, we tested "Repair Drive", a novel method for improving targeted gene insertion in the liver by selectively expanding correctly repaired hepatocytes in vivo. Our system consists of transient conditioning of the liver by knocking down an essential gene, and delivery of an untargetable version of the essential gene in cis with a therapeutic transgene. We show that Repair Drive dramatically increases the percentage of correctly targeted hepatocytes, up to 25%. This resulted in a five-fold increased expression of a therapeutic transgene. Repair Drive was well-tolerated and did not induce toxicity or tumorigenesis in long term follow up. This approach will broaden the range of liver diseases that can be treated with somatic genome editing.

genetics↗

bioRxiv2023

Proguanil and chlorhexidine augment the antibacterial activities of clarithromycin and rifampicin against Acinetobacter baumannii

The emergence of Acinetobacter baumannii infections as a significant healthcare concern in hospital settings, coupled with their association with poorer clinical outcomes, has prompted extensive investigation into novel therapeutic agents and innovative treatment strategies. Proguanil and chlorhexidine, both categorized as biguanide compounds, have displayed clinical efficacy as antimalarial and topical antibacterial agents, respectively. In this study, we conducted an investigation to assess the effectiveness of combining proguanil and chlorhexidine with clarithromycin or rifampicin against both laboratory strains and clinical isolates of A. baumannii. The combination therapy demonstrated rapid bactericidal activity against planktonic multidrug-resistant A. baumannii, exhibiting efficacy in eradicating mature biofilms and impeding the development of antibiotic resistance in vitro. Additionally, when administered in conjunction with clarithromycin or rifampicin, proguanil enhanced the survival rate of mice afflicted with intraperitoneal A. baumannii infections, and chlorhexidine expedited wound healing in mice with skin infections. These findings are likely attributable to the disruption of A. baumannii cell membrane integrity by proguanil and chlorhexidine, resulting in heightened membrane permeability and enhanced intracellular accumulation of clarithromycin and rifampicin. Overall, this study underscores the potential of employing proguanil and chlorhexidine in combination with specific antibiotics to effectively combat A. baumannii infections and improve treatment outcomes in clinically challenging scenarios. IMPORTANCEA. baumannii has emerged as a globally significant nosocomial pathogen due to its remarkable ability to acquire antibiotic resistance and develop biofilms on both biotic and abiotic surfaces. Recent research has demonstrated that the antidiabetic drug metformin has a potentiation effect on doxycycline and minocycline against certain multidrug-resistant bacterial pathogens, suggesting the potential of this biguanide agent as a novel tetracyclines adjuvant. In this study, we provide evidence showing that the combination of proguanil and chlorhexidine with clarithromycin or rifampicin exhibits rapid bactericidal activities against both planktonic cells and mature biofilms of A. baumannii, the capacity to inhibit the development of antibiotic resistance and improvement of the treatment outcomes in A. baumannii-infected mice. Given the advantages of repurposing non-antibiotic drugs as antibiotic adjuvants, proguanil and chlorhexidine show promise as adjuvants of specific antibiotics in combating clinically significant pathogenic A. baumannii.

microbiology↗

bioRxiv2023

Latitudinal scaling of aggregation with abundance and its consequences for coexistence in species rich forests

The search for simple principles underlying the complex spatial structure and dynamics of plant communities is a long-standing challenge in ecology1-6. In particular, the relationship between the spatial distribution of plants and species coexistence is challenging to resolve in species-rich communities7-9. Analysing the spatial patterns of tree species in 21 large forest plots, we find that rare species tend to be more spatially aggregated than common species, and a latitudinal gradient in the strength of this negative correlations that increases from tropical to temperate forests. Our analysis suggests that latitudinal gradients in animal seed dispersal10 and mycorrhizal associations11,12,13 may jointly generate this intriguing pattern. To assess the consequences of negative aggregation-abundance correlations for species coexistence, we present here a framework to incorporate the observed spatial patterns into population models8 along with an analytical solution for the local extinction risk14 of species invading from low abundances in dependence of spatial structure, demographic parameters, and immigration. For example, the stabilizing effect of the observed spatial patterns reduced the local extinction risk of species when rare almost by a factor of two. Our approach opens up new avenues for integrating observed spatial patterns into mathematical theory, and our findings demonstrate that spatial patterns, such as species aggregation and segregation, can contribute substantially to coexistence in species-rich communities. This underscores the need to understand the interactions between multiple ecological processes and spatial patterns in greater detail.

ecology↗

bioRxiv2023

Comparative transcriptomics reveals divergence in pathogen response gene families amongst twenty forest tree species

Forest trees provide critical ecosystem services for humanity that are under threat due to ongoing global change. Measuring and characterizing genetic diversity is key to understanding adaptive potential and developing strategies to mitigate negative consequences arising from climate change. In the area of forest genetic diversity, genetic divergence caused by large-scale changes at the chromosomal level has been largely understudied. In this study, we used the RNA-seq data of twenty co-occurring forest trees species from genera including Acer, Alnus, Amelanchier, Betula, Cornus, Corylus, Dirca, Fraxinus, Ostrya, Populus, Prunus, Quercus, Ribes, Tilia, and Ulmus sampled from Upper Peninsula of Michigan. These data were used to infer the origin and maintenance of gene family variation, species divergence time, as well as gene family expansion and contraction. We identified a signal of common whole genome duplication events shared by core eudicots. We also found rapid evolution, namely fast expansion or fast contraction of gene families, in plant-pathogen interaction genes amongst the studied diploid species. Finally, the results lay the foundation for further research on the genetic diversity and adaptive capacity of forest trees, which will inform forest management and conservation policies.

plant biology↗

bioRxiv2023

Decomposing intraspecific phenotypic variation: implications for species and functional diversity

Researchers have a history of seeking explanation for and understanding of diversity patterns. High-dimensional trait-based trade-offs have been hypothesized as important for maintaining species and functional diversity. These relationships have primarily been investigated at the community-level, despite the importance of intraspecific variation to diversity maintenance. The goal of this research is to determine if alternative phenotypes are present within species and the impacts of this on diversity in a tropical seedling community in China. We ask 1) do trait combinations found across species, at the community-level, also exist within species?; 2) how consistent are alternative phenotypes and their contributions to growth across species?; and 3) how do findings align with species co-occurrence patterns? We model species-specific growth with individual-level trait measurements, environmental data, and their interactions, allowing for identification of intraspecific alternative phenotypes and quantification of the contribution of variables to growth. We find that two of three species have intraspecific alternative phenotypes. Specifically, individuals within these species share a trait combination, but how they combine the traits differs depending on the type and level of soil nutrients. Furthermore, we find that similarity among species in alternative phenotypes and variables that contribute most to growth may lead to negative spatial co-occurrence of species. Overall, we find that multiple traits or interactions between traits and the environment drive species-specific strategies for growth. These results highlight how individuals are highly variable, with phenotypically different individuals having similar growth performance, and suggest how high species and functional diversity can be maintained in communities.

ecology↗

bioRxiv2022

Latitude influences stability via stabilizing mechanisms in naturally-assembled forest ecosystems at different spatial grains

Ecosystem stability reveals how ecosystems respond to global change over time. Yet, the focus of past research on small spatial grains and extents overlooks scale dependence and how broad-scale environmental gradients shape stability. Here, we use forest inventory data covering a broad latitudinal gradient from the temperate to the tropical zone to examine cross-scale variation in stability of aboveground biomass and underlying stabilizing mechanisms. While stability did not shift systematically with latitude at either spatial grain, we found evidence that species asynchrony increased towards the tropics at the small spatial grain while species stability decreased at both spatial grains. Moreover, latitude stabilized forest communities via its effects on both stabilizing mechanisms, which compensated for the weak and destabilizing effects of species richness. Yet, the trade-off in the relative importance of species stability and species asynchrony for stability was not mediated by latitude, suggesting that context-dependent factors - to a greater extent than macroecological ones - underlie large-scale patterns of stability. Our results highlight the crucial role of species asynchrony and species stability in determining ecosystem stability across broad-scale environmental gradients, suggesting that conserving biodiversity alone may not be sufficient for stabilizing naturally-assembled forest ecosystems.

ecology↗

bioRxiv2022

A Peroxiredoxin-P38 MAPK scaffold increases MAPK activity by MAP3K-independent mechanisms

Peroxiredoxins (Prdx) utilize reversibly oxidized cysteine residues to reduce peroxides but also to promote H2O2 signal transduction, including H2O2-induced activation of P38 MAPK. Prdx form H2O2-induced disulfide complexes with many proteins, including multiple kinases involved in P38 MAPK signaling. Here we show that a genetically-encoded fusion between Prdx and the P38 MAPK is sufficient to hyperactivate the kinase in yeast and human cells by a mechanism that does not require the H2O2-sensing cysteine of the Prdx. In yeast, we demonstrate that a P38-Prdx fusion protein compensates for the loss of a scaffold protein and upstream MAP3K kinase activity, driving entry into mitosis. Based on our findings, we propose that the H2O2-induced formation of Prdx-MAPK disulfide complexes provides a scaffold and signaling platform for MAPKK-MAPK signaling. The demonstration that formation of a complex with a Prdx can be sufficient to modify the activity of a kinase has broad implications for peroxide-based signal transduction in eukaryotes. HighlightsP38-Prdx complexes increase P38 (Sty1/MAPK14) phosphorylation in yeast and human cells The S. pombe Prdx promotes transient thioredoxin-mediated oxidation of a MAPK tyrosine phosphatase P38-Prdx complexes increase P38(Sty1) activity by phosphatase and MAP3K-independent mechanisms P38-Prdx complexes increase the stability and phosphorylation of the S. pombe P38 MAPKK (Wis1) Non-canonical, H2O2-induced autophosphorylation contributes to activation of the Wis1 MAPKK

biochemistry↗

bioRxiv2022

Ubiquitination steers SRF3 plasma membrane nano-organization to specify signaling outputs

Organisms cope with myriads of competing and conflicting environmental signals. These signals are often perceived by cell surface receptor kinases to mount appropriate adaptive responses. However, it is not well understood by which mechanism single receptor kinases can transduce different signals. The plant receptor kinase SRF3 transduces low iron and bacteria-derived signals. We found that upon these signals, ubiquitinated SRF3 is recognized by clathrin-mediated endocytosis for vacuolar targeting. Live super resolution microscopy revealed that cell surface SRF3 is present in a fast diffusible fraction, which is sustained by ubiquitination, and that non-ubiquitinated SRF3 is present in immobile nanodomains. Ubiquitination-mediated degradation of SRF3 is required for signaling only under low iron but not upon flg22 perception. Flg22-triggered SRF3 phosphorylation leads to SRF3 accumulation in the immobile fraction in which degradation is restricted, thereby preventing low iron signaling. We therefore propose that ubiquitination-dependent plasma membrane nano-organization of SRF3 specifies its signal transduction pathways.

plant biology↗

bioRxiv2022

Factors determining success of the chronically instrumented unanesthetized fetal sheep model of human development: a retrospective cohort study

AimChronically instrumented non-anesthetized fetal sheep (CINAFS) have been the mainstay model of human fetal development for 60 years. As a large "two for one" animal model, with instrumentation of the ewe and her fetus, the model poses challenges to implement de novo and to maintain overtime at the highest standards of operating procedures to ensure its ongoing performance. A common, yet conventionally underreported issue researchers face is the rate of animal loss. Here, we investigate what determines the success of the pregnant sheep model. MethodsWe conducted a retrospective cohort study consisting of 82 experiments spanning the course of six years. Our team identified ten variables that we anticipated were likely to influence the experimental outcome, such as the time of year, animal size, and surgical complexity. ResultsThe single variable identified in this study as determining the successful outcome of the experiments is the experience level of the team. ConclusionThe CINAFS model offers enormous potential to further our understanding of human fetal development and to create interventional technologies. However, to improve the outcomes of CINAFS models, improved communication and training are needed. We discuss the implications of our findings for the successful implementation of this challenging yet scientifically advantageous animal model of human physiology. Key pointsO_LIThe fetal sheep model closely mirrors the physiology of human fetal development C_LIO_LIIn addition to its high translational potential, this model is known to have some generally not reported rate of experimental failure C_LIO_LIWe show that factors such as animal characteristics & surgical complexity do not influence the experimental outcomes C_LIO_LIInstead, the key factor in model experimental success is the level of the research teams experience C_LIO_LIThe key factors to improve the animal model outcomes are an intra- and inter-team communication C_LI

physiology↗

bioRxiv2022

Synergistic effect of mutations in the Parkinson's disease-linked proteins synaptojanin 1 and auxilin

Parkinsons disease (PD) is a neurodegenerative disorder characterized by defective dopaminergic (DAergic) input to the striatum. Mutations in two genes encoding synaptically enriched clathrin-uncoating factors, synaptojanin 1 (SJ1) and auxilin, have been implicated in atypical Parkinsonism. SJ1 knock-in (SJ1-KIRQ) mice carrying a disease-linked mutation display neurological manifestations reminiscent of Parkinsonism. Here we report that auxilin knockout (Aux-KO) mice display dystrophic changes of a subset of nigrostriatal DAergic terminals similar to those of SJ1-KIRQ mice. Furthermore, Aux-KO/SJ1-KIRQ double mutant mice have shorter lifespan and more severe synaptic defects than single mutant mice. These include increase in dystrophic striatal nerve terminals positive for DAergic markers and for the PD risk protein SV2C, as well as adaptive changes in striatal interneurons. The synergistic effect of the two mutations demonstrates a special lability of DAergic neurons to defects in clathrin uncoating, with implications for PD pathogenesis in at least some forms of this condition.

neuroscience↗

bioRxiv2022

Metabolic Engineering of Oleaginous Yeast Rhodotorula toruloides for Overproduction of Triacetic Acid Lactone

The plant-sourced polyketide triacetic acid lactone (TAL) has been recognized as a promising platform chemical for the biorefinery industry. However, its practical application was rather limited due to low natural abundance and inefficient cell factories for biosynthesis. Here we report the metabolic engineering of oleaginous yeast Rhodotorula toruloides for TAL overproduction. We first introduced a 2-pyrone synthase gene from Gerbera hybrida (GhPS) into R. toruloides and investigated the effects of different carbon sources on TAL production. We then systematically employed a variety of metabolic engineering strategies to increase the flux of acetyl-CoA by enhancing its biosynthetic pathways and disrupting its competing pathways. We found that overexpression of citrate lyase (ACL1) improved TAL production by 45% compared to the GhPS overexpressing strain, and additional overexpression of acetyl-CoA carboxylase (ACC1) further increased TAL production by 29%. Finally, we characterized the resulting strain I12-ACL1-ACC1 using fed-batch bioreactor fermentation in glucose or oilcane juice medium with acetate supplementation and achieved a titer of 28 g/L or 23 g/L TAL, respectively. This study demonstrates that R. toruloides is a promising host for production of TAL and other acetyl-CoA-derived polyketides from low-cost carbon sources. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=57 SRC="FIGDIR/small/481788v1_ufig1.gif" ALT="Figure 1"> View larger version (12K): org.highwire.dtl.DTLVardef@32eb52org.highwire.dtl.DTLVardef@f786dborg.highwire.dtl.DTLVardef@b6d3f5org.highwire.dtl.DTLVardef@115aa67_HPS_FORMAT_FIGEXP M_FIG C_FIG Triacetic acid lactone (TAL) is a promising platform chemical. Cao et al. overexpressed 2-pyrone synthase in oleaginous yeast Rhodotorula toruloides to produce TAL. They systematically evaluated various metabolic gene targets to increase acetyl-CoA and malonyl-CoA levels for TAL production and found that overexpression of both ACL1 and ACC1 led to 28 g/L or 23 g/L of TAL from glucose or oilcane juice with acetate supplementation, respectively, in fed-batch fermentation.

synthetic biology↗

bioRxiv2022

Identification of a small molecule, Mebendazole, as a novel ethylene signaling activator reveals a role of ethylene signaling on the regulation of lateral root angles

The lateral root angle or gravitropic set-point angle (GSA) is an important trait for root system architecture (RSA) that determines the radial expansion of the root system. The GSA therefore plays a crucial role for the ability of plants to access nutrients and water in the soil. Despite its importance, only few regulatory pathways and mechanisms that determine GSA are known, and these mostly relate to auxin and cytokinin pathways. Here, we report the identification of a small molecule, Mebendazole (MBZ) that modulates GSA in Arabidopsis thaliana roots and acts via the activation of ethylene signaling. We uncover that MBZ directly acts on the serine/threonine protein kinase CTR1, which is a negative regulator of ethylene signaling. Our study not only reveals that the ethylene signaling pathway is essential for GSA regulation, but it also identifies a small molecular modulator of RSA and the first small molecule that acts downstream of ethylene receptors and that directly activates ethylene signaling. In briefHe et al. identify a small molecule that regulates lateral root angle. They show that the compound increases lateral root angle by inhibiting CTR1 kinase activity, which in turn activates ethylene signaling. Therefore, they uncover that the ethylene pathway is involved in lateral root angle regulation. HighlightsO_LIMBZ increases lateral root angle C_LIO_LIMBZ regulates lateral root angle by activating ethylene signaling C_LIO_LIMBZ inhibits CTR1 kinase activity C_LIO_LIThe ethylene pathway is involved in lateral root angle regulation C_LI

plant biology↗

bioRxiv2022

Diverse innate immune factors protect yeast from lethal viral pathogenesis

In recent years, newly characterized anti-viral systems have proven to be remarkably conserved from bacteria to mammals, demonstrating that unique insights into these systems can be gained by studying microbial organisms. Despite the enthusiasm generated by these findings, the key microbial model organism Saccharomyces cerevisiae (budding yeast) has been minimally exploited for studies of viral defense, primarily because it is not infected with exogenously transmitted viruses. However, most yeast strains are infected with an endogenous double stranded RNA (dsRNA) virus called L-A, and previous studies identified conserved antiviral systems that attenuate L-A replication. Although these systems do not completely eradicate L-A, we show here that they do prevent proteostatic stress and lethality caused by L-A over-proliferation. Exploiting this new finding, we demonstrate that the genetic screening methods available in yeast can be used to identify additional conserved antiviral systems. Using these approaches, we discovered antiviral functions for the yeast homologs of polyA-binding protein (PABPC1) and the La-domain containing protein Larp1, which are both involved in viral innate immunity in humans. We also identified new antiviral functions for the RNA exonucleases REX2 and MYG1, both of which have distinct but poorly characterized human and bacterial homologs. These findings highlight the potential of yeast as a powerful model system for the discovery and characterization of conserved antiviral systems. Significance StatementThe budding yeast Saccharomyces cerevisiae has been minimally exploited for investigation of host-virus interactions despite its chronic infection with a double-stranded RNA virus called L-A. Controverting its presumed harmless nature, we show here that L-A causes pathogenesis in cells lacking parallel-acting viral attenuation pathways. Taking advantage of the genetic tools available in budding yeast, we identify several highly conserved proteins to play a role in antiviral defense. Some of these have been recently identified in humans to be involved in viral innate immunity, thus highlighting the potential of budding yeast as a model organism to identify and investigate new antiviral systems.

microbiology↗