Biology subjects

Ding, Q.

Publications and source records attributed to Ding, Q..

At least 19 recordsLinked to original sources

bioRxiv2026

Coronavirus nucleocapsid proteins differentially antagonize RIG-I-like receptor signaling to shape pathogenicity

Coronaviruses cause human infections with divergent clinical outcomes. Viral proteins likely play important roles in the severity of human diseases but are poorly defined. In this study, we discovered that viral nucleocapsid (N) proteins from various human coronaviruses have distinct abilities to antagonize human innate immune responses. N proteins from more pathogenic coronaviruses, such as SARS-CoV and SARS-CoV-2, have more potent activities specifically against human RIG-I-like receptor (RLR) activation than less pathogenic coronaviruses including OC43 and HKU1. Mechanistically, the SARS-CoV-2 N protein interacts with RLR pathway viral RNA sensors MDA5 and RIG-I and inhibits their interaction with MAVS. The CTD of SARS-CoV-2 N protein is an important region for RLR antagonism. Consequently, N proteins from more pathogenic coronaviruses promote viral replication more effectively than N proteins from less pathogenic coronaviruses. Blocking N protein function may be a promising antiviral strategy.

microbiology↗

bioRxiv2026

The cellular and genetic basis of inflorescence divergence between maize and teosinte

The domestication of maize from teosinte involved dramatic remodeling of the ear, yet the cellular and genetic bases of this transformation remain unclear. Here, we generate a single-nucleus and spatial transcriptome atlas of developing maize and teosinte ears. Comparative analysis reveals divergence in cob-associated cell types, with enhanced cytokinin signaling and reduced growth-inhibitory signals collectively driving cob thickening and enlargement in maize. We further demonstrate that domestication expanded the spatial expression domain of key transcription factors in maize meristem cells, enhancing the potential for increasing kernel number. Additionally, we verified a major domestication gene, ZmSPD1, in which two nonsynonymous SNPs differentiate maize from teosinte and alter jasmonic acid (JA) levels in the ear, thereby suppressing spikelet abortion to effectively double kernel production. These findings provide a cell-resolved mechanistic framework for how cob architecture and kernel number were shaped during maize domestication, offering new insights into the formation of key agronomic traits.

plant biology↗

bioRxiv2026

Bacillus velezensis-derived muropeptide promotes growth of zebrafish via NOD2-mediated induction of IGF1 signaling

The role of gut microbiome in regulating vertebrate metabolism has been well-recognized. However, the effects of gut bacteria on growth have been less studied. Bacillus is a prevalent genus in the gut microbiota of human and animals. In this study, the effect of gut-derived Bacillus velezensis T23 on growth was investigated in zebrafish. B. velezensis T23 improved the growth of zebrafish and promoted IGF1 production in the liver and muscle, with a concomitant activation of the AKT/mTOR signaling pathway. The growth-promoting effect of B. velezensis T23 was not dependent on lipopeptides and polyketides. Cell wall peptidoglycan isolated from B. velezensis T23, as well as muramyl dipeptide (MDP), was sufficient to stimulate IGF1 signaling and growth. Further, the effect of B. velezensis T23 on growth and IGF1 production was abrogated in nod2-/- zebrafish, confirming that B. velezensis T23 promoted growth via MDP-NOD2 signaling. Gut transcriptomic analysis indicated that B. velezensis T23 promoted renewal and differentiation of intestinal cells, suggesting an involvement of gut-liver axis in the effect of B. velezensis T23 on systemic IGF1 production. Together, our results revealed an effect of gut Bacillus-derived muropeptide on growth via NOD2-IGF1 signaling, and provided novel mechanistic insights in the beneficial effect of Bacillus spp. as probiotics.

microbiology↗

bioRxiv2026

Endothelial MRG15 Is a Mechanosensitive Suppressor of Atherosclerosis

Disturbed blood flow induces early endothelial inflammation in atherosclerosis, yet the precise mechanisms of endothelial sensing of disturbed flow remain incompletely understood. In this study, we integrated proteomic profiling of human endothelial cells (ECs) subjected to disturbed flow with coronary artery disease risk related genes from large-scale genome-wide association studies (GWAS). We identified mortality factor 4-like protein 1 (MORF4L1, also called MRG15) as a critical modulator in the pathogenesis of atherosclerosis induced by disturbed flow. We show that the expression of MRG15 is markedly reduced in ECs of human aortic atherosclerotic plaques, as well as in ECs exposed to disturbed flow in mouse carotid artery and in cultured human umbilical vein endothelial cells (HUVECs). Endothelial-specific deletion of Mrg15 significantly worsened, while its overexpression attenuated endothelial inflammation and atherosclerotic lesions in turbulent blood flow- or Western diet-induced mouse atherosclerosis model. Single-cell transcriptomics showed that Mrg15 deficiency increased endothelial inflammation and intercellular adhesion molecule 1 (Icam1) expression, and enhanced integrin-mediated adhesion pathways. Mechanistically, MRG15 facilitated the recruitment of enhancer of zeste homolog 2 (EZH2) to maintain repressive histone H3 lysine 27 trimethylation (H3K27me3) marks on the promoters of ICAM1 and integrin subunit alpha 5 (ITGA5). Disturbed blood flow rapidly led to an elevation of protein neddylation, which subsequently induced neddylation-dependent degradation of MRG15 within endothelial cells. This degradation of MRG15 alleviated the transcriptional repression of ICAM1 and ITGA5, thereby enhancing monocyte adhesion to ECs. These findings highlight endothelial MRG15 as a mechanosensitive suppressor of atherosclerosis induced by disturbed flow. Consequently, MRG15 emerges as a promising novel therapeutic target for atherosclerosis.

molecular biology↗

bioRxiv2026

When CycloneSEQ meets Oxford Nanopore Technologies: a performance comparison of contemporary nanopore DNA sequencing platforms

Nanopore sequencing enables direct analysis of native DNA modifications, but these modifications can also introduce systematic basecalling errors. Here, we investigated how bacterial DNA methylation contributes to nanopore substitution errors using matched native whole-genome sequencing (WGS) and methylation-depleted whole-genome amplification (WGA) datasets from six bacterial species across CycloneSEQ (CS) and Oxford Nanopore Technologies platforms (ONT). Adenine-to-guanine (A2G) and guanine-to-adenine (G2A) substitutions were consistently enriched across species, nanopore platforms, sequencing configurations, and basecalling models, indicating a shared nanopore-associated substitution bias. This enrichment remained detectable in WGA reads, whereas native WGS reads showed a further increase. Using independent PacBio methylation profiling, we found that the WGS-associated substitution excess was strongly concentrated around bacterial methylation motifs and was minimal in non-motif regions. The magnitude and substitution pattern of these errors varied among motifs and sequencing platforms. At a subset of motif-associated positions, alternative-base fractions exceeded 50%, producing SNP-like signals. In ONT data, 28 WGS-specific calls survived the applied SNP-calling filters, all within PacBio-supported methylation contexts, and most showed significant strand imbalance. Together, these results identify a shared A2G/G2A substitution bias in all nanopore datasets and support a methylation-associated increase in these errors near bacterial methylation motifs, with some loci producing SNP-like artifacts.

bioinformatics↗

bioRxiv2025

ZIKV NS5-mediated STAT2 degradation as a determinant of immune evasion and pathogenicity

Type I interferon (IFN) signaling is a central antiviral defense, with STAT2 driving the expression of IFN-stimulated genes (ISGs) to restrict viral infection. Many flaviviruses, including Zika virus (ZIKV), evade this pathway through non-structural protein 5 (NS5)-mediated ubiquitination and proteasomal degradation of STAT2, yet the contribution of this immune evasion strategy to viral fitness and pathogenesis remains incompletely defined. Here, using a multi-step mutational scanning strategy that jointly assessed STAT2 degradation and viral RNA replication, we identified a single NS5 residue, L162, as uniquely permissive to substitution that abolishes STAT2 degradation without compromising intrinsic replication functions. Substitution of L162 with alanine or glycine (L162A or L162G) selectively disrupted NS5 recruitment of the ZSWIM8-CUL3 E3 ubiquitin ligase, thereby preserving STAT2 stability and restoring IFN signaling. Recombinant ZIKV carrying these mutations exhibited reduced replication and enhanced ISG induction in human cells, defects fully rescued by STAT2 knockout. In A129 mice (type I IFN receptor deficient), mutant and WT viruses replicated comparably, but in human STAT2 knock-in mice, ZIKV-NS5L162G exhibited markedly reduced viral loads and disease. Notably, infection with ZIKV-NS5L162G elicited robust neutralizing antibody and T cell responses that conferred protection against WT challenge. Together, these findings establish NS5-mediated STAT2 degradation as a central determinant of ZIKV immune evasion, viral fitness and pathogenesis, and highlight disruption of NS5-STAT2 antagonism as a promising strategy for antiviral intervention and rational attenuation.

microbiology↗

bioRxiv2025

Sex-specific brain structural predictors and outcomes of adolescent depression trajectories

ObjectivesDepressive symptoms often emerge and increase during adolescence, yet the neural predictors and long-term brain outcomes associated with depressive trajectories remain poorly understood. This study adopts a trajectory-based approach to explore the temporal relationship between brain structure and dynamic changes in depressive symptoms across adolescence. MethodsWe used a large longitudinal adolescent neuroimaging sample across five annual waves (n = 11,862; mean age = 9.91 at baseline) from the ABCD study. First, growth mixture models were applied separately for males and females to identify distinct developmental trajectories of depressive symptoms. We then used linear mixed-effects models to identify which baseline brain structural features differentiated trajectory classes, and how these trajectories influenced subsequent brain structure. ResultsWe identified high-decreasing, stable-low, and low-increasing trajectories in females, and relatively stable high, moderate, and low trajectories in males. No baseline brain regions were found to be associated with female trajectories, whereas smaller global brain measures (total subcortical volume, cortical volume, and surface area) predicted the high trajectory in males. Regarding brain outcomes, a low-increasing trajectory in females was associated with smaller global subcortical and cortical volumes, while high and moderate trajectories in males predicted thinner global cortices. Additional trajectory-related regional brain alterations were observed in both sexes. ConclusionsThese findings highlight distinct neurodevelopmental patterns linked to depressive symptom trajectories in males and females, underscoring the importance of a sex-specific and longitudinal approach to identifying neural risk and outcomes in adolescent depression.

neuroscience↗

bioRxiv2025

Neuroanatomical signatures of depression and anxiety in at-risk adolescents: A symptom-oriented perspective

BackgroundMajor depressive disorder (MDD) and generalized anxiety disorder (GAD) often emerge in adolescence. Identifying their symptom structures and neural biomarkers in youth with elevated risk is critical for early detection and developing interventions. This study investigated the central symptoms of MDD and GAD and identified the key brain regions ("brain bridges") linking structural neuroanatomy to symptoms in at-risk adolescents. MethodsA total of 1,568 adolescents at high risk for MDD and 413 adolescents at high risk for GAD were identified from the Adolescent Brain Cognitive Development (ABCD) study. Participants completed MDD and GAD symptom assessments and underwent Magnetic Resonance Imaging scanning. We constructed 10 psychological network models incorporating symptoms and brain structural indices to identify central symptoms and brain bridges. ResultsConcentration difficulties emerged as the shared core symptom, while self-hatred and irritability were the unique central symptoms for MDD and GAD, respectively. Left- and right-pallidum volumes exhibited the highest bridge centrality for MDD symptoms, whereas left-nucleus accumbens volume showed the highest bridge centrality for GAD symptoms. ConclusionOur findings highlight the pallidum and nucleus accumbens as key brain regions linking structural anatomy to symptom networks in high-risk youth. These results provide novel insights into early neurobiological markers of MDD and GAD from a symptom-oriented perspective and may inform targeted interventions.

neuroscience↗

bioRxiv2025

SARS-CoV-2 nucleocapsid induces hyperinflammation and vascular leakage through the Toll-like receptor signaling axis in macrophages

Tens of thousands of severe COVID-19 cases are hospitalized weekly in the U.S., often driven by an imbalance between antiviral responses and inflammatory signaling, leading to uncontrolled cytokine secretion. The SARS-CoV-2 nucleocapsid (N) protein is a known immune antagonist, but its role in macrophage-driven cytokine storms is unclear. We demonstrate that N functions in a pathway-specific manner, specifically amplifying nuclear factor {kappa}B-related transcripts upon Toll-like receptor 7/8 stimulation. Moreover, we show that this is a conserved feature of pathogenic coronaviruses, with the delta variant N being the most pro-inflammatory. Our interaction networks suggest the delta variant N drives inflammation through interactions with several stress granule-related proteins. Profiling of secreted cytokines revealed that supernatants from the delta variant N-expressing macrophages disrupt brain and heart endothelial barriers, implicating N in COVID-19-associated cognitive and cardiac complications. Our findings highlight N-mediated immune imbalance as a driver of severe COVID-19 and identify N as a promising therapeutic target to mitigate hyperinflammation.

microbiology↗

bioRxiv2025

UHRF1 restricts HCoV-229E infection through epigenetic silencing of the viral receptor APN

The emergence of SARS-CoV-2 has posed significant threats to global health, particularly for the older population. Similarly, common human coronaviruses, such as HCoV-229E, which typically cause mild cold-like symptoms, have also been linked to severe diseases, underscoring the need to understand virus-host interactions and identify host factors contributing to viral pathogenesis and disease progression. In this study, we performed a genome-wide CRISPR knockout screen using HCoV-229E and identified Ubiquitin-like with PHD and RING finger domain 1 (UHRF1) as a potent restriction factor. Mechanistically, UHRF1 suppressed HCoV-229E infection by downregulating the expression of its cell entry receptor, aminopeptidase N (APN), through promoter hypermethylation. Focused CRISPR activation screens of UHRF1-downregulated genes confirmed the critical role of APN in HCoV-229E infection and identified additional genes (e.g., SIGLEC1, PLAC8, and heparan sulfate biosynthesis genes) contributing to the restrictive functions of UHRF1. Transcriptomic and single-cell RNA sequencing analysis revealed that UHRF1 expression decreases with age, negatively correlating with increased APN expression. This age-related decline in UHRF1 was further validated in primary alveolar macrophages isolated from elderly individuals, which exhibited heightened susceptibility to HCoV-229E infection compared to those from younger individuals. Our findings highlight UHRF1 as a key age-related host defense factor against coronavirus infection and provide novel insights into the epigenetic regulation of viral entry receptors.

microbiology↗

bioRxiv2025

A mechanism linking dopamine's roles in reinforcement, movement and motivation

Dopamine neurons (DANs) play seemingly distinct roles in reinforcement,1-3 motivation,4,5 and movement,6,7 and DA-modulating therapies relieve symptoms across a puzzling spectrum of neurologic and psychiatric symptoms.8 Yet, the relationship among these roles is unknown. Here, we show DAs tripartite functions are causally linked by a process in which phasic striatal DA rapidly and persistently recalibrates the propensity to move, a measure of vigor. Using a self-timed movement task, we found that single exposures to reward-related DA transients (both endogenous and exogenously-induced) exerted one-shot updates to movement timing--but in a surprising fashion. Rather than reinforce specific movement times, DA transients quantitatively changed movement timing on the next trial, with larger transients leading to earlier movements (and smaller to later), consistent with a stochastic search process that calibrates the frequency of movement. Both abrupt and gradual changes in external and internal contingencies--such as timing criterion, reward content, and satiety state--caused changes to the amplitude of DA transients that causally altered movement timing. The rapidity and bidirectionality of the one-shot effects are difficult to reconcile with gradual synaptic plasticity, and instead point to more flexible cellular mechanisms, such as DA-dependent modulation of neuronal excitability. Our findings shed light on how natural reinforcement, as well as DA-related disorders such as Parkinsons disease, could affect behavioral vigor.

neuroscience↗

bioRxiv2025

DAZAP2 functions as a pan-coronavirus restriction factor by inhibiting viral entry and genomic replication

The SARS-CoV-2 pandemic and the emergence of novel variants underscore the need to understand host-virus interactions and identify host factors that restrict viral infection. Here, we perform a genome-wide CRISPR knockout screen to identify host restriction factors for SARS-CoV-2, revealing DAZAP2 as a potent antiviral gene. DAZAP2, previously implicated in SARS-CoV-2 restriction, is found to inhibit viral entry by blocking virion fusion with both endolysosomal and plasma membranes. Additionally, DAZAP2 suppresses genomic RNA replication without affecting the primary translation of viral replicases. We demonstrate that DAZAP2 functions as a pan-coronavirus restriction factor across four genera of coronaviruses. Importantly, knockout of DAZAP2 enhances SARS-CoV-2 infection in mouse models and in human primary airway epithelial cells, confirming its physiological relevance. Mechanistically, antiviral activity of DAZAP2 appears to be indirect, potentially through the regulation of host gene expression, as it primarily localizes to the nucleus. Our findings provide new insights into the host defense system against coronaviruses and highlight DAZAP2 as a potential target for host-directed antiviral therapies. IMPORTANCEDuring viral infection, the host defense response is mediated by a variety of host factors through distinct mechanisms that have yet to be fully elucidated. Although DAZAP2 was previously implicated in SARS-CoV-2 restriction, its mechanisms of action and in vivo relevance remain unclear. In this study, we identify the DAZAP2 as a potent pan-coronavirus restriction factor that inhibits viral infection through dual mechanisms: blocking virion fusion with both endolysosomal and plasma membranes, and suppressing genomic RNA replication. We confirm its physiological relevance in host defense using mouse models and primary cell cultures. This study advances our understanding of host-pathogen interactions. Targeting DAZAP2 or its regulatory pathways could provide a new approach to enhance host defense against current and future coronavirus threats.

microbiology↗

bioRxiv2025

METTL3 Aggravates Intimal Hyperplasia by Facilitating the m6A-YTHDC1-dependent SGK1 Gene Transcription

BackgroundVascular smooth muscle cell (VSMC) migration and proliferation substantially contribute to neointimal hyperplasia related to in-stent restenosis. N6-methyladenosine (m6A) catalyzed by the methyltransferase-like 3 (METTL3)-involved methyltransferase complex is the most abundant RNA epigenetic modification in eukaryotes, but the role of m6A RNA methylation in VSMC migration and proliferation as well as neointima formation remains highly controversial. MethodsPrimary human and rat VSMCs were utilized for in vitro experiments. VSMC-specific METTL3 knockout mice (Mettl3flox/floxMyh11-CreERT2) were generated to explore wire injury in carotid arteries in vivo. Methylated RNA immunoprecipitation sequencing (MeRIP-Seq) was performed to screen for target genes by METTL3-catalyzed m6A RNA methylation. Methylation site mapping, MeRIP-quantitative PCR (MeRIP-qPCR), chromatin immunoprecipitation-qPCR (ChIP-qPCR) and reporter gene assays were applied to explore how METTL3 modulates its target gene expression. ResultsMETTL3 was consistently upregulated in the neointima from mice subjected to carotid wire injury and patients undergoing carotid endarterectomy. VSMC-specific METTL3 deficiency significantly attenuated neointima formation in carotid arteries following wire injury in mice. Accordingly, METTL3 ablation markedly repressed VSMC proliferation both in vitro and in vivo. Mechanistically, METTL3 directly catalyzed m6A methylation on serum/glucocorticoid regulated kinase 1 (SGK1) mRNA and subsequently facilitated its transcription, which relies on the established association between the SGK1 transcript and SGK1 promoter DNA by recruiting the m6A reader YTHDC1. Conversely, SGK1 overexpression abolished METTL3 deficiency-mediated suppression of VSMC proliferation and postinjury neointima formation. ConclusionsMETTL3-catalyzed m6A RNA methylation promoted VSMC proliferation and aggravated postinjury neointima formation by facilitating YTHDC1-dependent SGK1 gene transcription. Targeting the METTL3-YTHDC1-SGK1 axis to modulate VSMC proliferation may be a potential strategy for in-stent restenosis therapy.

molecular biology↗

bioRxiv2024

Regulation of alternative polyadenylation isoforms of Timp2 is an effector event of RAS signaling in cell transformation

Alternative polyadenylation (APA) generates mRNA isoforms with different lengths of the 3 untranslated region (3 UTR). The tissue inhibitor of metalloproteinase 2 (TIMP2) plays a key role in extracellular matrix remodeling under various developmental and disease conditions. Both human and mouse genes encoding TIMP2 contain two highly conserved 3UTR APA sites, leading to mRNA isoforms that differ substantially in 3UTR size. APA of Timp2 is one of the most significantly regulated events in multiple cell differentiation lineages. Here we show that Timp2 APA is highly regulated in transformation of NIH3T3 cells by the oncogene HRASG12V. Perturbations of isoform expression with long 3UTR isoform-specific knockdown or genomic removal of the alternative UTR (aUTR) region indicate that the long 3UTR isoform contributes to the secreted Timp2 protein much more than the short 3UTR isoform. The short and long 3UTR isoforms differ in subcellular localization to endoplasmic reticulum (ER). Strikingly, Timp2 aUTR enhances secreted protein expression but no effect on intracellular proteins in reporter assays. Furthermore, downregulation of Timp2 long isoform mitigates gene expression changes elicited by HRASG12V. Together, our data indicate that regulation of Timp2 protein expression through APA isoform changes is an integral part of RAS-mediated cell transformation and 3UTR isoforms of Timp2 can have distinct impacts on expression of secreted vs. intracellular proteins.

molecular biology↗

bioRxiv2024

IGF2BP3 Promotes Autophagy-Mediated TNBC Metastasis via M6A-Dependent, Cap-Independent c-Met Translation

Tumor metastasis involves a series of complex processes and is a major challenge in clinical treatment. The cooperation of epigenetic modifications and metabolic adaptations endows tumor cells with dynamic adaptations for survival in variable environments, which is crucial for tumor metastasis and worth exploring in depth. In this study, we found IGF2BP3 could link epigenetic modification and metabolic adaptation in promoting autophagy-mediated triple-negative breast cancer (TNBC) metastasis. As a TNBC specifically high expressed N6-methyladenosine (m6A) binding protein, IGF2BP3 could bind to the m6A motif of c-Met mRNA, regulating autophagy-mediated epithelial-to-mesenchymal transition (EMT) progress by c-Met/PI3K/AKT/mTOR pathway. Moreover, through the recruitment of eIF4G2 as a collaborator, IGF2BP3 induced the changes in c-Met protein expression not by affecting mRNA stability, but by facilitating its mRNA translation initiation in an m6A-dependent and cap-independent manner. In conclusion, our study extended the role of IGF2BP3 in autophagy mediated TNBC metastasis, found IGF2BP3 could bind to the m6A motif on the 5', 3'-UTR of c-Met mRNA to facilitate its translation in a cap-independent manner.

cancer biology↗

bioRxiv2024

PointTree: Automatic and accurate reconstruction of long-range axonal projections of single-neuron

Single-neuron axonal projections reveal the route map of neuron output and provide a key cue for understanding how information flows across the brain. Reconstruction of single-neuron axonal projections requires intensive manual operations in tens of terabytes of brain imaging data, and is highly time-consuming and labor-intensive. The main issue lies in the need for precise reconstruction algorithms to avoid reconstruction errors, yet current methods struggle with densely distributed axons, focusing mainly on skeleton extraction. To overcome this, we introduce a point assignment-based method that uses cylindrical point sets to accurately represent axons and a minimal information flow tree model to suppress the snowball effect of reconstruction errors. Our method successfully reconstructs single-neuron axonal projections across hundreds of GBs (Gigabytes) images with an average of 80% F1-score, while current methods only provide less than 40% F1-score reconstructions from a few hundred MBs (Megabytes) images. This huge improvement is helpful for high-throughput mapping of neuron projections.

neuroscience↗

bioRxiv2024

A Newborn F-box Gene Blocks Gene Flow by Selectively Degrading Phosphoglucomutase in Species Hybrids

The establishment of reproductive barriers such as postzygotic hybrid incompatibility (HI) remains the key to speciation. Gene duplication followed by differential functionalization has long been proposed as a major model underlying HI, but few supporting evidence exists. Here, we demonstrate that a new-born F-box gene, Cni-neib-1, of the nematode Caenorhabditis nigoni specifically inactivates an essential phosphoglucomutase encoded by Cbr-shls-1 in its sister species C. briggsae and their hybrids. Zygotic expression of Cni-neib-1 specifically depletes Cbr-SHLS-1, but not Cni-SHLS-1, in approximately 40 minutes starting from gastrulation, causing embryonic death. Cni-neib-1 is one of thirty-three paralogues emerging from a recent surge in F-box gene duplication events within C. nigoni, all of which are evolving under positive selection. Cni-neib-1 undergoes turnover even among C. nigoni populations. Differential expansion of F-box genes between the two species could reflect their distinctive innate immune responses. Collectively, we demonstrate how recent duplication of genes involved in protein degradation can cause unintended destruction of targets in hybrids that leads to HI, providing an invaluable insight into mechanisms of speciation. Significance statementUnderstanding how reproductive isolation forms and triggers speciation remains a central topic in evolutionary biology. In this study, the authors reveal a novel molecular mechanism that obstructs gene flow between the nematodes Caenorhabditis briggsae and C. nigoni. A recently evolved, species-specific F-box gene in C. nigoni selectively depletes an essential phosphoglucomutase enzyme in C. briggsae, leading to embryonic lethality in hybrids. This mechanism effectively prevents gene flow from C. nigoni to C. briggsae. This discovery underscores how a newborn gene, arising from recent gene duplication, can contribute to reproductive isolation by inadvertently disrupting a functionally important protein in hybrid offspring.

evolutionary biology↗

bioRxiv2024

TRIM32 inhibits Venezuelan Equine Encephalitis Virus Infection by targeting a late step in viral entry

Alphaviruses are mosquito borne RNA viruses that are a reemerging public health threat. Alphaviruses have a broad host range, and can cause diverse disease outcomes like arthritis, and encephalitis. The host ubiquitin proteasome system (UPS) plays critical roles in regulating cellular processes to control the infections with various viruses, including alphaviruses. Previous studies suggest alphaviruses hijack UPS for virus infection, but the molecular mechanisms remain poorly characterized. In addition, whether certain E3 ubiquitin ligases or deubiquitinases act as alphavirus restriction factors remains poorly understood. Here, we employed a cDNA expression screen to identify E3 ubiquitin ligase TRIM32 as a novel intrinsic restriction factor against alphavirus infection, including VEEV-TC83, SINV, and ONNV. Ectopic expression of TRIM32 reduces alphavirus infection, whereas depletion of TRIM32 with CRISPR-Cas9 increases infection. We demonstrate that TRIM32 inhibits alphaviruses through a mechanism that is independent of the TRIM32-STING-IFN axis. Combining reverse genetics and biochemical assays, we found that TRIM32 interferes with genome translation after membrane fusion, prior to replication of the incoming viral genome. Furthermore, our data indicate that the monoubiquitination of TRIM32 is important for its antiviral activity. Notably, we also show two TRIM32 pathogenic mutants R394H and D487N, related to Limb-girdle muscular dystrophy (LGMD), have a loss of antiviral activity against VEEV-TC83. Collectively, these results reveal that TRIM32 acts as a novel intrinsic restriction factor suppressing alphavirus infection and provides insights into the interaction between alphaviruses and the host UPS. Author summaryDue to climate change, wildlife habitat loss, and human activities, alphavirus infections are a growing threat to public health. The host UPS has critical role in virus-host interaction, but how the UPS impact alphavirus infection is not completely understood. In this study, we found that the E3 ubiquitin ligase TRIM32 inhibits diverse alphaviruses in multiple cell types. Mechanistically, TRIM32 impairs primary translation of incoming viral genome in a manner that depends on. monoubiquitination of TRIM32. Additionally, disease-associated alleles of TRIM32 have a loss-of-function with respect to viral inhibition. Together, these findings uncover a novel biological function of TRIM32 in regulating alphavirus infection and provide important insights into the interplay between alphaviruses and the host USP.

microbiology↗