Biology subjects

Li, S.

Publications and source records attributed to Li, S..

At least 451 records · Page 25Linked to original sources

bioRxiv2025

APMAT analysis reveals the association between CD8 T cell receptors, cognate antigen, and T cell phenotype and persistence

Elucidating the relationships between a class I peptide antigen, a CD8 T cell receptor (TCR) specific to that antigen, and the T cell phenotype that emerges following antigen stimulation, remains a mostly unsolved problem, largely due to the lack of large data sets that can be mined to resolve such relationships. Here, we describe Antigen-TCR Pairing and Multiomic Analysis of T-cells (APMAT), an integrated experimental-computational framework designed for the high-throughput capture and analysis of CD8 T cells, with paired antigen, TCR sequence, and single-cell transcriptome. Starting with 951 putative antigens representing a comprehensive survey of the SARS-CoV-2 viral proteome, we utilize APMAT for the capture and single cell analysis of CD8 T cells from 62 HLA A*02:01 COVID-19 participants. We leverage this unique, comprehensive dataset to integrate with peptide antigen properties, TCR CDR3 sequences, and T cell phenotypes to show that distinct physicochemical features of the antigen-TCR pairs strongly associate with both T cell phenotype and T cell persistence. This analysis suggests that CD8+ T cell phenotype following antigen stimulation is at least partially deterministic, rather than the result of stochastic biological properties.

immunology↗

bioRxiv2025

Tissue-specific modulation of NADH consumption as an anti-aging intervention in Drosophila

Aging is characterized by extensive metabolic dysregulation. Redox coenzyme nicotinamide adenine dinucleotide (NAD) can exist in oxidized (NAD+) or reduced (NADH) states, which together form a key NADH/NAD+ redox pair. Total levels of NAD decline with age in a tissue-specific manner, thereby playing a significant role in the aging process. Supplementation with NAD precursors boosts total cellular NAD levels and provides some therapeutic benefits in human clinical trials. However, supplementation studies cannot determine tissue-specific effects of an altered NADH/NAD+ ratio. Here, we created transgenic Drosophila expressing a genetically encoded xenotopic tool LbNOX to directly manipulate the cellular NADH/NAD+ ratio. We found that LbNOX expression in Drosophila impacts both NAD(H) and NADP(H) metabolites in a sex-specific manner. LbNOX rescues neuronal cell death induced by the expression of mutated alpha-B crystallin in the Drosophila eye, a widely used system to study reductive stress. Utilizing LbNOX, we demonstrate that targeting redox NAD metabolism in different tissues may have drastically different outcomes, as the expression of LbNOX solely in the muscle is much more effective for rescuing paraquat-induced oxidative stress compared to whole-body expression. Excitingly, we demonstrate that perturbing NAD(P) metabolism in non-neuronal tissues is sufficient to rejuvenate sleep profiles in aged flies to a youthful state. In summary, we used xenotopic tool LbNOX to identify tissues and metabolic processes which benefited the most from the modulation of the NAD metabolism thereby highlighting important aspects of rebalancing the NAD and NADP pools, all of which can be translated into novel designs of NAD-related human clinical trials. Significance statementTotal levels of NAD decline with age in a tissue-specific manner, thereby playing a significant role in the aging process. Supplementation with NAD precursors boosts organismal NAD levels but cannot determine tissue-specific effects of altered NAD metabolism. Here, we created transgenic Drosophila expressing a genetically encoded xenotopic tool, LbNOX, to directly manipulate NAD metabolism. We demonstrate that targeting NAD metabolism in just one tissue may be more effective than altering whole-body metabolism and can reverse some aging-related manifestations in a sex-specific manner. We anticipate that our work will define the tissues that benefit the most from targeting NAD metabolism and aid in designing better human clinical trials.

synthetic biology↗

bioRxiv2025

Neuronal LAG3 facilitates pathogenic α-synuclein neuron-to-neuron propagation

Lymphocyte activation gene 3 (LAG3) is a key receptor involved in the propagation of pathological proteins in Parkinsons disease (PD). This study investigates the role of neuronal LAG3 in mediating the binding, uptake, and propagation of -synuclein (Syn) preformed fibrils (PFFs). Using neuronal LAG3 conditional knockout mice and human induced pluripotent stem cells-derived dopaminergic (DA) neurons, we demonstrate that LAG3 expression is critical for pathogenic Syn propagation. Our results show that the absence of neuronal LAG3 significantly reduces Syn pathology, alleviates motor dysfunction, and inhibits neurodegeneration in vivo. Electrophysiological recordings revealed that Syn PFFs induce pronounced neuronal hyperactivity in wild-type (WT) neurons, increasing firing rates in cell-attached and whole-cell configurations, and reducing miniature excitatory postsynaptic currents. In contrast, neurons lacking LAG3 resisted these electrophysiological effects. Moreover, treatment with an anti-human LAG3 antibody in human DA neurons inhibited Syn PFFs binding and uptake, preventing pathology propagation. These findings confirm the essential function of neuronal LAG3 in mediating Syn propagation and associated disruptions, identifying LAG3 as a potential therapeutic target for PD and related -synucleinopathies.

neuroscience↗

bioRxiv2025

AncestryHub: A web server for local ancestry analysis

SummaryAncestryHub is a web version of local ancestry analysis software. It contains four built-in software and a set of built-in population reference panels. AncestryHub will significantly reduce the efforts and requirements for the users on their personal computational skills and computational hardware environment for ancestry analysis. Availabilityhttps://www.ancestryhub.4dgenome.com Contact: lima@4dgenome.com

bioinformatics↗

bioRxiv2024

Maize TIR-only Proteins ZmTIR1 and ZmTIR2, but not ZmTIR3 Confer Auto-active Hypersensitive Response Likely by Forming Condensation

Nucleotide binding, leucine-rich-repeat (NLR) proteins are the major intracellular receptors for defending against pathogen infection. The recognition between NLRs and pathogen secreted effectors often triggers a localized programmed cell death termed hypersensitive response (HR). Despite significant progresses have been achieved in understanding canonical NLRs with the N-terminal Toll/interleukin-1 receptor (TIR) domains, the molecular mechanisms underlying TIR-only proteins in plant immune responses remain unclear. In this study, we identified six TIR-containing proteins in maize, including three TIR-only proteins. Functional analysis showed that ZmTIR1 and ZmTIR2, but not ZmTIR3, confer autoactive HR when transiently expressed in N. benthamiana. The autoactivity conferred by ZmTIR1 and ZmTIR2 depends on EDS1-PAD4-RNL module and their putative NADase activities. Interestingly, ZmTIR1 and ZmTIR2 predominantly localize in the punctate dots and likely form condensation, while ZmTIR3 mainly localizes in the cytoplasm and the nucleus. Two specific amino acids in the BB-loop region were identified to be required for ZmTIR1- and ZmTIR2-mediated condensation formation and auto-HR. Furthermore, ZmTIR and ZmTIR2 are induced by Cochliobolus heterostrophus, the causal agent of southern leaf blight (SLB) in maize, and knock-down the expression of ZmTIR1 or ZmTIR2 decreased the resistance to SLB in maize. Our study reveals a novel mechanism of monocot TIR-only proteins in maize immune responses.

plant biology↗

bioRxiv2024

Chicken shank color determined by Inhibition of dermal melanin (ID) is mediated by a structural variation regulating CDKN2A expression

It is well established that the color of a chickens shank is primarily determined by four genetic loci. Among these, the Inhibition of dermal melanin (ID) locus, which suppresses black pigmentation in the dermal layer of the shank, is the sole sex-linked mutation and its molecular mechanisms remained elusive. In this study, a resource family with segregating shank colors was constructed. A genome-wide association study utilizing FarmCPU software identified a top-associated SNP located on the Z chromosome. Subsequent linkage mapping further refined the candidate region, enabling the screening of the candidate structural variation. The candidate structural variation is associated with the yellow shank and characterized by a 143 bp deletion accompanied by a 2 bp insertion. Within the same Topologically Associating Domain, only the CDKN2A gene showed differential expression. Functional studies, including CRISPR/Cas9-edited cells, provided evidence that this mutation regulates CDKN2A transcription and is responsible for the ID shank color in chickens. The absence of melanocytes is likely due to their apoptosis. This study completes the puzzle of chicken shank color genetics and paves the way for the application of the ID mutation in the auto-sexing of chicks which is intensively needed in layer and broiler industries.

genetics↗

bioRxiv2024

Cancer Histone Mutations Impact Binding and DNA Repair Processes, Leading to Increased Mutagenesis

Histones are key epigenetic factors for regulating the accessibility and compaction of eukaryotic genomes, affecting the replication, repair, and expression of DNA. Recent studies have demonstrated that histone missense mutations can perturb normal histone function, promoting the development of phenotypically distinguishable cancers. However, most histone mutations observed in cancer patients remain enigmatic in their potential to promote cancer development. To assess the oncogenic potential of histone missense mutations, we have gathered whole-exome sequencing data for the tumors of over 12,000 patients. Overall, histone mutations occurred in about 16% of cancer patients, although specific cancer types showed substantially higher rates. Using a combination of genomic, structural, and biophysical analyses, we found several predominant modes of action, where cancer missense mutations in histones affected acidic patches and protein binding interfaces in a cancer-specific manner and targeted interaction sites with specific DNA repair proteins. Consistent with this finding, we observed a high tumour mutational burden in patients with histone mutations affecting interactions of DNA repair proteins. We also identified potential cancer driver mutations in several histone genes, including histone H4-a highly conserved histone without previously documented driver mutations.

bioinformatics↗

bioRxiv2024

Red-shifted GRAB acetylcholine sensors for multiplex imaging in vivo

The neurotransmitter acetylcholine (ACh) is essential in both the central and peripheral nervous systems. Recent studies highlight the significance of interactions between ACh and various neuromodulators in regulating complex behaviors. The ability to simultaneously image ACh and other neuromodulators can provide valuable information regarding the mechanisms underlying these behaviors. Here, we developed a series of red fluorescent G protein-coupled receptor activation-based (GRAB) ACh sensors, with a wide detection range and expanded spectral profile. The high-affinity sensor, rACh1h, reliably detects ACh release in various brain regions, including the nucleus accumbens, amygdala, hippocampus, and cortex. Moreover, rACh1h can be co-expressed with green fluorescent sensors in order to record ACh release together with other neurochemicals in various behavioral contexts using fiber photometry and two-photon imaging, with high spatiotemporal resolution. These new ACh sensors can therefore provide valuable new insights regarding the functional role of the cholinergic system under both physiological and pathological conditions.

neuroscience↗

bioRxiv2024

In vivo multiplex imaging of dynamic neurochemical networks with designed far-red dopamine sensors

Neurochemical signals like dopamine (DA) play a crucial role in a variety of brain functions through intricate interactions with other neuromodulators and intracellular signaling pathways. However, studying these complex networks has been hindered by the challenge of detecting multiple neurochemicals in vivo simultaneously. To overcome this limitation, we developed a single-protein chemigenetic DA sensor, HaloDA1.0, which combines a cpHaloTag-chemical dye approach with the G protein-coupled receptor activation-based (GRAB) strategy, providing high sensitivity for DA, sub-second response kinetics, and an extensive spectral range from far-red to near-infrared. When used together with existing green and red fluorescent neuromodulator sensors, Ca2+ indicators, cAMP sensors, and optogenetic tools, HaloDA1.0 provides high versatility for multiplex imaging in cultured neurons, brain slices, and behaving animals, facilitating in-depth studies of dynamic neurochemical networks.

neuroscience↗

bioRxiv2024

Same-Slide Spatial Multi-Omics Integration Reveals Tumor Virus-Linked Spatial Reorganization of the Tumor Microenvironment

The advent of spatial transcriptomics and spatial proteomics have enabled profound insights into tissue organization to provide systems-level understanding of diseases. Both technologies currently remain largely independent, and emerging same slide spatial multi-omics approaches are generally limited in plex, spatial resolution, and analytical approaches. We introduce IN-situ DEtailed Phenotyping To High-resolution transcriptomics (IN-DEPTH), a streamlined and resource-effective approach compatible with various spatial platforms. This iterative approach first entails single-cell spatial proteomics and rapid analysis to guide subsequent spatial transcriptomics capture on the same slide without loss in RNA signal. To enable multi-modal insights not possible with current approaches, we introduce k-bandlimited Spectral Graph Cross-Correlation (SGCC) for integrative spatial multi-omics analysis. Application of IN-DEPTH and SGCC on lymphoid tissues demonstrated precise single-cell phenotyping and cell-type specific transcriptome capture, and accurately resolved the local and global transcriptome changes associated with the cellular organization of germinal centers. We then implemented IN-DEPTH and SGCC to dissect the tumor microenvironment (TME) of Epstein-Barr Virus (EBV)-positive and EBV-negative diffuse large B-cell lymphoma (DLBCL). Our results identified a key tumor-macrophage-CD4 T-cell immunomodulatory axis differently regulated between EBV-positive and EBV-negative DLBCL, and its central role in coordinating immune dysfunction and suppression. IN-DEPTH enables scalable, resource-efficient, and comprehensive spatial multi-omics dissection of tissues to advance clinically relevant discoveries.

systems biology↗

bioRxiv2024

Temporally overlapping mechanisms diversify clonal B cell responses in vivo.

Naive B cells amplify and diversify their responses when activated by cognate antigen, via Myc-dependent clonal expansion, immunoglobulin class switch recombination (CSR), phenotypic variation, and somatic hypermutation (SHM). Whether these mechanisms act combinatorially in vivo to diversify clonal responses to a single pathogen remains unclear. Since diversity in the antigenic targets, functional classes, and production kinetics of parasite-specific antibodies influences immunity to malaria, we test here whether individual B cell clones diversify over time during Plasmodium infection and treatment. During the first week of infection, amid widespread Type I Interferon (IFN)-mediated bystander activation, CSR initiates soon after Myc up-regulation, and overlaps partially with clonal expansion, resulting in isotype variegation amongst clones. During the second week of infection, expanded clones that seed germinal centres (GC) bifurcate into extra-follicular plasmablasts, exhibit isotype variegation, and initiate SHM, revealing substantial intra-clonal diversification. Over the following month, GC clones exhibit SHM at approximately four mutations per week, with IgG mutational diversity and IgM+ cells also preserved in GCs over time. Anti-malarial intervention does not impede SHM, but instead exerts quantitative limits on GC size, plasma cell emergence, circulating IgG levels, and protection against re-infection. Finally, contemporaneous B cell development relocates from bone marrow to spleen during infection and treatment. Thus, multiple temporally overlapping mechanisms combine in vivo to amplify, diversify, and safeguard humoral immune responses. We present this data as a temporal, multi-parameter atlas of B cell differentiation in vivo: https://bcell-dynamics.science.unimelb.edu.au Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=130 SRC="FIGDIR/small/628863v2_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@c57890org.highwire.dtl.DTLVardef@6e5936org.highwire.dtl.DTLVardef@a2e872org.highwire.dtl.DTLVardef@14abbac_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIPartial temporal overlap of CSR with clonal expansion leads to isotype variegation in clones. C_LIO_LIClones seeding GCs bifurcate into plasmablasts and exhibit isotype variegation. C_LIO_LIGC B cells accrue [~]4 mutations/week, a rate unaffected by anti-malarials. C_LIO_LIPlasmodium infection triggers antigen-independent Type I IFN-mediated bystander activation. C_LIO_LIB cell development is preserved in malaria by shifting from bone marrow to spleen. C_LI

immunology↗

bioRxiv2024

Risk assessment of zoonotic viruses in urban-adapted wildlife

The repeated emergence of pandemic viruses underscores the linkages between land-use change and wildlife disease, and urban-adapted wildlife are of special interest due to their close proximity to humans. However, viral diversity within urban-adapted species and their zoonotic potential remains largely unexplored. We compiled a large dataset on seven priority urban-adapted mammal species and their viruses covering over 115 countries from 1574 to 2023. These urban-adapted species host 286 virus species spanning 24 orders and 38 families, 14 of which are potentially high risk for human infection. Raccoons carried the most high-risk viruses, while raccoon dogs had increased viral positivity in urban habitats compared to raccoons, wild boars, and red foxes. Many viruses in urban-adapted species were phylogenetically related to those found in humans, and we also observed evidence of possible viral spillback. These results highlight zoonotic risks associated with urban-adapted species and suggest enhanced surveillance to mitigate future outbreaks.

ecology↗

bioRxiv2024

Deciphering the thiolactonization mechanism in thiolactomycin biosynthesis

Thiolactomycin (1), which features a unique{gamma} -thiolactone ring, is a promising antibiotic candidate that specifically targets bacterial type II fatty acid synthase. Despite extensive studies on its pharmacological activities, modes of action, and chemical synthesis, the enzymatic processes responsible for forming the activity-determining{gamma} -thiolactone ring have remained largely unknown. Here, we resolve this problem by revealing that the condensation and heterocyclization (Cy) domain of the nonribosomal peptide synthetase (NRPS) TlnC (TlnCCy), along with the cytochrome P450 enzyme TlnA, cooperatively enable the{gamma} -thiolactone assembly. TlnCCy mediates an unusual sulfurtransfer reaction to sulfurate the polyketide intermediate, generating a thiocarboxylate intermediate. Subsequently, TlnA acts as a{gamma} -thiolactone synthase, converting the linear thiocarboxylate intermediate into 1 via a distal radical-based cyclization mechanism. These findings not only expand the functional and catalytic repertoires of NRPS Cy domains and P450 enzymes, but also highlight a special enzymatic strategy for{gamma} -thiolactone biosynthesis in nature. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=80 SRC="FIGDIR/small/629141v2_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@7e0ad2org.highwire.dtl.DTLVardef@f86b80org.highwire.dtl.DTLVardef@159d136org.highwire.dtl.DTLVardef@1b633ff_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2024

Unexpected Activities of CYP152 Peroxygenases towards Non-carboxylic Substrates Reveal Novel Substrate Recognition Mechanism and Catalytic Versatility

Exploring and exploiting the catalytic promiscuity of enzymes is a central topic and captivating challenge in enzymology. CYP152 peroxygenases are attractive biocatalysts for diverse reactions under mild conditions using H2O2 as cofactor. However, their substrate scope is limited by a carboxyl group required for acid-base catalysis, following the well-accepted principle that heme-dependent H2O2-utilizing enzymes employ a carboxyl group within their active sites to facilitate H2O2 activation. Herein, we reveal for the first time that several CYP152 family members can directly degrade various aromatic pollutants without any carboxyl group, exhibiting novel aromatic hydroxylation and dehalogenation activities. Through crystal structure analysis, isotope tracing experiments, and QM/MM calculations, we elucidate that the phenolic hydroxyl group activated by electron-withdrawing substituent(s) functionally replaces the carboxyl group, forming hydrogen bonds with the conserved arginine leading to Compound I formation. The oxygen atom of the newly formed hydroxyl group originates from water, bypassing the conventional oxygen rebound step. These findings provide first insights into the mechanisms of P450 peroxygenases towards non-carboxylic substrates, expanding our knowledge of biological C-H activation and C-halogen bond cleavage beyond canonical P450 reactions. This discovery holds immense potential for harnessing these enzymes in innovative strategies for industrial biocatalysis and environmental remediation.

biochemistry↗

bioRxiv2024

Targeting and anchoring the mechanosensitive ion channel Piezo to facilitate its inhibition of axon regeneration

Mechanical force orchestrates a myriad of cellular events including inhibition of axon regeneration, by locally activating the mechanosensitive ion channel Piezo enriched at the injured axon tip. However, the cellular mechanics underlying Piezo localization and function remains poorly characterized. We show that the RNA repair/splicing enzyme Rtca acts upstream of Piezo to modulate its expression and transport/targeting to the plasma membrane via Rab10 GTPase, whose expression also relies on Rtca. Loss or gain of function of Rab10 promotes or impedes Drosophila sensory neuron axon regeneration, respectively. Rab10 mediates the cell surface expression of integrin {beta}1 (Itgb1)/mys, which colocalizes and genetically interacts with Piezo, facilitating its anchorage and engagement with the microenvironment, and subsequent activation of mechanotransduction to inhibit regeneration. Importantly, loss of Rtca, Rab10 or Itgb1 promotes CNS axon regeneration after spinal cord injury or optic nerve crush in adult mice, indicating the evolutionary conservation of the machinery.

neuroscience↗

bioRxiv2024

Venomics AI: a computational exploration of global venoms for antibiotic discovery

The relentless emergence of antibiotic-resistant pathogens, particularly Gram-negative bacteria, highlights the urgent need for novel therapeutic interventions. Drug-resistant infections account for approximately 5 million deaths annually, yet the antibiotic development pipeline has largely stagnated. Venoms, representing a remarkably diverse reservoir of bioactive molecules, remain an underexploited source of potential antimicrobials. Venom-derived peptides, in particular, hold promise for antibiotic discovery due to their evolutionary diversity and unique pharmacological profiles. In this study, we mined comprehensive global venomics datasets to identify new antimicrobial candidates. Using machine learning, we explored 16,123 venom proteins, generating 40,626,260 venom-encrypted peptides (VEPs). Using APEX, a deep learning model combining a peptide-sequence encoder with neural networks for antimicrobial activity prediction, we identified 386 VEPs structurally and functionally distinct from known antimicrobial peptides. Our analyses showed that these VEPs possess high net charge and elevated hydrophobicity, characteristics conducive to bacterial membrane disruption. Structural studies revealed considerable conformational flexibility, with many VEPs transitioning to -helical conformations in membrane-mimicking environments, indicative of their antimicrobial potential. Of the 58 VEPs selected for experimental validation, 53 displayed potent antimicrobial activity. Mechanistic assays indicated that VEPs primarily exert their effects through bacterial membrane depolarization, mirroring AMP-like mechanisms. In vivo studies using a mouse model of Acinetobacter baumannii infection demonstrated that lead VEPs significantly reduced bacterial burdens without notable toxicity. This study highlights the value of venoms as a resource for new antibiotics. By integrating computational approaches and experimental validation, venom-derived peptides emerge as promising candidates to combat the global challenge of antibiotic resistance.

bioengineering↗

bioRxiv2024

ldentify potential feature genes and immune cell infiltration of HIRI based on branched-chain amino acid-related genes by machine learning and experimental validation

BackgroundBranched-chain amino acid metabolism is involved in the pathogenesis of various liver diseases. In this study, we investigate the potential role of branched-chain amino acid metabolism-related genes in the pathogenesis of hepatic ischemia reperfusion (HIRI). MethodsThe gene Expression profiles of HIRI were obtained from the Gene Expression Omnibu database. To determine the differential expression of branched-chain amino acid metabolism-related genes between HIRI and normal tissues. Then, the GO and KEGG analyses were performed, and the protein-protein interaction network was constructed. Next, the random forest and LASSO algorithms were used to screen hub genes, and machine learning techniques were used to build diagnostic models. immunoinfiltration was analyzed in both HIRI patients and controls and the ceRNA network was established. Finally, quantitative real-time PCR was used to verify the expression of hub gene. ResultsBased on data set GSE23649, three central DEGs (SLC7A5, SLC1A5, SLC43A2) were determined by the intersection of three machine learning algorithms and used to establish a nomogram that yielded a high predictive performance (area under the curve 0.733-0.922). In the external GSE15480 dataset, AUC value for three key genes is as high as 1.000. Further analysis of nomogram, decision curve and calibration curve also confirme the predictive efficacy of diagnosis. GSEA and GSVA suggest that these three marker genes were involved in multiple pathways associated with HIRI progression. Immunoinfiltration analysis suggest that the proportion of macrophages, neutrophils, aDCs, Treg, and Th1 cells in HIRI group is higher than that in control group, with statistical significance(P<0.05). The ceRNA network demonstrates the complex regulatory relationships among the three hub genes and these mRNA levels were further confirmed in mouse HIRI liver samples. ConclusionsOur study have provided a comprehensive understanding of the association between branched-chain amino acid and HIRI, may provide potential target for HIRI treatment and diagnosis. And provide new insights into the mechanisms of HIRI. Graphical Abstract

bioinformatics↗

bioRxiv2024

Encephalomyocarditis virus non-structural protein 2C degrades NDP52 autophagy protein to promote its own survival

Encephalomyocarditis virus (EMCV) is an important zoonotic pathogen that causes encephalitis and myocarditis, primarily in pigs and in some mammals. Nuclear dot protein (NDP) 52 is an important autophagy adaptor protein that is known to target microbial pathogens, including viruses into autophagosomes to facilitate the selective autophagy process. Here, we wanted to investigate how an important zoonotic virus such as EMCV interacts with NDP52. We found that NDP52 negatively regulates the entry and replication phases of EMCV and interacts with EMCV VP1/VP2 proteins to mediate its autophagic degradation. EMCV counteracts this by exerting autophagy induction through its encoded 2C protein. The autophagy machinery then hijacks NDP52 and transports it to lysosomes for subsequent degradation via late endosomal molecules Rab7 and Rab9. Our study describes a novel mechanism by which EMCV escapes the hosts antiviral response to promote its survival by hijacking the autophagy pathway using the non-structural protein 2C of EMCV. ImportanceEMCV is an important zoonotic pathogen that can induce autophagy, but the regulatory role of autophagy receptors in EMCV infection has been rarely reported. Herein, we show that NDP52 is a novel host limiting factor for EMCV, which not only inhibits early EMCV endocytosis, but also restricts EMCV replication in vitro by controlling autophagic degradation of EMCV structural proteins VP1 and VP2. In order to counteract this, EMCV uses the N-terminal region of its non-structural protein 2C to interact with NDP52, and hijacks the autophagy machine to transport NDP52 to lysosomes for degradation, which weakens NDP52-mediated degradation of VP1 and VP2. Importantly, we reveal a novel mechanism by which EMCV evades the host antiviral response, contributing to a deeper understanding of the infectious mechanism of EMCV and providing new ideas for the design of antiviral drug targets.

microbiology↗