Biology subjects

Zhang, R.

Publications and source records attributed to Zhang, R..

At least 415 records · Page 23Linked to original sources

bioRxiv2022

Membrane-Bound O-Acyltransferase 7 (MBOAT7)-Driven Lysophosphatidylinositol (LPI) Acylation in Adipocytes Contributes to Systemic Glucose Homeostasis

Non-alcoholic fatty liver disease (NAFLD) is becoming increasingly common and is a leading cause of end stage liver diseases such as cirrhosis and hepatocellular carcinoma. The rise in NAFLD closely parallels the global epidemic of obesity and type 2 diabetes mellitus (T2DM), and there is a clear interrelationship between abnormal lipid metabolism, insulin resistance, and NAFLD progression. Several genetic loci have been identified as contributors to NAFLD progression, all of which are consistently linked to abnormal lipid metabolic processes in the liver. The common loss-of-function variant rs641738 (C>T) near the gene encoding Membrane-Bound O-Acyltransferase 7 (MBOAT7) is associated with increased susceptibility to NAFLD as well as the entire spectrum of NAFLD progression. The MBOAT7 gene encodes a lipid metabolic enzyme that is capable of esterifying polyunsaturated fatty acyl-CoAs to LPI substrates to generate phosphatidylinositol (PI) lipids. We previously showed that antisense oligonucleotide (ASO)-mediated knockdown of Mboat7 in mice promoted high fat diet-induced hepatic steatosis, hyperinsulinemia, and systemic insulin resistance (Helsley et al., 2019). Thereafter, other groups showed that hepatocyte-specific genetic deletion of Mboat7 promoted striking fatty liver and NAFLD progression but does not alter insulin sensitivity, suggesting the potential for cell autonomous roles. Here, we show that MBOAT7 function in adipocytes contributes to diet-induced metabolic disturbances including hyperinsulinemia and systemic insulin resistance. The expression of Mboat7 in white adipose tissue closely correlates with diet-induced obesity across a panel of [~]100 inbred strains of mice fed a high fat/high sucrose diet. Moreover, adipocyte-specific genetic deletion of Mboat7 is sufficient to promote hyperinsulinemia, systemic insulin resistance, and mild fatty liver. Unlike in the liver, where Mboat7 plays a relatively minor role in maintaining arachidonic acid (AA)-containing PI pools, Mboat7 is the major source of AA-containing PI pools in adipose tissue. Our data demonstrate that MBOAT7 is a critical regulator of adipose tissue PI homeostasis, and adipocyte MBOAT7-driven PI biosynthesis is closely linked to hyperinsulinemia and insulin resistance in mice.

biochemistry↗

bioRxiv2022

A toxin-mediated policing system in Bacillus improves population fitness via penalizing non-cooperating phenotypic cheaters

Microbial cooperation is vulnerable to exploitation by social cheaters. Although the strategies for controlling genotypic cheaters have been well investigated, the mechanism and significance of preventing phenotypic cheating remain largely unknown. Here, we revealed the molecular mechanism and ecological significance of a policing system for punishing phenotypic cheaters in the community of a plant beneficial strain Bacillus velezensis SQR9. Coordinated activation of extracellular matrix (ECM) production and autotoxin bacillunoic acids (BAs) biosynthesis/self-immunity, punished public goods-nonproducing cheaters in strain SQR9s community. Spo0A was identified to be the co-regulator for triggering both ECM production and BAs synthesis/immunity, which activates acetyl-CoA carboxylase (ACC) to produce malonyl-CoA, an essential precursor for BAs biosynthesis, thereby stimulating BAs production and self-immunity. Elimination of phenotypic cheaters by this policing system, significantly enhanced population fitness under different stress conditions and in plant rhizosphere. This study provides insights into our understanding of maintenance and evolution of microbial cooperation.

microbiology↗

bioRxiv2022

Inflammatory stress signaling via NF-kB alters accessible cholesterol to upregulate SREBP2 transcriptional activity in endothelial cells

There is a growing appreciation that a tight relationship exists between cholesterol homeostasis and immunity in leukocytes, however, this relationship has not been deeply explored in the vascular endothelium. Endothelial cells (ECs) rapidly respond to extrinsic signals, such as tissue damage or microbial infection, by upregulating factors to activate and recruit circulating leukocytes to the site of injury and aberrant activation of ECs leads to inflammatory based diseases, such as multiple sclerosis and atherosclerosis. Here, we studied the role of cholesterol and its master regulator, SREBP2, in the EC responses to inflammatory stress. Treatment of ECs with pro-inflammatory cytokines upregulates SREBP2 cleavage and cholesterol biosynthetic gene expression within the late phase of the acute inflammatory response. Furthermore, SREBP2 activation was dependent on NF-{kappa}B DNA binding and canonical SCAP-SREBP2 processing. Mechanistically, inflammatory activation of SREBP was mediated by a reduction in accessible cholesterol, leading to heightened sterol sensing and downstream SREBP2 cleavage. Detailed analysis of NF-{kappa}B inducible genes that may impact sterol sensing resulted in the identification of a novel RELA-inducible target, STARD10, that mediates accessible cholesterol homeostasis in ECs. Thus, this study provides an in-depth characterization of the relationship between cholesterol homeostasis and the acute inflammatory response in EC.

cell biology↗

bioRxiv2022

Deeply conserved super-enhancers maintain stem cell pluripotency in placental mammals

Despite pluripotent stem cells sharing key transcription factors, their maintenance involves distinct genetic inputs. Emerging evidence suggests that super-enhancers (SEs) can function as master regulatory hubs to control cell identity and pluripotency in humans and mice. However, whether pluripotency-associated SEs share a deep evolutionary origin in mammals remains elusive. Here, we performed comprehensive comparative epigenomic and transcription factor binding analyses among pigs, humans, and mice to identify pluripotency-associated SEs. Like typical enhancers, SEs displayed rapid evolution in mammals. We showed that BRD4 is an essential and conserved activator for mammalian pluripotency-associated SEs. Comparative motif enrichment analysis revealed 30 shared transcription factor binding motifs among the three species. The majority of the transcriptional factors that bind to identified motifs are known regulators associated with pluripotency. Further, we discovered three pluripotency-associated SEs (SE-SOX2, SE-PIM1, and SE-FGFR1) which displayed deep conservation in placental mammals and are sufficient to drive reporter gene expression in a pluripotency-dependent manner. Disruption of these conserved SEs through the CRISPR/Cas9 approach severely impaired the proliferative potential and the ability to form undifferentiated colonies. Our study provides insights into the understanding of conserved regulatory mechanisms underlying the maintenance of pluripotency as well as species-specific modulation of the pluripotency-associated regulatory networks in mammals. Significance statementSuper-enhancers (SEs) hold stronger power than regular enhancers to direct gene expression in the regulation of stem cell pluripotency. To dissect how pluripotency-associated SEs have evolved in mammals, we performed a systematic comparison of SEs among pigs, humans, and mice. Our analysis allowed the identification of three pluripotency-associated SEs (SE-SOX2, SE-PIM1, and SE-FGFR1) that are highly conserved in Placentalia (accounting for 94% of mammals) as well as many species-specific SEs. All three SEs were sufficient to direct pluripotency-dependent gene expression and disruption of each conserved SE caused the loss of stem cell pluripotency. Our work highlights a small number of highly conserved SEs essential for the maintenance of pluripotency.

cell biology↗

bioRxiv2022

Angiotensin II regulates the neural expression of subjective fear in humans

BackgroundRodent models and pharmacological neuroimaging studies in humans have been employed to test novel pharmacological agents to reduce fear. However, these strategies are limited with respect to determining process-specific effects on the actual subjective experience of fear which represents the key symptom why patients seek treatment. We here employed a novel precision pharmacological fMRI approach that is based on process-specific neuroaffective signatures to determine effects of the selective angiotensin II type 1 receptor (ATR1) antagonist losartan on the subjective experience of fear. MethodsIn a double-blind, placebo-controlled randomized pharmacological fMRI design n = 87 healthy participants were administered 50mg losartan or placebo before they underwent an oddball paradigm which included neutral, novel and fear oddballs. Losartan effects on brain activity and connectivity as well as on process-specific multivariate neural signatures were examined. ResultsAT1R blockade selectively reduces the neurofunctional reactivity to fear-inducing visual oddballs in terms of attenuating dorsolateral prefrontal activity and amygdala-ventral anterior cingulate (vACC) communication. Neurofunctional decoding further demonstrates fear-specific effects given that ATR1 blockade (1) reduces the neural expression of subjective fear, but not threat or non-specific negative expressions, and (2) does not affect reactivity to novel oddballs. ConclusionsThese results show a specific role of the AT1R in regulating subjective fear experience and demonstrate the feasibility of a precision pharmacological fMRI approach to the affective characterization of novel receptor targets for fear in humans.

neuroscience↗

bioRxiv2022

Increased glucose availability sensitizes pancreatic cancer to chemotherapy

Pancreatic cancer (Pancreatic Ductal Adenocarcinoma; PDAC) is highly resistant to chemotherapy. Effective alternative therapies have yet to emerge, leaving chemotherapy as the best available systematic treatment. The discovery of safe and available adjuncts that improve chemotherapeutic efficacy would potentially improve survival outcomes. We show that a hyperglycemic state enhances the efficacy of conventional single- and multi-agent chemotherapies against PDAC. Molecular analyses of tumors exposed to relatively high glucose levels revealed that a key metabolic pathway, glutathione biosynthesis, is diminished and underlies chemo-sensitization by enhancing oxidative injury to cancer cells. Inhibition of this pathway under normal conditions phenocopied a hyperglycemic state by enhancing chemotherapeutic efficacy in mouse PDAC, while rescuing the pathway under high glucose abrogated the anti-tumor effects observed with chemotherapy.

cancer biology↗

bioRxiv2022

Ultrafast and interpretable single-cell 3D genome analysis with Fast-Higashi

Single-cell Hi-C (scHi-C) technologies can probe three-dimensional (3D) genome structures in single cells and their cell-to-cell variability. However, existing scHi-C analysis methods are hindered by the data quality and the complex 3D genome patterns. The lack of computational scalability and interpretability poses further challenges for large-scale scHi-C analysis. Here, we introduce Fast-Higashi, an ultrafast and interpretable method based on tensor decomposition that can jointly identify cell identities and chromatin meta-interactions. Fast-Higashi is able to simultaneously model multiple tensors with unmatched features of different sizes. A new partial random walk with restart (Partial RWR) algorithm in Fast-Higashi efficiently mitigates data sparseness. Extensive evaluations on real scHi-C datasets demonstrate the advantage of Fast-Higashi over existing methods for embedding, leading to improved delineation of rare cell types and better reconstruction of developmental trajectories. Fast-Higashi can directly infer chromatin meta-interactions, identify 3D genome features that define distinct cell types, and help elucidate cell type-specific connections between genome structure and function. Moreover, Fast-Higashi can be generalized to incorporate other single-cell omics data. Fast-Higashi provides a highly efficient and interpretable scHi-C analysis solution that is applicable to a broad range of biological contexts.

bioinformatics↗

bioRxiv2022

Housekeeping gene gyrA, a potential molecular marker for Bacillus ecology study

Bacillus is a ubiquitous microorganism and is one of the most commercially important species widely used in industry, agriculture and healthcare. Bacillus is relatively well understood at the single-cell level; however, molecular tools that determine diversity and ecology of Bacillus community are limited, which limits our understanding of how the Bacillus community works. In the present study, we investigated the potential of the housekeeping gene gyrA as a molecular marker for determining the diversity of Bacillus species. The amplification efficiency for Bacillus species diversity could be greatly improved by primer design. Therefore, we designed a novel primer pair gyrA3 that can detect at least 92 Bacillus species and related species. For Bacillus amyloliquefaciens, Bacillus pumilus, and Bacillus megaterium, we observed that the high variability of the gyrA gene allows for more detailed clustering at the subspecies level that cannot be achieved by the 16S rRNA gene. Since gyrA provides better phylogenetic resolution than 16S rRNA and informs on the diversity of the Bacillus community, we propose that gyrA gene may have broad application prospects in the study of Bacillus ecology.

microbiology↗

bioRxiv2022

Ultra-high-throughput microbial single-cell whole genome sequencing for genome-resolved metagenomics

Microbes exist widely in nature. However, less than 1% of the species of microorganisms have been discovered so far, and more than 99% of microorganisms still remain unknown, which is called microbial dark matter. Unravelling microbial dark matter is not only helpful for exploring the unknown microbial world, but also of great significance for human health research. Ever since a long time ago, due to technical limitations, the microbiome, to a great extent, is still a black box. The traditional population-based metagenomic analysis tools are without single microbial resolution and they are stretched when studying rare and unknown microbial species. Here, we use high-throughput microdroplet technology to achieve the whole genome amplification of microbial single-cell genomes in pico-litter sized microdroplets, and develop subsequent library preparation steps such as indexing of the genome, to achieve the development of ultra-high-throughput microbial single-cell whole genome sequencing for genome-resolved metagenomics, aiming to provide a powerful new weapon for exploring microbial dark matter and other microbiological studies.

microbiology↗

bioRxiv2022

CHA1: A New Combinatorial Therapy That Reciprocally Regulates Wnt and JAK/STAT/Interferon Signaling to Re-program Breast Tumors and the Tumor-Resident Landscape.

Triple negative breast cancers (TNBC) pose exceptional challenges with fatal brain metastases as a clear and unmet need. Immune checkpoint inhibitors (ICIs) are promising therapeutic strategies, but most TNBC are resistant, or "cold" tumors, due to lack of tumor-resident immune engagement. No FDA-approved therapies exist which promote a "cold-to-hot" transition or induce the important biomarker PD-L1, often used for ICI clinical decision-making. Maximal ICI susceptibility, or a full "cold-to-hot" transition, requires reciprocal Wnt signaling inhibition and Jak/STAT/interferon signaling activation. We report a new compound combination (CHA1) that fits the above criteria. CHA1 is comprised of EGCG (epigallocatechin-3-gallate; green-tea compound) and decitabine (DNA-methyltransferase (DNMT1) inhibitor; 5deaza-cytidine; FDA-approved for hematologic malignancies). We used immune-compromised and syngeneic TNBC pre-clinical models to investigate tumor-intrinsic and tumor-resident T-cell effects, respectively. All results required CHA1 (but not EGCG or decitabine alone) and utilized attainable human dose equivalences with manageable safety profiles. CHA1 triggered efficient Wnt signaling inhibition by elevating Wnt pathway inhibitors (HBP1 and SFRP1) and traversed the blood-brain barrier to reduce both tumor and brain metastatic growth. Transcriptomic and expression analyses revealed that CHA1 treatment effectuated a robust tumor-intrinsic JAK/STAT/IFN response 1) to induce PDL1 and 2) to induce antigen presentation and processing genes, including MHC-1, MHC-2 and numerous genes attributed to professional antigen-presenting cells; 3) to induce CD8+-T-cell infiltration and activation. Additionally, CHA1 pre-treatment improved anti-PDL1 efficacy in a syngeneic setting. Lastly, we derived a composite gene signature emblematic of CHA1 treatment and of a favorable clinical prognosis in-silico. Together, our work supports a model in which CHA1 influences epigenetics, Wnt and Jak/STAT/IFN signaling mechanisms--all to reprogram an epithelial-mesenchymal TNBC tumor to express antigen-presenting properties and to recruit and activate tumor-resident CD8+-T-cells. We discuss our findings in the context of cancer biology and immunity with implications for improving ICI susceptibility for TNBC.

cancer biology↗

bioRxiv2022

Fast-synaptic axo-axonal transmission from striatal cholinergic interneurons onto dopamine fibers.

Transmission from striatal cholinergic interneurons (CINs) controls dopamine release through nicotinic acetylcholine receptors (nAChRs) on dopaminergic axons. Anatomical studies suggest that cholinergic terminals signal predominantly through non-synaptic volume transmission. However, the influence of cholinergic transmission on electrical signaling in axons remains unclear. We examined axo-axonal transmission from CINs onto dopaminergic axons using perforated-patch recordings which revealed rapid spontaneous EPSPs with properties characteristic of fast synapses. Pharmacology showed that axonal EPSPs (axEPSPs) were mediated primarily by high-affinity 6-containing receptors. Remarkably, axEPSPs triggered spontaneous action potentials locally in dopaminergic axons, suggesting these axons perform integration to convert synaptic input into spiking, a function associated with somatodendritic compartments. We investigated cross-species validity of cholinergic axo-axonal transmission by recording dopaminergic axons in macaque putamen and found similar axEPSPs. Thus, we reveal that fast synaptic-like neurotransmission underlies cholinergic signaling onto dopaminergic axons, providing insight into how nicotinic receptors shape electrical signaling directly in axon terminals.

neuroscience↗

bioRxiv2022

LSMMD-MA: Scaling multimodal data integration for single-cell genomics data analysis

MotivationModality matching in single-cell omics data analysis--i.e., matching cells across data sets collected using different types of genomic assays--has become an important problem, because unifying perspectives across different technologies holds the promise of yielding biological and clinical discoveries. However, single-cell dataset sizes can now reach hundreds of thousands to millions of cells, which remains out of reach for most multi-modal computational methods. ResultsWe propose LSMMD-MA, a large-scale Python implementation of the MMD-MA method for multimodal data integration. In LSMMD-MA we reformulate the MMD-MA optimization problem using linear algebra and solve it with KeOps, a CUDA framework for symbolic matrix computation in Python. We show that LSMMD-MA scales to a million cells in each modality, two orders of magnitude greater than existing implementations. AvailabilityLSMMD-MA is freely available at https://github.com/google-research/large_scale_mmdma Contactlpapaxanthos@google.com

bioinformatics↗

bioRxiv2022

Global Spatial Transcriptome of Macaque Brain at Single-Cell Resolution

Global profile of gene expression at single-cell resolution remains to be determined for primates. Using a recently developed technology ("Stereo-seq"), we have obtained a comprehensive single-cell spatial transcriptome map at the whole-brain level for cynomolgus monkeys, with [~]600 genes per cell for 10 m-thick coronal sections (up to 15 cm2 in size). Large-scale single-nucleus RNA-seq analysis for [~]1 million cells helped to identify cell types corresponding to Stereo-seq gene expression profiles, providing a 3-D cell type atlas of the monkey brain. Quantitative analysis of Stereo-seq data revealed molecular fingerprints that mark distinct neocortical layers and subregions, as well as domains within subcortical structures including hippocampus, thalamus, striatum, cerebellum, hypothalamus and claustrum. Striking whole-brain topography and coordinated patterns were found in the expression of genes encoding receptors and transporters for neurotransmitters and neuromodulators. These results pave the way for cellular and molecular understanding of organizing principles of the primate brain.

cell biology↗

bioRxiv2022

Configurable Compartmentation Enables In vitro Reconstitution of Sustained Synthetic Biology Systems

The compartmentalized and communicative nature of biological cells contributes to the complexity and endurance of living organisms. Current in vitro compartmentalization systems such as droplet emulsions reproduce the compartmentalization property of cells yet fail to recapture the configurability of cellular communication with the environment. To mimic biological cells a step further and expand the capabilities of in vitro compartmentalization, we present here a general strategy that inherits the passive transport phenomenon of biology. The strategy incorporates layered, micrometer-sized, hydrogel-based compartments featuring configurability in composition, functionality, and selective permeability of biomolecules. We demonstrated the unique advantage of our strategy in two scenarios of synthetic biology. First, a compartmentalized cell-free protein synthesis system was reconstituted that could support multiple rounds of reactions. Second, we constructed living bacteria-based biosensors in the hydrogel compartments, which could achieve long-lasting functioning with markedly enhanced fitness in complex environments. Looking forward, our strategy should be widely applicable for constructing complex, robust, and sustained in vitro synthetic molecular and cellular systems, paving the way for their practical applications.

synthetic biology↗

bioRxiv2022

Angiotensin blockade enhances motivational reward learning via enhancing ventral striatal prediction error and frontostriatal communication

Adaptive human learning utilizes reward prediction errors (RPEs) that scale the differences between expected and actual outcomes to optimize future choices. Depression has been linked with biased RPE signaling and an exaggerated impact of negative outcomes on learning which may promote amotivation and anhedonia. The present proof-of-concept study combined computational modelling and multivariate decoding with neuroimaging to determine the influence of the selective competitive angiotensin II type 1 receptor antagonist losartan on learning from positive or negative outcomes and the underlying neural mechanisms in healthy humans. In a double-blind, between-subjects, placebo-controlled pharmaco-fMRI experiment, 61 healthy male participants (losartan, n=30; placebo, n=31) underwent a probabilistic selection reinforcement learning task incorporating a learning and transfer phase. Losartan improved choice accuracy for the hardest stimulus pair via increasing expected value sensitivity towards the rewarding stimulus relative to the placebo group during learning. Computational modelling revealed that losartan reduced the learning rate for negative outcomes and increased exploitatory choice behaviors while preserving learning for positive outcomes. These behavioral patterns were paralleled on the neural level by increased RPE signaling in orbitofrontal-striatal regions and enhanced positive outcome representations in the ventral striatum (VS) following losartan. In the transfer phase, losartan accelerated response times and enhanced VS functional connectivity with left dorsolateral prefrontal cortex when approaching maximum rewards. These findings elucidate the potential of losartan to reduce the impact of negative outcomes during learning and subsequently facilitate motivational approach towards maximum rewards in the transfer of learning. This may indicate a promising therapeutic mechanism to normalize distorted reward learning and fronto-striatal functioning in depression.

neuroscience↗

bioRxiv2022

High salinity activates CEF and attenuates state transitions in both psychrophilic and mesophilic Chlamydomonas species

In the last decade, studies have revealed the importance of PSI-driven cyclic electron flow (CEF) in stress acclimation in model organisms like C. reinhardtii; however, these studies focused on transient, short-term stress. In addition, PSI-supercomplexes are associated with CEF during state transition response to short-term stress. On the other hand, the role of CEF during long-term stress acclimation is still largely unknown. In this study, we elucidate the involvement of CEF in acclimation response to long-term high salinity in three different Chlamydomonas species displaying varying salinity tolerance. We compared CEF rates, capacity for state transitions, and formation of supercomplexes after salinity acclimation in the model mesophile C. reinhardtii and two psychrophilic green algae C. priscuii (UWO241) and C. sp. ICE-MDV. CEF was activated under high salt in all three species, with the psychrophilic Chlamydomonas spp. exhibiting the highest CEF rates. High salt acclimation was also correlated with reduced state transition capacity and a PSI-supercomplex was associated with high CEF. We propose that under long-term stress, CEF is constitutively activated through assembly of a stable PSI-supercomplex. The proteomic composition of the long-term PSI-supercomplex is distinct from the supercomplex formed during state transitions, and its presence attenuates the state transition response.

plant biology↗

bioRxiv2022

LCK-14-3-3ζ-TRPM8 axis for regulating TRPM8 function/assembly promotes pancreatic cancer malignancy

The transient receptor potential melastatin 8 (TRPM8), function as a Ca2+-permeable channel in the plasma membrane (PM). Dysfunction of TRPM8 is associated with human pancreatic cancer and several other diseases in clinical patients, but with unclear underlying mechanisms. Here, we found lymphocyte-specific protein tyrosine kinase (LCK) directly interacts with TRPM8 and potentiates TRPM8 phosphorylation at Y1022. LCK positively regulated channel function characterized by increased TRPM8 currents densities through enhancing TRPM8 multimerization. Furthermore, 14-3-3{zeta} interacted with TRPM8 and positively modulated channel multimerization. LCK significantly enhanced the binding of 14-3-3{zeta} and TRPM8, whereas mutant TRPM8-Y1022F impaired TRPM8 multimerization and the binding of TRPM8 and 14-3-3{zeta}. Knockdown of 14-3-3{zeta} impaired the regulation of LCK on TRPM8 multimerization. Additionally, TRPM8 phosphotyrosine at Y1022 feedback regulated LCK activity by inhibition of Tyr505 phosphorylation and modulation of LCK ubiquitination. Finally, we revealed the importance of TRPM8 phosphorylation at Y1022 in the proliferation, migration and tumorigenesis of pancreatic cancer cells. Our findings demonstrate that LCK-14-3-3{zeta}-TRPM8 axis for regulating TRPM8 assembly, channel function, LCK activity and providing potential therapeutic targets for pancreatic cancer.

cell biology↗

bioRxiv2022

Structural basis for the neurotropic AAV9 and the engineered AAVPHP.eB recognition with cellular receptors

Clade F adeno-associated virus (AAV) 9 has been utilized as therapeutic gene delivery vector, and it is capable of crossing blood brain barrier (BBB). Recently, an AAV9 based engineering serotype with enhanced BBB crossing ability, AAVPHP.eB, further expand clade F AAVs usages in the central nervous system (CNS) gene delivery. In this study, we determined the cryo-electron microscopy (cryo-EM) structures of the AAVPHP.eB, and its parental serotype AAV9 alone or in complex with their essential receptor Adeno-associated virus receptor (AAVR). These structures reveal the molecular details of their AAVR recognition, where the polycystic kidney disease (PKD) repeat domain 2 (PKD2) of AAVR interact to the 3-fold protrusions and the raised capsid regions between the 2- and 5-fold axes termed the 2/5-fold wall of both AAV9 and AAVPHP.eB virions. The interacting patterns of AAVR to AAV9 and AAVPHP.eB are similar with what was observed in AAV1/AAV2-AAVR complexes. Moreover, we found that AAVPHP.eB variable region VIII (VR-VIII) may independently facilitate the new receptor recognition responsible for enhanced CNS transduction. Our study provides insights into different receptor recognition for engineered AAVPHP.eB and parental serotype AAV9, and further reveal the potential molecular basis underlying their different tropism.

microbiology↗