Biology subjects

Sakurai, M.

Publications and source records attributed to Sakurai, M..

At least 19 recordsLinked to original sources

bioRxiv2026

Effects of CO2 on the growth and metabolism of Akkermansia muciniphila

The human gut is home to more than 100 trillion bacteria, where various environmental factors, such as nutrients and gases, exist and influence them. The levels of fermentation gases in the gut, including CO2, fluctuate depending on the host's diet. However, how CO2, an environmental factor, affects the physiological states of gut anaerobes remains poorly understood, but CO2 is often utilized in their cultivation. Akkermansia muciniphila (A. muciniphila) is widely studied as a beneficial human gut microbe. However, the effects of CO2 on the physiological state of A. muciniphila are not fully understood. In this study, we focused on CO2 as an environmental factor and aimed to clarify how CO2 affects the physiological state of A. muciniphila. Culture experiments showed that compared with the absence of CO2, the presence of CO2 significantly increased the growth of A. muciniphila. The results of the metabolomic analysis revealed distinct metabolic profiles in the presence or absence of CO2. The tracing analysis using stable 13C-labelled CO2 demonstrated that CO2 was incorporated into various metabolites in the TCA cycle, the de novo purine/pyrimidine synthesis pathways, and other pathways. In addition, the activity of pyruvate carboxylase, which catalyses an anaplerotic reaction involving CO2 fixation to supply oxaloacetate (OAA) to the TCA cycle, was significantly higher in A. muciniphila cells grown in the presence of CO2. Moreover, supplementation with OAA increased the growth of A. muciniphila in a dose-dependent manner, mirroring the effects of CO2 supplementation. These findings suggest that A. muciniphila utilizes CO2 for an anaplerotic reaction in the TCA cycle and other pathways involving CO2 incorporation, facilitating metabolic flux to promote its robust growth.

microbiology↗

bioRxiv2026

STING activation drives pericentrosomal positioning of acidic organelles via the VAIL-LRRK2-Rab35 pathway

The cGAS-STING pathway is an innate immune system that responds to cytoplasmic double-stranded DNA, but recent studies have highlighted its noncanonical role in facilitating lysosomal stress responses. Specifically, STING activation has been shown to trigger V-ATPase-ATG16L1-induced LC3 lipidation (VAIL) and to activate LRRK2, a Parkinson disease-associated kinase, but the detailed molecular mechanism and the physiological roles of the activation have remained unclear. Here, we found that STING activation in microglia induces the translocation of LRRK2 to the pericentrosomal area, where lysosomes and recycling endosomes (REs) concentrate. This process was VAIL-dependent, and LRRK2 was found to be localized to the organelles. The translocation of LRRK2 required intact microtubule structures and was mediated by LRRK2 kinase activity, its substrate Rab35 and the motor adaptor proteins including JIP4. All these proteins were concentrated at the pericentrosomal area upon STING stimulation. The hyperactivating G2019S mutation of LRRK2 promoted the pericentrosomal translocation of these proteins. Overall, we propose a novel STING-induced noncanonical pathway that involves LRRK2 to facilitate pericentrosomal organelle positioning.

cell biology↗

bioRxiv2026

Subtype-specific secretion of extracellular vesicles by LRRK2 and Rab GTPases under lysosomal stress

LRRK2, the Parkinsons disease-associated kinase, phosphorylates a subset of Rab GTPases and regulates membrane dynamics. We previously reported that lysosomal stress activates LRRK2 and thereby induces the exocytic secretion of lysosomal contents, but the detailed secretion mechanism remained unclear. Here we found that, under lysosomal stress, endolysosomal luminal and membrane components were secreted with extracellular vesicles (EVs) via LRRK2. Bis(monoacylglycerol)phosphate, an endolysosomal lipid and a urinary marker of LRRK2 activity, was similarly secreted via LRRK2, whereas CD9-positive EVs were not involved. Further dissection of the secreted EVs revealed that Alix-positive EVs were secreted via Rab8a as well as the ESCRT component VPS4, whereas LAMP1/cathepsin B-positive EVs were secreted via Rab10/Rab35, and SNARE proteins syntaxin 2 and VAMP8 regulated the secretion of both EV subtypes. These findings suggest a distinctive stress-induced secretory mechanism whereby LRRK2 facilitates the secretion of multiple EV subtypes by controlling Rab GTPases involved in each pathway.

cell biology↗

bioRxiv2025

LRRK2 is activated by phosphatidylinositol 3-phosphate in conjunction with CASM

LRRK2 is a Parkinsons disease (PD)-associated kinase that phosphorylates Rab GTPases. Hyperactivation of LRRK2, which is thought to cause PD, occurs on stressed endolysosomal membranes via CASM (conjugation of ATG8 to single membranes) and Rab, whereas the involvement of specific membrane lipids remained unclear. Here, we found that LRRK2 was potently activated upon treatment with PIKfyve inhibitors that increase cellular phosphatidylinositol 3-phosphate (PI3P) levels, and that additional treatment with the class III phosphoinositide 3-kinase (PI3K) inhibitors blocking PI3P generation suppressed LRRK2 activation. Cellular PI3P levels were indeed correlated with the LRRK2 kinase activity. CASM-induced LRRK2 activation, but not CASM itself, was suppressed by PI3K inhibitors, whereas inhibition of CASM or Rab12/Rab29 suppressed LRRK2 activation induced by PIKfyve inhibitors. LRRK2 and phospho-Rab10 were co-localized with PI3P on LAMP1-positive enlarged vacuoles, and LRRK2 directly bound PI3P in vitro via its N-terminal positively charged amino acids. Together, we propose an updated mechanism of LRRK2 activation that requires CASM, Rab and PI3P-rich membranes.

cell biology↗

bioRxiv2025

Progeny-based genomic selection reveals untapped genetic potential in an underutilized medicinal plant, Perilla frutescens

O_LIDespite their substantial therapeutic value, medicinal plants have undergone limited genetic improvement through breeding because of the scarcity of expert breeders. Moreover, quantifying bioactive compounds is expensive. Genomic selection (GS), which leverages genome-wide markers to predict breeding values and assemble favorable alleles, offers a practical way to unlock latent genetic potential. As a model case, we evaluated GS in red perilla (Perilla frutescens). C_LIO_LIBuilding on previous work, we implemented a cross-selection strategy that prioritized segregation variance by selecting crosses based on predicted additive genotypic values of the progeny, and evaluated its effectiveness through actual crossing experiments targeting three key medicinal compounds. C_LIO_LIProgeny from GS-based crosses (Crs1-Crs7) outperformed those from phenotypic selection (Crs8) in the G2 generation, demonstrating a higher mean, greater variance, and superior top individuals. The best G2 individual exhibited nearly twofold higher levels of two target compounds relative to the existing cultivar Sekiho. C_LIO_LIThis study provides the first empirical demonstration that GS can improve multiple medicinal compounds in red perilla and highlights the effectiveness of cross-selection based on predicted progeny performance. In addition, the evidence presented here supports the broader application of GS in underutilized medicinal plants. C_LI

genetics↗

bioRxiv2025

The caninized anti-canine PD-1 monoclonal antibody in canine oral malignant melanoma: Efficacy and exploratory biomarker analysis

BackgroundCanine oral malignant melanoma (OMM) is a highly aggressive tumor with few treatment options. Because of its biological similarity to human mucosal melanoma, canine OMM represents a valuable spontaneous model for translational immunotherapy studies. Anti-PD-1 antibody therapy has shown promise in canine OMM; however, predictive biomarkers for treatment response and survival have not been identified. MethodsWe conducted a multicenter, prospective, investigator-initiated clinical trial to evaluate the safety and efficacy of a caninized anti-canine PD-1 monoclonal antibody (ca-4F12-E6) in 150 dogs with advanced OMM. The dogs were administered 3 mg/kg ca-4F12-E6 intravenously every two weeks. Treatment response was assessed using cRECIST v1.0. Biomarker analyses included peripheral blood parameters, cytokine/chemokines, peripheral lymphocyte subsets, microsatellite instability (MSI), immunohistochemistry for immune cell and mismatch repair protein markers, and RNA sequencing of the tumor tissue. Associations with clinical outcomes were determined by logistic regression and Cox proportional hazard models. ResultsThe best overall response rate was 16.7%. Treatment-related adverse events occurred in 40.0% of the dogs, which were primarily grade 1-3. Increased baseline white blood cell, neutrophil count, and C-reactive protein (CRP) levels were significantly associated with poor response, shorter progression-free survival (PFS), and reduced overall survival (OS). MSI-high tumors were associated with significantly prolonged OS compared with MSI-low/microsatellite stable tumors. Transcriptome analysis revealed differentially expressed genes and enriched immune-related pathways in responders, though limited by sample size. Conclusionca-4F12-E6 exhibited durable antitumor activity and an acceptable safety profile in dogs with OMM. Baseline systemic inflammatory markers and MSI status may serve as predictive biomarkers for clinical outcomes. The results support the use of canine OMM as a comparative model for human immuno-oncology and biomarker discovery.

cancer biology↗

bioRxiv2025

Mitotic phosphorylation of ADAR1 regulates its centromeric localization and is required for faithful mitotic progression

Adenosine Deaminase Acting on RNA 1 p110 (ADAR1p110), the constitutively expressed nuclear isoform of the RNA-editing enzyme ADAR1, plays well-established roles in adenosine-to-inosine RNA editing, but its functions during mitosis remain poorly defined. Here, we identify ADAR1p110 as a chromatin-associated factor essential for mitotic chromosome segregation and cell viability. Depletion of ADAR1 caused metaphase arrest, DNA damage accumulation, and apoptosis. Co-immunoprecipitation experiments revealed that ADAR1p110 physically interacts with Structural Maintenance of Chromosome 3 (SMC3), a core component of the cohesin complex. Genome-wide DNA immunoprecipitation sequencing (DIP-seq) showed that ADAR1p110 selectively binds centromeric -satellite DNA during mitosis, a finding validated by DNA immunoprecipitation quantitative polymerase chain reaction (DIP-qPCR). Complementary DNA-RNA immunoprecipitation sequencing (DRIP-seq) revealed that RNA:DNA hybrids (R-loops) are enriched in centromeric regions during mitosis and are further augmented by ADAR1 overexpression. We identified serine 614 (S614) as a key mitosis-specific phosphorylation site on ADAR1p110, and demonstrated that this post-translational modification is essential for its chromatin recruitment, stability, and mitotic function. Rescue experiments using phospho-mimetic mutants (S614D and 3xD) successfully restored mitotic progression in ADAR1-deficient cells, whereas non-phosphorylatable variants failed to do so. These results reveal that ADAR1p110 is phosphorylated in a cell cycle-dependent manner and functions at the intersection of post-transcriptional and post-translational regulation. By coordinating R-loop recognition at centromeres with chromosome cohesion, ADAR1p110 safeguards genome integrity during mitosis. Our findings uncover a previously uncharacterized mechanism through which a canonical RNA-editing enzyme contributes to chromosomal dynamics independent of its deaminase activity.

molecular biology↗

bioRxiv2025

Optimization of crossing strategy based on the usefulness criterion in inter-population crosses considering different genetic effects among populations

In the breeding programs of self-pollinated plants, achieving genetic improvement in multiple traits can be challenging when relying solely on a single biparental population. Interpopulation crosses are employed to integrate favorable alleles from multiple biparental populations to overcome this limitation. In this context, it is crucial to consider the distinct genetic effects in different populations. In this study, we utilized a selection method based on the usefulness criterion (UC) to identify cross pairs suitable for interpopulation crosses. We expanded this approach to enhance breeding programs accounting for varying genetic backgrounds within the genomic selection framework. Using the medicinal plant red perilla as the study material, we conducted simulations to compare the efficacy of selection based on estimated genomic breeding values with that based on UC. Our findings demonstrate that the proposed method is effective in facilitating the simultaneous improvement of multiple traits, particularly by considerably increasing genetic gains among the top-performing individuals in the population. Furthermore, we provide guidelines for implementing interpopulation crosses, including recommendations for the optimal generation for crossing and the appropriate reference generation for calculating the UC. The results obtained in this study offer valuable insights for small-scale breeding programs aimed at simultaneously enhancing multiple traits through inter-population crosses and are applicable to a wide range of crops, including neglected and underutilized species. Key MessageHerein, a method has been proposed for selecting optimal cross pairs based on the genetic potential of progeny in inter-population crosses, considering different genetic effects among populations.

bioinformatics↗

bioRxiv2024

Dysregulation of FicD AMPylation causes diabetes by disrupting pancreatic endocrine homeostasis

Bi-functional enzyme FicD regulates the endoplasmic reticulum chaperone BiP using AMPylation and deAMPylation during ER homeostasis and stress, respectively. Human FicD with an arginine-to-serine mutation disrupts FicD deAMPylation activity resulting in severe neonatal diabetes. We generated the FicDR371S mutation in mice to create a pre-clinical murine model for neonatal diabetes. We observed elevated BiP AMPylation levels across multiple tissues and signature markers for diabetes including glucose intolerance and reduced serum insulin levels. While the pancreas of FicDR371S mice appeared normal at birth, adult FicDR371S mice displayed disturbed pancreatic islet organization that progressed with age. FicDR371S mice provide a preclinical mouse model for the study of UPR associated diabetes and demonstrate the essentiality of FicD for tissue resilience.

physiology↗

bioRxiv2024

Ephrin Forward Signaling Controls Interspecies Cell Competition in Pluripotent Stem Cells

In the animal kingdom, evolutionarily conserved mechanisms known as cell competition eliminate unfit cells during development. Interestingly, cell competition also leads to apoptosis of donor cells upon direct contact with host cells from a different species during interspecies chimera formation. The mechanisms underlying how host animal cells recognize and transmit cell death signals to adjacent xenogeneic human cells remain incompletely understood. In this study, we developed an interspecies cell contact reporter system to dissect the mechanisms underlying competitive interactions between mouse and human pluripotent stem cells (PSCs). Through single-cell RNA-seq analyses, we discovered that Ephrin A ligands in mouse cells play a crucial role in signaling cell death to adjacent human cells that express EPHA receptors during interspecies PSC co-culture. We also demonstrated that blocking the Ephrin A-EPHA receptor interaction pharmacologically, and inhibiting Ephrin forward signaling genetically in the mouse cells, enhances the survival of human PSCs and promotes chimera formation both in vitro and in vivo. Our findings elucidate key mechanisms of interspecies PSC competition during early embryogenesis and open new avenues for generating humanized tissues or organs in animals, potentially revolutionizing regenerative medicine.

cell biology↗

bioRxiv2024

B chromosome and its non-Mendelian inheritance in Atractylodes lancea

Supernumerary B chromosomes contribute to intraspecific karyotypic variation. B chromosomes have been detected in more than 2000 organisms; they possess unique and diverse features, including non-Mendelian inheritance. Here we report one or more B chromosomes in the gynodioecious plant, Atractylodes lancea. Among 54 A. lancea lines, 0-2 B chromosomes were detected in both hermaphroditic and female plants, with the B chromosomes appearing as DAPI-bright regions within the nuclei. Genomic in situ hybridization revealed that the B chromosomes had no conserved A chromosome DNA sequences, which was confirmed by fluorescence in situ hybridization probed with independently dissected B chromosomes. In male meiosis, the B chromosome did not pair with an A chromosome and was therefore eliminated; accordingly, only 20.1% and 18.6% of these univalent B chromosomes remained at the end of meiosis for the 1B lines of KY17-148 and KY17-118, respectively. However, we also found that B chromosomes were transmitted from male parents in 40.8%-44.2% and 47.2% of the next generation; although these transmission rates from male parents were not essentially different from Mendelian inheritance (0.5), the transmission of gametes carrying B chromosomes increased through fertilization or seed development. B chromosomes were transmitted from three of four 1B female parents to 64.3%-92.6% of the next generation, suggesting B chromosome accumulation. We propose that the B chromosome of A. lancea has a specific sequence and persists via non-Mendelian inheritance from female parents. Overall, A. lancea is a useful material for understanding the structure, evolution, and mechanism of non-Mendelian inheritance of B chromosomes.

genetics↗

bioRxiv2024

Biochemical and structural insights into a 5' to 3' RNA ligase reveal a potential role in tRNA ligation

ATP-grasp superfamily enzymes contain a hand-like ATP-binding fold and catalyze a variety of reactions using a similar catalytic mechanism. More than 30 protein families are categorized in this superfamily, and they are involved in a plethora of cellular processes and human diseases. Here we identify C12orf29 as an atypical ATP-grasp enzyme that ligates RNA. Human C12orf29 and its homologs auto-adenylate on an active site Lys residue as part of a reaction intermediate that specifically ligates RNA halves containing a 5-phosphate and a 3-hydroxyl. C12orf29 binds tRNA in cells and can ligate tRNA within the anticodon loop in vitro. Genetic depletion of c12orf29 in female mice alters global tRNA levels in brain. Furthermore, crystal structures of a C12orf29 homolog from Yasminevirus bound to nucleotides reveal a minimal and atypical RNA ligase fold with a unique active site architecture that participates in catalysis. Collectively, our results identify C12orf29 as an RNA ligase and suggest its involvement in tRNA biology. Significance StatementATP-grasp enzymes share an atypical ATP-binding fold and catalyze a diverse set of reactions involved in many essential cellular processes. We identified C12orf29 as an atypical ATP-grasp enzyme. Our biochemical and structural characterizations reveal this enzyme to be a 5 to 3 RNA ligase, structurally and functionally similar to the phage T4 RNA ligase. C12orf29 can ligate tRNAs in vitro and C12orf29 knockout female mice have altered tRNA levels in brain. We also report structures of C12orf29, which have revealed critical insights into the mode of ATP binding and catalysis. Our work suggests that C12orf29 may be a new player in the regulation of tRNAs.

biochemistry↗

bioRxiv2024

TASOR expression in naive embryonic stem cells safeguards their developmental potential

The seamless transition through stages of pluripotency relies on a delicate balance between transcription factor networks and epigenetic silencing mechanisms that ensure proper regulation of the developmental program, critical for normal development. Here, we uncover the pivotal role of the transgene activation suppressor (TASOR), a component of the human silencing hub (HUSH) complex, in sustaining cell viability during the transition from naive to primed pluripotency, despite its rapid downregulation during this transition. Loss of TASOR in naive cells triggers replication stress, disrupts H3K9me3 heterochromatin formation, and compromise the transcriptional and post-transcriptional silencing of LINE-1 (L1) transposable elements (TEs), with these effects become more pronounced in primed cells. Remarkably, the survival of Tasor-knockout cells during naive to primed transition can be restored through the inhibition of cysteine-aspartic acid protease (Caspase) or deletion of mitochondrial antiviral signaling protein (MAVS). This suggests that unscheduled L1 expression activates an innate immune response, leading to programmed cell death, specifically in cells exiting naive pluripotency. Additionally, we propose that HUSH-promoted H3K9me3 in naive PSCs sets the stage for ensuing DNA methylation in primed cells, establishing long-term silencing during differentiation. Our findings shed insights on the crucial impact of epigenetic programs established in early developmental stages on subsequent phases, underscoring their significance in the developmental process.

developmental biology↗

bioRxiv2024

An inappropriate decline in ribosome levels drives a diverse set of neurodevelopmental disorders

Many neurodevelopmental defects are linked to perturbations in genes involved in housekeeping functions, such as those encoding ribosome biogenesis factors. However, how reductions in ribosome biogenesis can result in tissue and developmental specific defects remains a mystery. Here we describe new allelic variants in the ribosome biogenesis factor AIRIM primarily associated with neurodevelopmental disorders. Using human cerebral organoids in combination with proteomic analysis, single-cell transcriptome analysis across multiple developmental stages, and single organoid translatome analysis, we identify a previously unappreciated mechanism linking changes in ribosome levels and the timing of cell fate specification during early brain development. We find ribosome levels decrease during neuroepithelial differentiation, making differentiating cells particularly vulnerable to perturbations in ribosome biogenesis during this time. Reduced ribosome availability more profoundly impacts the translation of specific transcripts, disrupting both survival and cell fate commitment of transitioning neuroepithelia. Enhancing mTOR activity by both genetic and pharmacologic approaches ameliorates the growth and developmental defects associated with intellectual disability linked variants, identifying potential treatment options for specific brain ribosomopathies. This work reveals the cellular and molecular origins of protein synthesis defect-related disorders of human brain development. HighlightsO_LIAIRIM variants reduce ribosome levels specifically in neural progenitor cells. C_LIO_LIInappropriately low ribosome levels cause a transient delay in radial glia fate commitment. C_LIO_LIReduced ribosome levels impair translation of a selected subset of mRNAs. C_LIO_LIGenetic and pharmacologic activation of mTORC1 suppresses AIRIM-linked phenotypes. C_LI

developmental biology↗

bioRxiv2023

Assessing the potential for genome-assisted breeding in red perilla using quantitative trait locus analysis and genomic prediction

Red perilla is an important medicinal plant used in Kampo medicine, and the development of elite varieties of this species is urgently necessary. Medicinal compounds are generally considered target traits in medicinal plant breeding; however, selection based on the phenotypes of the compounds (i.e., conventional selection) is expensive and time-consuming. Here, we proposed genomic selection (GS) and marker-assisted selection (MAS) as suitable selection methods for medicinal plants, and evaluated the effectiveness of GS and MAS in red perilla breeding. Three breeding populations generated from crosses between one red and three green perilla genotypes were used to elucidate the genetic mechanisms underlying the production of major medicinal compounds using quantitative trait locus analysis and to evaluate the accuracy of genomic prediction (GP). We found that GP had sufficiently high accuracy for all traits, confirming that GS was an effective method for perilla breeding. Moreover, the three populations showed varying degrees of segregation, suggesting that use of these populations in breeding may yield simultaneous enhancements of different target traits. This study can contribute to research on the genetic mechanisms of the major medicinal compounds of red perilla as well as the breeding efficiency of this medicinal plant.

genomics↗

bioRxiv2023

The V-ATPase-ATG16L1 axis recruits LRRK2 to facilitate lysosomal stress responses

Leucine-rich repeat kinase 2 (LRRK2), a Rab kinase associated with Parkinsons disease and several inflammatory diseases, has been shown to localize to stressed lysosomes and get activated to regulate lysosomal homeostasis. However, the mechanisms of LRRK2 recruitment and activation have not been well understood. Here we found that the ATG8 conjugation system regulates the recruitment of LRRK2 as well as LC3 onto single membranes of stressed lysosomes/phagosomes. This recruitment did not require FIP200-containing autophagy initiation complex, nor did it occur on double-membrane autophagosomes, suggesting independence from canonical autophagy. Consistently, LRRK2 recruitment was regulated by the V-ATPase-ATG16L1 axis, which requires the WD40 domain of ATG16L1 and specifically mediates ATG8 lipidation on single membranes. This mechanism was also responsible for the lysosomal stress-induced activation of LRRK2 and the resultant regulation of lysosomal secretion and enlargement. These results indicate that the V-ATPase-ATG16L1 axis serves a novel non-autophagic role in the maintenance of lysosomal homeostasis by recruiting LRRK2.

molecular biology↗

bioRxiv2023

Building functional circuits in multispecies brains.

The genome is the ultimate architect of the brain. Its evolutionary variations build the neural circuits that endow each species with its innate senses and behaviors. A central question for neuroscience and translational medicine is whether neural circuits from two species can be made to function in an intact brain. Here, we establish genetic tools and use blastocyst complementation to selectively build and test interspecies neural circuits in rat-mouse brains. Despite [~]10-20 million years of evolution and prominent differences in brain size and cellular composition, rat pluripotent stem cells injected into mouse blastocysts widely populate and persist in the mouse brain. Unexpectedly, the mouse niche reprograms the birthdates of cortical and hippocampal rat neurons, where they also form synaptically active rat-mouse circuits. By genetically disabling host olfactory circuitry, we show that rat neurons restore synaptic information flow from the nose to the cortex. Rat neurons can also rescue a primal olfactory behavior (food-seeking), though less than mouse controls. By enabling a mouse to sense the world with rat neurons, we highlight the power of interspecies neural blastocyst complementation to uncover mechanisms of neural circuit development and evolution, and to inform efforts to rescue neural circuits affected by injury or disease.

developmental biology↗

bioRxiv2023

RNA Sensing and Innate Immunity Constitutes a Barrier for Interspecies Chimerism

Interspecies chimera formation with human pluripotent stem cells (PSCs) holds great promise to generate humanized animal models and provide donor organs for transplant. However, the approach is currently limited by low levels of human cells ultimately represented in chimeric embryos. Different strategies have been developed to improve chimerism by genetically editing donor human PSCs. To date, however, it remains unexplored if human chimerism can be enhanced in animals through modifying the host embryos. Leveraging the interspecies PSC competition model, here we discovered retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) signaling, an RNA sensor, in "winner" cells plays an important role in the competitive interactions between co-cultured mouse and human PSCs. We found that genetic inactivation of Ddx58/Ifih1-Mavs-Irf7 axis compromised the "winner" status of mouse PSCs and their ability to outcompete PSCs from evolutionarily distant species during co-culture. Furthermore, by using Mavs-deficient mouse embryos we substantially improved unmodified donor human cell survival. Comparative transcriptome analyses based on species-specific sequences suggest contact-dependent human-to-mouse transfer of RNAs likely plays a part in mediating the cross-species interactions. Taken together, these findings establish a previously unrecognized role of RNA sensing and innate immunity in "winner" cells during cell competition and provides a proof-of-concept for modifying host embryos, rather than donor PSCs, to enhance interspecies chimerism.

cell biology↗