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RLR-mediated type I IFN production plays a pivotal role in elevating host immunity for viral clearance and cancer immune surveillance. Here, we report that glycolysis, which is inactivated during RLR activation, serves as a barrier to impede type I IFN production upon RLR activation. RLR-triggered MAVS-RIG-I recognition hijacks hexokinase binding to MAVS, leading to the impairment of hexokinase mitochondria localization and activation. Lactate serves as a key metabolite responsible for glycolysis-mediated RLR signaling inhibition by directly binding to MAVS transmembrane (TM) domain and preventing MAVS aggregation. Notably, lactate restoration reverses increased IFN production caused by lactate deficiency. Using pharmacological and genetic approaches, we show that lactate reduction by lactate dehydrogenase A (LDHA) inactivation heightens type I IFN production to protect mice from viral infection. Our study establishes a critical role of glycolysis-derived lactate in limiting RLR signaling and identifies MAVS as a direct sensor of lactate, which functions to connect energy metabolism and innate immunity.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteína 58 DEAD Box/antagonistas & inhibidores , Proteína 58 DEAD Box/metabolismo , Ácido Láctico/farmacología , Receptores de Superficie Celular/antagonistas & inhibidores , Receptores de Superficie Celular/metabolismo , Animales , Femenino , Glucólisis , Células HEK293 , Humanos , Interferón beta/metabolismo , L-Lactato Deshidrogenasa/genética , L-Lactato Deshidrogenasa/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Células RAW 264.7 , Receptores Inmunológicos , Transducción de Señal/efectos de los fármacos , TransfecciónRESUMEN
Mitochondrial dynamics regulated by mitochondrial fusion and fission maintain mitochondrial functions, whose alterations underline various human diseases. Here, we show that inositol is a critical metabolite directly restricting AMPK-dependent mitochondrial fission independently of its classical mode as a precursor for phosphoinositide generation. Inositol decline by IMPA1/2 deficiency elicits AMPK activation and mitochondrial fission without affecting ATP level, whereas inositol accumulation prevents AMPK-dependent mitochondrial fission. Metabolic stress or mitochondrial damage causes inositol decline in cells and mice to elicit AMPK-dependent mitochondrial fission. Inositol directly binds to AMPKγ and competes with AMP for AMPKγ binding, leading to restriction of AMPK activation and mitochondrial fission. Our study suggests that the AMP/inositol ratio is a critical determinant for AMPK activation and establishes a model in which AMPK activation requires inositol decline to release AMPKγ for AMP binding. Hence, AMPK is an inositol sensor, whose inactivation by inositol serves as a mechanism to restrict mitochondrial fission.
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Proteínas Quinasas Activadas por AMP/metabolismo , Inositol/metabolismo , Dinámicas Mitocondriales/fisiología , Proteínas Quinasas Activadas por AMP/fisiología , Animales , Línea Celular , Humanos , Inositol/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mitocondrias/metabolismo , Células PC-3 , Monoéster Fosfórico Hidrolasas/metabolismo , Fosforilación , Estrés Fisiológico/fisiologíaRESUMEN
A large number of studies have established a causal relationship between the gut microbiota and human disease. In addition, the composition of the microbiota is substantially influenced by the human genome. Modern medical research has confirmed that the pathogenesis of various diseases is closely related to evolutionary events in the human genome. Specific regions of the human genome known as human accelerated regions (HARs) have evolved rapidly over several million years since humans diverged from a common ancestor with chimpanzees, and HARs have been found to be involved in some human-specific diseases. Furthermore, the HAR-regulated gut microbiota has undergone rapid changes during human evolution. We propose that the gut microbiota may serve as an important mediator linking diseases to human genome evolution.
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Microbioma Gastrointestinal , Hominidae , Microbiota , Animales , Humanos , Microbioma Gastrointestinal/genética , Genoma Humano/genética , Hominidae/genética , Pan troglodytes/genética , Evolución MolecularRESUMEN
ICEberg 3.0 (https://tool2-mml.sjtu.edu.cn/ICEberg3/) is an upgraded database that provides comprehensive insights into bacterial integrative and conjugative elements (ICEs). In comparison to the previous version, three key enhancements were introduced: First, through text mining and manual curation, it now encompasses details of 2065 ICEs, 607 IMEs and 275 CIMEs, including 430 with experimental support. Secondly, ICEberg 3.0 systematically categorizes cargo gene functions of ICEs into six groups based on literature curation and predictive analysis, providing a profound understanding of ICEs'diverse biological traits. The cargo gene prediction pipeline is integrated into the online tool ICEfinder 2.0. Finally, ICEberg 3.0 aids the analysis and exploration of ICEs from the human microbiome. Extracted and manually curated from 2405 distinct human microbiome samples, the database comprises 1386 putative ICEs, offering insights into the complex dynamics of Bacteria-ICE-Cargo networks within the human microbiome. With the recent updates, ICEberg 3.0 enhances its capability to unravel the intricacies of ICE biology, particularly in the characterization and understanding of cargo gene functions and ICE interactions within the microbiome. This enhancement may facilitate the investigation of the dynamic landscape of ICE biology and its implications for microbial communities.
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Bacterias , Conjugación Genética , Bases de Datos Genéticas , Humanos , Bacterias/genética , Bases de Datos Factuales , Elementos Transponibles de ADN , MicrobiotaRESUMEN
TADB 3.0 (https://bioinfo-mml.sjtu.edu.cn/TADB3/) is an updated database that provides comprehensive information on bacterial types I to VIII toxin-antitoxin (TA) loci. Compared with the previous version, three major improvements are introduced: First, with the aid of text mining and manual curation, it records the details of 536 TA loci with experimental support, including 102, 403, 8, 14, 1, 1, 3 and 4 TA loci of types I to VIII, respectively; Second, by leveraging the upgraded TA prediction tool TAfinder 2.0 with a stringent strategy, TADB 3.0 collects 211 697 putative types I to VIII TA loci predicted in 34 789 completely sequenced prokaryotic genomes, providing researchers with a large-scale dataset for further follow-up analysis and characterization; Third, based on their genomic locations, relationships of 69 019 TA loci and 60 898 mobile genetic elements (MGEs) are visualized by interactive networks accessible through the user-friendly web page. With the recent updates, TADB 3.0 may provide improved in silico support for comprehending the biological roles of TA pairs in prokaryotes and their functional associations with MGEs.
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Proteínas Bacterianas , Bases de Datos Genéticas , Secuencias Repetitivas Esparcidas , Sistemas Toxina-Antitoxina , Proteínas Bacterianas/genética , Genoma Bacteriano , Sistemas Toxina-Antitoxina/genética , Sitios GenéticosRESUMEN
Tn3 family transposons are a widespread group of replicative transposons, notorious for contributing to the dissemination of antibiotic resistance, particularly the global prevalence of carbapenem resistance. The transposase (TnpA) of these elements catalyzes DNA breakage and rejoining reactions required for transposition. However, the molecular mechanism for target site selection with these elements remains unclear. Here, we identify a QLxxLR motif in N-terminal of Tn3 TnpAs and demonstrate that this motif allows interaction between TnpA of Tn3 family transposon Tn1721 and the host ß-sliding clamp (DnaN), the major processivity factor of the DNA replication machinery. The TnpA-DnaN interaction is essential for Tn1721 transposition. Our work unveils a mechanism whereby Tn3 family transposons can bias transposition into certain replisomes through an interaction with the host replication machinery. This study further expands the diversity of mobile elements that use interaction with the host replication machinery to bias integration.
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Delusions of control in schizophrenia are characterized by the striking feeling that one's actions are controlled by external forces. We here tested qualitative predictions inspired by Bayesian causal inference models, which suggest that such misattributions of agency should lead to decreased intentional binding. Intentional binding refers to the phenomenon that subjects perceive a compression of time between their intentional actions and consequent sensory events. We demonstrate that patients with delusions of control perceived less self-agency in our intentional binding task. This effect was accompanied by significant reductions of intentional binding as compared to healthy controls and patients without delusions. Furthermore, the strength of delusions of control tightly correlated with decreases in intentional binding. Our study validated a critical prediction of Bayesian accounts of intentional binding, namely that a pathological reduction of the prior likelihood of a causal relation between one's actions and consequent sensory events-here captured by delusions of control-should lead to lesser intentional binding. Moreover, our study highlights the import of an intact perception of temporal contiguity between actions and their effects for the sense of agency.
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Esquizofrenia , Percepción del Tiempo , Humanos , Desempeño Psicomotor , Teorema de Bayes , Emociones , Intención , PercepciónRESUMEN
Embryo implantation, a crucial step in human reproduction, is tightly controlled by estrogen and progesterone (P4) via estrogen receptor alpha and progesterone receptor (PGR), respectively. Here, we report that N6-methyladenosine (m6A), the most abundant mRNA modification in eukaryotes, plays an essential role in embryo implantation through the maintenance of P4 signaling. Conditional deletion of methyltransferase-like 3 (Mettl3), encoding the m6A writer METTL3, in the female reproductive tract using a Cre mouse line with Pgr promoter (Pgr-Cre) resulted in complete implantation failure due to pre-implantation embryo loss and defective uterine receptivity. Moreover, the uterus of Mettl3 null mice failed to respond to artificial decidualization. We further found that Mettl3 deletion was accompanied by a marked decrease in PGR protein expression. Mechanistically, we found that Pgr mRNA is a direct target for METTL3-mediated m6A modification. A luciferase assay revealed that the m6A modification in the 5' untranslated region (5'-UTR) of Pgr mRNA enhances PGR protein translation efficiency in a YTHDF1-dependent manner. Finally, we demonstrated that METTL3 is required for human endometrial stromal cell decidualization in vitro and that the METTL3-PGR axis is conserved between mice and humans. In summary, this study provides evidence that METTL3 is essential for normal P4 signaling during embryo implantation via m6A-mediated translation control of Pgr mRNA.
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Progesterona , Receptores de Progesterona , Femenino , Ratones , Humanos , Animales , Progesterona/metabolismo , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Implantación del Embrión/genética , Útero/metabolismo , Metiltransferasas/genética , Metiltransferasas/metabolismo , Ratones Noqueados , ARN Mensajero/metabolismoRESUMEN
Great progress has been made in identifying positive regulators that activate adipocyte thermogenesis, but negative regulatory signaling of thermogenesis remains poorly understood. Here, we found that cardiotrophin-like cytokine factor 1 (CLCF1) signaling led to loss of brown fat identity, which impaired thermogenic capacity. CLCF1 levels decreased during thermogenic stimulation but were considerably increased in obesity. Adipocyte-specific CLCF1 transgenic (CLCF1-ATG) mice showed impaired energy expenditure and severe cold intolerance. Elevated CLCF1 triggered whitening of brown adipose tissue by suppressing mitochondrial biogenesis. Mechanistically, CLCF1 bound and activated ciliary neurotrophic factor receptor (CNTFR) and augmented signal transducer and activator of transcription 3 (STAT3) signaling. STAT3 transcriptionally inhibited both peroxisome proliferator-activated receptor-γ coactivator (PGC) 1α and 1ß, which thereafter restrained mitochondrial biogenesis in adipocytes. Inhibition of CNTFR or STAT3 could diminish the inhibitory effects of CLCF1 on mitochondrial biogenesis and thermogenesis. As a result, CLCF1-TG mice were predisposed to develop metabolic dysfunction even without external metabolic stress. Our findings revealed a brake signal on nonshivering thermogenesis and suggested that targeting this pathway could be used to restore brown fat activity and systemic metabolic homeostasis in obesity.
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Adipocitos Marrones , Biogénesis de Organelos , Animales , Ratones , Adipocitos Marrones/metabolismo , Tejido Adiposo Pardo/metabolismo , Homeostasis , Obesidad/genética , Obesidad/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Termogénesis/fisiologíaRESUMEN
Ataxin-2 (Atx2) is a polyglutamine (polyQ) tract-containing RNA-binding protein, while its polyQ expansion may cause protein aggregation that is implicated in the pathogenesis of neurodegenerative diseases such as spinocerebellar ataxia type 2 (SCA2). However, the molecular mechanism underlying how Atx2 aggregation contributes to the proteinopathies remains elusive. Here, we investigated the influence of Atx2 aggregation on the assembly and functionality of cellular processing bodies (P-bodies) by using biochemical and fluorescence imaging approaches. We have revealed that polyQ-expanded (PQE) Atx2 sequesters the DEAD-box RNA helicase (DDX6), an essential component of P-bodies, into aggregates or puncta via some RNA sequences. The N-terminal like-Sm (LSm) domain of Atx2 (residues 82-184) and the C-terminal helicase domain of DDX6 are responsible for the interaction and specific sequestration. Moreover, sequestration of DDX6 may aggravate pre-mRNA mis-splicing, and interfere with the assembly of cellular P-bodies, releasing the endoribonuclease MARF1 that promotes mRNA decay and translational repression. Rescuing the DDX6 protein level can recover the assembly and functionality of P-bodies, preventing targeted mRNA from degradation. This study provides a line of evidence for sequestration of the P-body components and impairment of the P-body homeostasis in dysregulating RNA metabolism, which is implicated in the disease pathologies and a potential therapeutic target.
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Ataxina-2 , ARN Helicasas DEAD-box , Homeostasis , Péptidos , ARN Helicasas DEAD-box/metabolismo , ARN Helicasas DEAD-box/genética , Humanos , Ataxina-2/metabolismo , Ataxina-2/genética , Péptidos/metabolismo , Péptidos/química , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas/genética , Células HEK293 , Ataxias Espinocerebelosas/metabolismo , Ataxias Espinocerebelosas/genética , Agregado de Proteínas , Empalme del ARN , Dominios Proteicos , Precursores del ARN/metabolismo , Precursores del ARN/genéticaRESUMEN
Liver can sense the nutrient status and send signals to other organs to regulate overall metabolic homoeostasis. Herein, we demonstrate that ketone bodies act as signals released from the liver that specifically determine the distribution of excess lipid in epididymal white adipose tissue (eWAT) when exposed to a ketogenic diet (KD). An acute KD can immediately result in excess lipid deposition in the liver. Subsequently, the liver sends the ketone body ß-hydroxybutyrate (BHB) to regulate white adipose expansion, including adipogenesis and lipogenesis, to alleviate hepatic lipid accumulation. When ketone bodies are depleted by deleting 3-hydroxy-3-methylglutaryl-CoA synthase 2 gene in the liver, the enhanced lipid deposition in eWAT but not in inguinal white adipose tissue is preferentially blocked, while lipid accumulation in liver is not alleviated. Mechanistically, ketone body BHB can significantly decrease lysine acetylation of peroxisome proliferator-activated receptor gamma in eWAT, causing enhanced activity of peroxisome proliferator-activated receptor gamma, the key adipogenic transcription factor. These observations suggest that the liver senses metabolic stress first and sends a corresponding signal, that is, ketone body BHB, to specifically promote eWAT expansion to adapt to metabolic challenges.
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Tejido Adiposo Blanco , Dieta Cetogénica , Hígado Graso , Cuerpos Cetónicos , Humanos , Tejido Adiposo Blanco/metabolismo , Hígado Graso/metabolismo , Cuerpos Cetónicos/metabolismo , Lípidos , Hígado/metabolismo , PPAR gamma/metabolismoRESUMEN
Primary effusion lymphoma (PEL) caused by Kaposi sarcoma-associated herpesvirus (KSHV) is an aggressive malignancy with poor prognosis even under chemotherapy. Currently, there is no specific treatment for PEL therefore requiring new therapies. Both histone deacetylases (HDACs) and bromodomain-containing protein 4 (BRD4) have been found as therapeutic targets for PEL through inducing viral lytic reactivation. However, the strategy of dual targeting with one agent and potential synergistic effects have never been explored. In the current study, we first demonstrated the synergistic effect of concurrently targeting HDACs and BRD4 on KSHV reactivation by using SAHA or entinostat (HDACs inhibitors) and (+)-JQ1 (BRD4 inhibitor), which indicated dual blockage of HDACs/BRD4 is a viable therapeutic approach. We were then able to rationally design and synthesize a series of new small-molecule inhibitors targeting HDACs and BRD4 with a balanced activity profile by generating a hybrid of the key binding motifs between (+)-JQ1 and entinostat or SAHA. Upon two iterative screenings of optimized compounds, a pair of epimers, 009P1 and 009P2, were identified to better inhibit the growth of KSHV positive lymphomas compared to (+)-JQ1 or SAHA alone at low nanomolar concentrations, but not KSHV negative control cells or normal cells. Mechanistic studies of 009P1 and 009P2 demonstrated significantly enhanced viral reactivation, cell cycle arrest and apoptosis in KSHV+ lymphomas through dually targeting HDACs and BRD4 signaling activities. Importantly, in vivo preclinical studies showed that 009P1 and 009P2 dramatically suppressed KSHV+ lymphoma progression with oral bioavailability and minimal visible toxicity. These data together provide a novel strategy for the development of agents for inducing lytic activation-based therapies against these viruses-associated malignancies.
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Herpesvirus Humano 8 , Linfoma de Efusión Primaria , Sarcoma de Kaposi , Humanos , Factores de Transcripción/metabolismo , Proteínas Nucleares/metabolismo , Inhibidores de Histona Desacetilasas/farmacología , Herpesvirus Humano 8/fisiología , Línea Celular Tumoral , Proteínas de Ciclo Celular/metabolismoRESUMEN
Nonalcoholic fatty liver disease (NAFLD) affects approximately a quarter of the population worldwide, and persistent overnutrition is one of the major causes. However, the underlying molecular basis has not been fully elucidated, and no specific drug has been approved for this disease. Here, we identify a regulatory mechanism that reveals a novel function of Rab2A in the progression of NAFLD based on energy status and PPARγ. The mechanistic analysis shows that nutrition repletion suppresses the phosphorylation of AMPK-TBC1D1 signaling, augments the level of GTP-bound Rab2A, and then increases the protein stability of PPARγ, which ultimately promotes the hepatic accumulation of lipids in vitro and in vivo. Furthermore, we found that blocking the AMPK-TBC1D1 pathway in TBC1D1S231A-knock-in (KI) mice led to a markedly increased GTP-bound Rab2A and subsequent fatty liver in aged mice. Our studies also showed that inhibition of Rab2A expression alleviated hepatic lipid deposition in western diet-induced obesity (DIO) mice by reducing the protein level of PPARγ and the expression of PPARγ target genes. Our findings not only reveal a new molecular mechanism regulating the progression of NAFLD during persistent overnutrition but also have potential implications for drug discovery to combat this disease.
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Proteínas Quinasas Activadas por AMP/metabolismo , Proteínas Activadoras de GTPasa/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Proteínas de Unión al GTP rab/metabolismo , Envejecimiento , Animales , Regulación de la Expresión Génica , Técnicas de Sustitución del Gen , Células Hep G2 , Humanos , Metabolismo de los Lípidos/fisiología , Ratones , Enfermedad del Hígado Graso no Alcohólico/metabolismo , PPAR gamma/genética , PPAR gamma/metabolismo , Proteínas de Unión al GTP rab/genéticaRESUMEN
Spatial transcriptomic (ST) clustering employs spatial and transcription information to group spots spatially coherent and transcriptionally similar together into the same spatial domain. Graph convolution network (GCN) and graph attention network (GAT), fed with spatial coordinates derived adjacency and transcription profile derived feature matrix are often used to solve the problem. Our proposed method STGIC (spatial transcriptomic clustering with graph and image convolution) is designed for techniques with regular lattices on chips. It utilizes an adaptive graph convolution (AGC) to get high quality pseudo-labels and then resorts to dilated convolution framework (DCF) for virtual image converted from gene expression information and spatial coordinates of spots. The dilation rates and kernel sizes are set appropriately and updating of weight values in the kernels is made to be subject to the spatial distance from the position of corresponding elements to kernel centers so that feature extraction of each spot is better guided by spatial distance to neighbor spots. Self-supervision realized by Kullback-Leibler (KL) divergence, spatial continuity loss and cross entropy calculated among spots with high confidence pseudo-labels make up the training objective of DCF. STGIC attains state-of-the-art (SOTA) clustering performance on the benchmark dataset of 10x Visium human dorsolateral prefrontal cortex (DLPFC). Besides, it's capable of depicting fine structures of other tissues from other species as well as guiding the identification of marker genes. Also, STGIC is expandable to Stereo-seq data with high spatial resolution.
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Perfilación de la Expresión Génica , Transcriptoma , Humanos , Transcriptoma/genética , Benchmarking , Análisis por Conglomerados , EntropíaRESUMEN
The detection of nucleic acid sequences in parallel with the discrimination of single nucleotide variations (SNVs) is critical for research and clinical applications. A few limitations make the detection technically challenging, such as too small variation in probe-hybridization energy caused by SNVs, the non-specific amplification of false nucleic acid fragments and the few options of dyes limited by spectral overlaps. To circumvent these limitations, we developed a single-molecule nucleic acid detection assay without amplification or fluorescence termed THREF (hybridization-induced tandem DNA hairpin refolding failure) based on multiplexed magnetic tweezers. THREF can detect DNA and RNA sequences at femtomolar concentrations within 30 min, monitor multiple probes in parallel, quantify the expression level of miR-122 in patient tissues, discriminate SNVs including the hard-to-detect G-U or T-G wobble mutations and reuse the probes to save the cost. In our demonstrative detections using mock clinic samples, we profiled the let-7 family microRNAs in serum and genotyped SARS-CoV-2 strains in saliva. Overall, the THREF assay can discriminate SNVs with the advantages of high sensitivity, ultra-specificity, multiplexing, reusability, sample hands-free and robustness.
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Técnicas Genéticas , Polimorfismo Genético , ARN , Humanos , COVID-19/diagnóstico , ADN/genética , Mutación , SARS-CoV-2/genética , ARN/análisisRESUMEN
The novel depth-sensing system presented here revolutionizes structured light (SL) technology by employing metasurfaces and photonic crystal surface-emitting lasers (PCSELs) for efficient facial recognition in monocular depth-sensing. Unlike conventional dot projectors relying on diffractive optical elements (DOEs) and collimators, our system projects approximately 45,700 infrared dots from a compact 297-µm-dimention metasurface, drastically more spots (1.43 times) and smaller (233 times) than the DOE-based dot projector in an iPhone. With a measured field-of-view (FOV) of 158° and a 0.611° dot sampling angle, the system is lens-free and lightweight and boasts lower power consumption than vertical-cavity surface-emitting laser (VCSEL) arrays, resulting in a 5-10 times reduction in power. Utilizing a GaAs-based metasurface and a simplified optical architecture, this innovation not only addresses the drawbacks of traditional SL depth-sensing but also opens avenues for compact integration into wearable devices, offering remarkable advantages in size, power efficiency, and potential for widespread adoption.
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Hard carbon (HC) is a promising anode candidate for Na-ion batteries (NIBs) because of its excellent Na-storage performance, abundance, and low cost. However, a precise understanding of its Na-storage behavior remains elusive. Herein, based on the D2O/H2SO4-based TMS results collected on charged/discharged state HC electrodes, detailed Na-storage mechanisms (the Na-storage states and active sites in different voltage regions), specific SEI dynamic evolution process (formation, rupture, regeneration and loss), and irreversible capacity contribution (dead Na0, NaH, etc.) were elucidated. Moreover, by employing the online electrochemical mass spectrometry (OEMS) to monitor the gassing behavior of HC-Na half-cell during the overdischarging process, a surprising rehydrogen evolution reaction (re-HER) process at around 0.02 V vs Na+/Na was identified, indicating the occurrence of Na-plating above 0 V vs Na+/Na. Additionally, the typical fluorine ethylene carbonate (FEC) additive was demonstrated to reduce the accumulation of dead Na0 and inhibit the re-HER process triggered by plated Na.
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Cancer continues to be a major health concern globally, although the advent of targeted therapy has revolutionized treatment options. Aurora Kinase B is a serine-threonine kinase that has been explored as an oncology therapeutic target for more than two decades. Aurora Kinase B inhibitors show promising biological results in in-vitro and in-vivo experiments. However, there are no inhibitors approved yet for clinical use, primarily because of the side effects associated with Aurora B inhibitors. Several studies demonstrate that Aurora B inhibitors show excellent synergy with various chemotherapeutic agents, radiation therapy, and targeted therapies. This makes it an excellent choice as an adjuvant therapy to first-line therapies, which greatly improves the therapeutic window and side effect profile. Recent studies indicate the role of Aurora B in some deadly cancers with limited therapeutic options, like triple-negative breast cancer and glioblastoma. Herein, we review the latest developments in Aurora Kinase B targeted research, with emphasis on its potential as an adjuvant therapy and its role in some of the most difficult-to-treat cancers.
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Antineoplásicos , Neoplasias , Humanos , Aurora Quinasa B/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Serina-Treonina Quinasas/uso terapéutico , Neoplasias/tratamiento farmacológico , Aurora Quinasa A/uso terapéutico , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/uso terapéuticoRESUMEN
Poly(A)-binding protein nuclear 1 (PABPN1) is an RNA-binding protein localized in nuclear speckles, while its alanine (Ala)-expanded variants accumulate as intranuclear aggregates in oculopharyngeal muscular dystrophy. The factors that drive PABPN1 aggregation and its cellular consequences remain largely unknown. Here, we investigated the roles of Ala stretch and poly(A) RNA in the phase transition of PABPN1 using biochemical and molecular cell biology methods. We have revealed that the Ala stretch controls its mobility in nuclear speckles, and Ala expansion leads to aggregation from the dynamic speckles. Poly(A) nucleotide is essential to the early-stage condensation that thereby facilitates speckle formation and transition to solid-like aggregates. Moreover, the PABPN1 aggregates can sequester CFIm25, a component of the pre-mRNA 3'-UTR processing complex, in an mRNA-dependent manner and consequently impair the function of CFIm25 in alternative polyadenylation. In conclusion, our study elucidates a molecular mechanism underlying PABPN1 aggregation and sequestration, which will be beneficial for understanding PABPN1 proteinopathy.
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Distrofia Muscular Oculofaríngea , Poliadenilación , Humanos , Alanina/metabolismo , Distrofia Muscular Oculofaríngea/genética , Distrofia Muscular Oculofaríngea/metabolismo , Proteína I de Unión a Poli(A)/genética , Proteína I de Unión a Poli(A)/metabolismo , ARN/metabolismoRESUMEN
Legionella is a common intracellular parasitic bacterium that infects humans via the respiratory tract, causing Legionnaires' disease, with fever and pneumonia as the main symptoms. The emergence of highly virulent and azithromycin-resistant Legionella pneumophila is a major challenge in clinical anti-infective therapy. The CRISPR-Cas acquired immune system provides immune defense against foreign nucleic acids and regulates strain biological functions. However, the distribution of the CRISPR-Cas system in Legionella and how it regulates gene expression in L. pneumophila remain unclear. Herein, we assessed 915 Legionella whole-genome sequences to determine the distribution characteristics of the CRISPR-Cas system and constructed gene deletion mutants to explore the regulation of the system based on growth ability in vitro, antibiotic sensitivity, and intracellular proliferation of L. pneumophila. The CRISPR-Cas system in Legionella was predominantly Type II-B and was mainly concentrated in the genome of L. pneumophila ST1 strains. The Type II-B CRISPR-Cas system showed no effect on the strain's growth ability in vitro but significantly reduced resistance to azithromycin and decreased proliferation ability due to regulation of the lpeAB efflux pump and the Dot/Icm type IV secretion system. Thus, the Type II-B CRISPR-Cas system plays a crucial role in regulating the virulence of L. pneumophila. This expands our understanding of drug resistance and pathogenicity in Legionella, provides a scientific basis for the prevention of Legionnaires' disease outbreaks and the rational use of clinical drugs, and facilitates effective treatment of Legionnaires' disease.