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1.
J Cell Sci ; 135(5)2022 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-34080635

RESUMEN

Despite the recognized significance of reversible protein lipidation (S-acylation) for T cell receptor signal transduction, the enzymatic control of this post-translational modification in T cells remains poorly understood. Here, we demonstrate that DHHC21 (also known as ZDHHC21), a member of the DHHC family of mammalian protein acyltransferases, mediates T cell receptor-induced S-acylation of proximal T cell signaling proteins. Using Zdhhc21dep mice, which express a functionally deficient version of DHHC21, we show that DHHC21 is a Ca2+/calmodulin-dependent enzyme critical for activation of naïve CD4+ T cells in response to T cell receptor stimulation. We find that disruption of the Ca2+/calmodulin-binding domain of DHHC21 does not affect thymic T cell development but prevents differentiation of peripheral CD4+ T cells into Th1, Th2 and Th17 effector T helper lineages. Our findings identify DHHC21 as an essential component of the T cell receptor signaling machinery and define a new role for protein acyltransferases in regulation of T cell-mediated immunity.


Asunto(s)
Linfocitos T CD4-Positivos , Calcio , Acetiltransferasas , Aciltransferasas/genética , Animales , Diferenciación Celular , Ratones , Receptores de Antígenos de Linfocitos T/genética
2.
J Cell Sci ; 135(5)2022 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-33771931

RESUMEN

The lipid composition of the primary cilia membrane is emerging as a critical regulator of cilia formation, maintenance and function. Here, we show that conditional deletion of the phosphoinositide 5'-phosphatase gene Inpp5e, mutation of which is causative of Joubert syndrome, in terminally developed mouse olfactory sensory neurons (OSNs), leads to a dramatic remodeling of ciliary phospholipids that is accompanied by marked elongation of cilia. Phosphatidylinositol (4,5)-bisphosphate [PI(4,5)P2], which is normally restricted to the proximal segment redistributed to the entire length of cilia in Inpp5e knockout mice with a reduction in phosphatidylinositol (3,4)-bisphosphate [PI(3,4)P2] and elevation of phosphatidylinositol (3,4,5)-trisphosphate [PI(3,4,5)P3] in the dendritic knob. The redistribution of phosphoinositides impaired odor adaptation, resulting in less efficient recovery and altered inactivation kinetics of the odor-evoked electrical response and the odor-induced elevation of cytoplasmic Ca2+. Gene replacement of Inpp5e through adenoviral expression restored the ciliary localization of PI(4,5)P2 and odor response kinetics in OSNs. Our findings support the role of phosphoinositides as a modulator of the odor response and in ciliary biology of native multi-ciliated OSNs.


Asunto(s)
Neuronas Receptoras Olfatorias , Animales , Cilios , Ratones , Odorantes , Fosfolípidos , Monoéster Fosfórico Hidrolasas/genética
3.
J Headache Pain ; 22(1): 62, 2021 Jun 30.
Artículo en Inglés | MEDLINE | ID: mdl-34193048

RESUMEN

BACKGROUND: Circadian patterns of migraine attacks have been reported by patients but remain understudied. In animal models, circadian phases are generally not taken into consideration. In particular, rodents are nocturnal animals, yet they are most often tested during their inactive phase during the day. This study aims to test the validity of CGRP-induced behavioral changes in mice by comparing responses during the active and inactive phases. METHODS: Male and female mice of the outbred CD1 strain were administered vehicle (PBS) or CGRP (0.1 mg/kg, i.p.) to induce migraine-like symptoms. Animals were tested for activity (homecage movement and voluntary wheel running), light aversive behavior, and spontaneous pain at different times of the day and night. RESULTS: Peripheral administration of CGRP decreased the activity of mice during the first hour after administration, induced light aversive behavior, and spontaneous pain during that same period of time. Both phenotypes were observed no matter what time of the day or night they were assessed. CONCLUSIONS: A decrease in wheel activity is an additional clinically relevant phenotype observed in this model, which is reminiscent of the reduction in normal physical activity observed in migraine patients. The ability of peripheral CGRP to induce migraine-like symptoms in mice is independent of the phase of the circadian cycle. Therefore, preclinical assessment of migraine-like phenotypes can likely be done during the more convenient inactive phase of mice.


Asunto(s)
Péptido Relacionado con Gen de Calcitonina , Trastornos Migrañosos , Animales , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Ratones , Trastornos Migrañosos/inducido químicamente , Actividad Motora
4.
BMC Res Notes ; 14(1): 246, 2021 Jun 30.
Artículo en Inglés | MEDLINE | ID: mdl-34193269

RESUMEN

OBJECTIVE: Chloroquine is used as a conventional drug therapy for the treatment of malaria. The existence of resistance to chloroquine shown among various species of Plasmodium leads to the search for more efficacious therapy to treat malaria. Probiotic (Lactobacillus casei) has been tried as an add-on therapy with chloroquine. Probiotics are ingested microorganisms associated with a beneficial effect on humans and other species. The study was done to check the efficacy of L. casei as an add-on therapy along with conventional drug therapy (chloroquine) to treat malaria. RESULTS: Probiotic in combination with chloroquine showed complete suppression in parasitemia rate. Representation of parasitemia rate was done using mean ± SD. p < 0.05 is considered as statistically significant. The results showed a reduction in parasitemia with probiotic treatment, which was further confirmed through histological observation of two major organs, the liver and spleen. Interestingly, further suppression of parasitemia and hemosiderosis was observed when probiotic was given along with chloroquine.


Asunto(s)
Antimaláricos , Malaria , Probióticos , Antimaláricos/uso terapéutico , Cloroquina/uso terapéutico , Humanos , Malaria/tratamiento farmacológico , Ratones , Parasitemia/tratamiento farmacológico
5.
Nihon Yakurigaku Zasshi ; 156(4): 225-229, 2021.
Artículo en Japonés | MEDLINE | ID: mdl-34193701

RESUMEN

Microglia originating from yolk sac exert various functions to maintain the homeostasis in the brain, and their functional breakdown appears to be involved in the pathophysiology of various neurological diseases. In this review article, loss of homeostatic microglia and new therapeutic approaches for rare neurological disorders are discussed. ASLP (adult-onset leukoencephalopathy with axonal spheroids and pigmented glia) known as a primary microgliopathy is an adult-onset leukoencephalopathy caused by CSF1R mutation. CSF1 receptor encoded by CSF1R plays an important role in the function of microglia. In brain of ALSP patients, homeostatic microglia are significantly reduced. The biallelic mutations for CSF1R cause childhood-onset severe phenotype and elimination of microglia from the brain parenchyma. Since microglia also almost disappear in CSF1R-deficient mice and rats, CSF1R deficiency and loss of microglia appear to be tightly associated across species. Based on the underlying mechanism of homeostatic microglia loss, novel approaches using cell transplantation of normal microglia-like cells have been attempted. Transplantation of wild-type bone marrow cells into Csf1r-/- mice results in replacement by donor-derived microglial-like cells in the recipient's brain. The concept of "microglial niche" may explain the rationale behind the microglial cell transplantation in disease condition(s). Hematopoietic stem cell transplantation (HSCT) has been attempted in 4 patients with ALSP. Beneficial effects by showing stabilization of the disease course have been observed. Although the effectiveness of HSCT for ALSP patients warrants further investigation, the approach of cell transplantation that replaces ruptured homeostatic microglia with normal microglia-like cells seems to be promising.


Asunto(s)
Leucoencefalopatías , Microglía , Adulto , Animales , Trasplante de Células , Niño , Homeostasis , Humanos , Ratones , Ratas , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos
6.
Nihon Yakurigaku Zasshi ; 156(4): 230-234, 2021.
Artículo en Japonés | MEDLINE | ID: mdl-34193702

RESUMEN

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS), and is designated as an intractable disease in Japan. It is characterized by dissemination of plaque-like sclerosis in space and time, accompanied with various symptoms corresponding to the CNS lesion site. Typically, neurological symptoms chronically progress accompanied with relapses and remissions, and there is still no curative therapy. A number of studies using MS specimen and the animal MS model experimental autoimmune encephalomyelitis (EAE) have shown that MS is an autoimmune disease that targets myelin sheath in the CNS. Autoreactive T cells and B cells play a central role in pathogenesis of MS. MS comprise relapsing-remitting MS and progressive MS, the latter accumulates clinical disability without relapse. Based on the importance of adaptive immunity, various disease-modifying drugs have been developed to treat relapsing-remitting MS. On the other hand, an effective treatment for progressive MS has not yet been established. Increasing evidence have been recognized glial cells as key components of MS immunopathology, in addition to innate immunity and adaptive immunity. However, molecular mechanisms of crosstalk between immune cells, glial cells and neurons remain to be elucidated. Here, we review MS pathology and recent advances in the disease-modifying therapy that efficiently reduce disease activity in relapsing-remitting MS and introduce an update of recent evidence that astrocyte is involved in the MS pathology with including our research analyzed in mouse EAE model.


Asunto(s)
Encefalomielitis Autoinmune Experimental , Esclerosis Múltiple , Animales , Astrocitos , Sistema Nervioso Central , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Japón , Ratones , Esclerosis Múltiple/tratamiento farmacológico
7.
Nihon Yakurigaku Zasshi ; 156(4): 235-238, 2021.
Artículo en Japonés | MEDLINE | ID: mdl-34193703

RESUMEN

Sandhoff disease (SD) is a genetic disorder caused by a mutation in the ß-hexosaminidase B (HexB) gene in humans. This results in the massive accumulation of GM2 gangliosides in the nervous system, causing progressive neurodegeneration. The symptoms of SD include muscle weakness, seizures, and mental illness;along with loss of muscle coordination, vision, and hearing. In the most severe form, the onset begins during early infancy, and death usually occurs within 3-5 years of age. The established animal model, Hexb-deficient (Hexb-/-) mouse, shows abnormalities that resemble the severe phenotype found in human infants. We have previously reported that activated microglia causes astrogliosis in Hexb-/- mouse at the early stage of development that can be ameliorated via immunosuppression. Moreover, within the cerebral cortices of Hexb-/- mouse, reactive astrocytes were found to express adenosine A2A receptors in later inflammatory phases. Inhibiting this receptor with istradefylline decreases the number of activated microglial cells and inflammatory cytokines/chemokines. Thus, we underline the importance of the astrocytic A2A receptor as a sensor, in regulating microglial activation in the late phase of inflammation.


Asunto(s)
Enfermedad de Sandhoff , Animales , Modelos Animales de Enfermedad , Gliosis , Hexosaminidasa B , Ratones , Ratones Noqueados , Neuroglía , Enfermedad de Sandhoff/tratamiento farmacológico , Enfermedad de Sandhoff/genética
8.
Nihon Yakurigaku Zasshi ; 156(4): 239-243, 2021.
Artículo en Japonés | MEDLINE | ID: mdl-34193704

RESUMEN

Alexander disease (AxD) is a rare neurodegenerative disorder caused by the mutations in glial fibrillary acidic protein (GFAP) gene. Rosenthal fiber formations in astrocytes are the pathological hallmarks of AxD. Astrocyte dysfunction in the AxD brain is considered to be involved in its pathogenesis. We have previously reported that in AxD model mice aberrant Ca2+ signals in astrocytes were associated with the upregulation of reactive phenotype. Reactive astrocytes are conditions that lead to morphological, functional, and molecular changes by responding to various pathological insults (trauma, inflammation, ischemia), and environmental stimuli. Recent technological advances in single-cell gene expression analysis have revealed that astrocytes have heterogeneity by indicating that they form sub population with different characteristics depending on the brain region, the growth development, aging stage, and the pathological condition. AxD astrocytes are also thought to constitute a heterogeneous population with diverse properties and functions. Moreover, it is presumed that AxD pathogenesis occur due to interactions with neurons and other glial cells, as well as the microenvironment in tissues. Research strategies based on these perspectives will help us understand AxD pathology better and may lead to the elucidation of disease modifiers and clinical diversity.


Asunto(s)
Enfermedad de Alexander , Enfermedad de Alexander/genética , Animales , Astrocitos , Proteína Ácida Fibrilar de la Glía/genética , Ratones , Mutación , Neuronas
9.
Vaccine ; 39(32): 4399-4403, 2021 07 22.
Artículo en Inglés | MEDLINE | ID: mdl-34226102

RESUMEN

The skin represents an attractive target tissue for vaccination against respiratory viruses such as SARS-CoV-2. Laser-facilitated epicutaneous immunization (EPI) has been established as a novel technology to overcome the skin barrier, which combines efficient delivery via micropores with an inherent adjuvant effect due to the release of danger-associated molecular patterns. Here we delivered the S1 subunit of the Spike protein of SARS-CoV-2 to the skin of BALB/c mice via laser-generated micropores with or without CpG-ODN1826 or the B subunit of heat-labile enterotoxin of E.coli (LT-B). EPI induced serum IgG titers of 1:3200 that could be boosted 5 to 10-fold by co-administration of LT-B and CpG, respectively. Sera were able to inhibit binding of the spike protein to its receptor ACE2. Our data indicate that delivery of recombinant spike protein via the skin may represent an alternative route for vaccines against Covid-19.


Asunto(s)
COVID-19 , Glicoproteína de la Espiga del Coronavirus , Animales , Anticuerpos Antivirales , Vacunas contra la COVID-19 , Humanos , Inmunización , Rayos Láser , Ratones , Ratones Endogámicos BALB C , Peptidil-Dipeptidasa A , Unión Proteica , SARS-CoV-2 , Vacunación
10.
Transl Psychiatry ; 11(1): 361, 2021 06 29.
Artículo en Inglés | MEDLINE | ID: mdl-34226493

RESUMEN

The precise control of the nervous system function under the vitality of synapses is extremely critical. Efforts have been taken to explore the underlying cellular and molecular mechanisms for synapse formation. Cell adhesion molecules have been found important for synapse assembly in the brain. Many trans-adhesion complexes have been identified to modulate excitatory synapse formation. However, little is known about the synaptogenic mechanisms for inhibitory synapses. ErbB4 is a receptor tyrosine kinase enriched in interneurons. Here, we showed that overexpressing ErbB4 in HEK293T cells induced gephyrin or GABAAR α1 puncta in co-cultured primary hippocampal neurons. This induction of ErbB4 was independent of its kinase activity. K751M, a kinase-dead mutant of ErbB4, can also induce gephyrin or GABAAR α1 puncta in the co-culture system. We further constructed K751M knock-in mice and found that the homozygous were viable at birth and fertile without changes in gross brain structure. The number of interneurons and inhibitory synapses onto pyramidal neurons (PyNs) were comparable between K751M and wild-type mice but decreased in ErbB4-Null mice. Moreover, ErbB4 can interact in trans with Slitrk3, a transmembrane postsynaptic protein at inhibitory synapses, through the extracellular RLD domain of ErbB4. The deletion of RLD diminished the induction of gephyrin or GABAAR α1 puncta by ErbB4. Finally, disruption of ErbB4-Slitrk3 interaction through neutralization of Slitrk3 by secretable RLD decreased inhibitory synapses onto PyNs and impaired GABAergic transmission. These results identify that ErbB4, as a cell adhesion molecule, promotes inhibitory synapse formation onto PyNs by interacting with Slitrk3 and in a kinase-independent manner, providing an unexpected mechanism of ErbB4 in inhibitory synapse formation.


Asunto(s)
Neurogénesis , Sinapsis , Animales , Adhesión Celular , Células HEK293 , Hipocampo , Humanos , Ratones , Receptor ErbB-4/genética
11.
Stem Cell Res Ther ; 12(1): 383, 2021 07 07.
Artículo en Inglés | MEDLINE | ID: mdl-34233738

RESUMEN

BACKGROUND: As a promising way to repair bone defect, bone tissue engineering has attracted a lot of attentions from researchers in recent years. Searching for new molecular target to modify the seed cells and enhance their osteogenesis capacity is one of the hot topics in this field. As a member of aldo-keto reductase family, aldo-keto reductase family 1 member C1 (AKR1C1) is reported to associate with various tumors. However, whether AKR1C1 takes part in regulating differentiation of adipose-derived mesenchymal stromal/stem cells (ASCs) and its relationship with progesterone receptor (PGR) remain unclear. METHODS: Lost-and-gain-of-function experiments were performed using knockdown and overexpression of AKR1C1 to identify its role in regulating osteogenic and adipogenic differentiation of hASCs in vitro. Heterotypic bone and adipose tissue formation assay in nude mice were used to conduct the in vivo experiment. Plasmid and siRNA of PGR, as well as western blot, were used to clarify the mechanism AKR1C1 regulating osteogenesis. RESULTS: Our results demonstrated that AKR1C1 acted as a negative regulator of osteogenesis and a positive regulator of adipogenesis of hASCs via its enzyme activity both in vitro and in vivo. Mechanistically, PGR mediated the regulation of AKR1C1 on osteogenesis. CONCLUSIONS: Collectively, our study suggested that AKR1C1 could serve as a regulator of osteogenic differentiation via targeting PGR and be used as a new molecular target for ASCs modification in bone tissue engineering.


Asunto(s)
20-Hidroxiesteroide Deshidrogenasas/genética , Osteogénesis , Receptores de Progesterona , Células Madre/citología , Tejido Adiposo/citología , Aldo-Ceto Reductasas/genética , Animales , Diferenciación Celular , Células Cultivadas , Humanos , Ratones , Ratones Desnudos
12.
Sci Transl Med ; 13(601)2021 07 07.
Artículo en Inglés | MEDLINE | ID: mdl-34233950

RESUMEN

Inflammation is a well-known driver of lung tumorigenesis. One strategy by which tumor cells escape tight homeostatic control is by decreasing the expression of the potent anti-inflammatory protein tumor necrosis factor alpha-induced protein 3 (TNFAIP3), also known as A20. We observed that tumor cell intrinsic loss of A20 markedly enhanced lung tumorigenesis and was associated with reduced CD8+ T cell-mediated immune surveillance in patients with lung cancer and in mouse models. In mice, we observed that this effect was completely dependent on increased cellular sensitivity to interferon-γ (IFN-γ) signaling by aberrant activation of TANK-binding kinase 1 (TBK1) and increased downstream expression and activation of signal transducer and activator of transcription 1 (STAT1). Interrupting this autocrine feed forward loop by knocking out IFN-α/ß receptor completely restored infiltration of cytotoxic T cells and rescued loss of A20 depending tumorigenesis. Downstream of STAT1, programmed death ligand 1 (PD-L1) was highly expressed in A20 knockout lung tumors. Accordingly, immune checkpoint blockade (ICB) treatment was highly efficient in mice harboring A20-deficient lung tumors. Furthermore, an A20 loss-of-function gene expression signature positively correlated with survival of melanoma patients treated with anti-programmed cell death protein 1. Together, we have identified A20 as a master immune checkpoint regulating the TBK1-STAT1-PD-L1 axis that may be exploited to improve ICB therapy in patients with lung adenocarcinoma.


Asunto(s)
Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/genética , Adenocarcinoma del Pulmón/genética , Animales , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Regulación hacia Abajo , Humanos , Interferón gamma/metabolismo , Neoplasias Pulmonares/genética , Ratones , Transducción de Señal
13.
Sci Transl Med ; 13(601)2021 07 07.
Artículo en Inglés | MEDLINE | ID: mdl-34233951

RESUMEN

Triggers of innate immune signaling in the CNS of patients with amyotrophic lateral sclerosis and frontotemporal degeneration (ALS/FTD) remain elusive. We report the presence of cytoplasmic double-stranded RNA (cdsRNA), an established trigger of innate immunity, in ALS-FTD brains carrying C9ORF72 intronic hexanucleotide expansions that included genomically encoded expansions of the G4C2 repeat sequences. The presence of cdsRNA in human brains was coincident with cytoplasmic TAR DNA binding protein 43 (TDP-43) inclusions, a pathologic hallmark of ALS/FTD. Introducing cdsRNA into cultured human neural cells induced type I interferon (IFN-I) signaling and death that was rescued by FDA-approved JAK inhibitors. In mice, genomically encoded dsRNAs expressed exclusively in a neuronal class induced IFN-I and death in connected neurons non-cell-autonomously. Our findings establish that genomically encoded cdsRNAs trigger sterile, viral-mimetic IFN-I induction and propagated death within neural circuits and may drive neuroinflammation and neurodegeneration in patients with ALS/FTD.


Asunto(s)
Esclerosis Amiotrófica Lateral , Proteína C9orf72 , Demencia Frontotemporal , Esclerosis Amiotrófica Lateral/genética , Animales , Encéfalo/metabolismo , Proteína C9orf72/genética , Expansión de las Repeticiones de ADN , Demencia Frontotemporal/genética , Humanos , Ratones , ARN Bicatenario
14.
Transl Psychiatry ; 11(1): 378, 2021 07 07.
Artículo en Inglés | MEDLINE | ID: mdl-34234103

RESUMEN

Biological responses to stress are complex and highly conserved. Corticotropin-releasing factor (CRF) plays a central role in regulating these lifesaving physiological responses to stress. We show that, in mice, CRF rapidly changes Schaffer Collateral (SC) input into hippocampal CA1 pyramidal cells (PC) by modulating both functional and structural aspects of these synapses. Host exposure to acute stress, in vivo CRF injection, and ex vivo CRF application all result in fast de novo formation and remodeling of existing dendritic spines. Functionally, CRF leads to a rapid increase in synaptic strength of SC input into CA1 neurons, e.g., increase in spontaneous neurotransmitter release, paired-pulse facilitation, and repetitive excitability and improves synaptic plasticity: long-term potentiation (LTP) and long-term depression (LTD). In line with the changes in synaptic function, CRF increases the number of presynaptic vesicles, induces redistribution of vesicles towards the active zone, increases active zone size, and improves the alignment of the pre- and postsynaptic compartments. Therefore, CRF rapidly enhances synaptic communication in the hippocampus, potentially playing a crucial role in the enhanced memory consolidation in acute stress.


Asunto(s)
Hormona Liberadora de Corticotropina , Células Piramidales , Animales , Hipocampo , Potenciación a Largo Plazo , Ratones , Sinapsis , Transmisión Sináptica
15.
Nat Commun ; 12(1): 4193, 2021 07 07.
Artículo en Inglés | MEDLINE | ID: mdl-34234122

RESUMEN

Interplay between EBV infection and acquired genetic alterations during nasopharyngeal carcinoma (NPC) development remains vague. Here we report a comprehensive genomic analysis of 70 NPCs, combining whole-genome sequencing (WGS) of microdissected tumor cells with EBV oncogene expression to reveal multiple aspects of cellular-viral co-operation in tumorigenesis. Genomic aberrations along with EBV-encoded LMP1 expression underpin constitutive NF-κB activation in 90% of NPCs. A similar spectrum of somatic aberrations and viral gene expression undermine innate immunity in 79% of cases and adaptive immunity in 47% of cases; mechanisms by which NPC may evade immune surveillance despite its pro-inflammatory phenotype. Additionally, genomic changes impairing TGFBR2 promote oncogenesis and stabilize EBV infection in tumor cells. Fine-mapping of CDKN2A/CDKN2B deletion breakpoints reveals homozygous MTAP deletions in 32-34% of NPCs that confer marked sensitivity to MAT2A inhibition. Our work concludes that NPC is a homogeneously NF-κB-driven and immune-protected, yet potentially druggable, cancer.


Asunto(s)
Infecciones por Virus de Epstein-Barr/inmunología , Herpesvirus Humano 4/genética , Carcinoma Nasofaríngeo/inmunología , Neoplasias Nasofaríngeas/inmunología , Escape del Tumor/genética , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Carcinogénesis/efectos de los fármacos , Carcinogénesis/genética , Carcinogénesis/inmunología , Línea Celular Tumoral , Inhibidor p15 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Infecciones por Virus de Epstein-Barr/genética , Infecciones por Virus de Epstein-Barr/terapia , Infecciones por Virus de Epstein-Barr/virología , Femenino , Regulación Viral de la Expresión Génica/inmunología , Herpesvirus Humano 4/inmunología , Herpesvirus Humano 4/patogenicidad , Interacciones Huésped-Patógeno/genética , Interacciones Huésped-Patógeno/inmunología , Humanos , Metionina Adenosiltransferasa/antagonistas & inhibidores , Metionina Adenosiltransferasa/metabolismo , Ratones , FN-kappa B/metabolismo , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/terapia , Carcinoma Nasofaríngeo/virología , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/terapia , Neoplasias Nasofaríngeas/virología , Nasofaringe/inmunología , Nasofaringe/patología , Nasofaringe/cirugía , Nasofaringe/virología , Receptor Tipo II de Factor de Crecimiento Transformador beta/genética , Receptor Tipo II de Factor de Crecimiento Transformador beta/metabolismo , Eliminación de Secuencia , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Transducción de Señal/inmunología , Escape del Tumor/efectos de los fármacos , Secuenciación Completa del Genoma , Ensayos Antitumor por Modelo de Xenoinjerto
16.
Nat Commun ; 12(1): 4175, 2021 07 07.
Artículo en Inglés | MEDLINE | ID: mdl-34234126

RESUMEN

Although we can now measure single-cell signaling responses with multivariate, high-throughput techniques our ability to interpret such measurements is still limited. Even interpretation of dose-response based on single-cell data is not straightforward: signaling responses can differ significantly between cells, encompass multiple signaling effectors, and have dynamic character. Here, we use probabilistic modeling and information-theory to introduce fractional response analysis (FRA), which quantifies changes in fractions of cells with given response levels. FRA can be universally performed for heterogeneous, multivariate, and dynamic measurements and, as we demonstrate, quantifies otherwise hidden patterns in single-cell data. In particular, we show that fractional responses to type I interferon in human peripheral blood mononuclear cells are very similar across different cell types, despite significant differences in mean or median responses and degrees of cell-to-cell heterogeneity. Further, we demonstrate that fractional responses to cytokines scale linearly with the log of the cytokine dose, which uncovers that heterogeneous cellular populations are sensitive to fold-changes in the dose, as opposed to additive changes.


Asunto(s)
Ensayos Analíticos de Alto Rendimiento/métodos , Interferón Tipo I/metabolismo , Leucocitos Mononucleares/metabolismo , Modelos Inmunológicos , Células 3T3 , Animales , Voluntarios Sanos , Humanos , Interferón Tipo I/inmunología , Leucocitos Mononucleares/inmunología , Ratones , Modelos Estadísticos , Cultivo Primario de Células , Transducción de Señal/inmunología , Análisis de la Célula Individual , Programas Informáticos
17.
Transl Psychiatry ; 11(1): 383, 2021 07 08.
Artículo en Inglés | MEDLINE | ID: mdl-34238925

RESUMEN

The release of neuropeptides from dense core vesicles (DCVs) modulates neuronal activity and plays a critical role in cognitive function and emotion. The granin family is considered a master regulator of DCV biogenesis and the release of DCV cargo molecules. The expression of the VGF protein (nonacronymic), a secreted neuropeptide precursor that also belongs to the extended granin family, has been previously shown to be induced in the brain by hippocampus-dependent learning, and its downregulation is mechanistically linked to neurodegenerative diseases such as Alzheimer's disease and other mood disorders. Currently, whether changes in translational efficiency of Vgf and other granin mRNAs may be associated and regulated with learning associated neural activity remains largely unknown. Here, we show that either contextual fear memory training or the administration of TLQP-62, a peptide derived from the C-terminal region of the VGF precursor, acutely increases the translation of VGF and other granin proteins, such as CgB and Scg2, via an mTOR-dependent signaling pathway in the absence of measurable increases in mRNA expression. Luciferase-based reporter assays confirmed that the 3'-untranslated region (3'UTR) of the Vgf mRNA represses VGF translation. Consistently, the truncation of the endogenous Vgf mRNA 3'UTR results in substantial increases in VGF protein expression both in cultured primary neurons and in brain tissues from knock in mice expressing a 3'UTR-truncation mutant encoded by the modified Vgf gene. Importantly, Vgf 3'UTR-truncated mice exhibit enhanced memory performance and reduced anxiety- and depression-like behaviors. Our results therefore reveal a rapid, transcription-independent induction of VGF and other granin proteins after learning that are triggered by the VGF-derived peptide TLQP-62. Our findings suggest that the rapid, positive feedforward increase in the synthesis of granin family proteins might be a general mechanism to replenish DCV cargo molecules that have been released in response to neuronal activation and is crucial for memory function and mood stability.


Asunto(s)
Neuronas , Péptidos , Animales , Cognición , Hipocampo , Memoria , Ratones
18.
Nat Commun ; 12(1): 4227, 2021 07 09.
Artículo en Inglés | MEDLINE | ID: mdl-34244482

RESUMEN

Glycine decarboxylase (GLDC) is a key enzyme of glycine cleavage system that converts glycine into one-carbon units. GLDC is commonly up-regulated and plays important roles in many human cancers. Whether and how GLDC is regulated by post-translational modifications is unknown. Here we report that mechanistic target of rapamycin complex 1 (mTORC1) signal inhibits GLDC acetylation at lysine (K) 514 by inducing transcription of the deacetylase sirtuin 3 (SIRT3). Upon inhibition of mTORC1, the acetyltransferase acetyl-CoA acetyltransferase 1 (ACAT1) catalyzes GLDC K514 acetylation. This acetylation of GLDC impairs its enzymatic activity. In addition, this acetylation of GLDC primes for its K33-linked polyubiquitination at K544 by the ubiquitin ligase NF-X1, leading to its degradation by the proteasomal pathway. Finally, we find that GLDC K514 acetylation inhibits glycine catabolism, pyrimidines synthesis and glioma tumorigenesis. Our finding reveals critical roles of post-translational modifications of GLDC in regulation of its enzymatic activity, glycine metabolism and tumorigenesis, and provides potential targets for therapeutics of cancers such as glioma.


Asunto(s)
Carcinogénesis/genética , Glioma/genética , Glicina-Deshidrogenasa (Descarboxilante)/metabolismo , Glicina/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Acetil-CoA C-Acetiltransferasa/metabolismo , Acetilación , Animales , Carcinogénesis/metabolismo , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Glioma/metabolismo , Glioma/patología , Células HEK293 , Humanos , Masculino , Ratones , Complejo de la Endopetidasa Proteasomal/metabolismo , Procesamiento Proteico-Postraduccional , Proteolisis , Pirimidinas/biosíntesis , Proteínas Represoras/metabolismo , Sirtuina 3/genética , Sirtuina 3/metabolismo , Activación Transcripcional , Ubiquitinación/genética , Ensayos Antitumor por Modelo de Xenoinjerto
19.
J Agric Food Chem ; 69(28): 8038-8049, 2021 Jul 21.
Artículo en Inglés | MEDLINE | ID: mdl-34236846

RESUMEN

Appropriately increasing intramuscular fat content can help improve meat quality, so it is necessary to explore the internal molecular mechanism of preadipocyte differentiation. The role of heme oxygenase 1 (HO1) in cell oxidative stress, energy metabolism, cell proliferation, and differentiation has gradually been revealed. Here, we used 3'RACE to identify the full-length 3' untranslated region (3'UTR) of HO1 and found that a very short 3'UTR variant was produced by alternative polyadenylation (APA). HO1 with a long 3'UTR variant was identified as a direct target of miR155-5P and miR377-3P. Our experimental results verified the inhibitory effect of HO1 on preadipocyte differentiation. In addition, our research confirms that by escaping microRNA inhibitory effects, the HO1 3'UTR short variant produced by APA has a higher level of expression. Thus, the HO1 3'UTR short variant has a stronger inhibitory effect on the preadipocyte differentiation than the HO1 3'UTR long variants in 3T3-L1.


Asunto(s)
MicroARNs , Poliadenilación , Regiones no Traducidas 3' , Células 3T3-L1 , Adipogénesis/genética , Animales , Hemo-Oxigenasa 1/genética , Ratones , MicroARNs/genética , MicroARNs/metabolismo
20.
Nat Cell Biol ; 23(7): 718-732, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-34239064

RESUMEN

Patients with Coronavirus disease 2019 exhibit low expression of interferon-stimulated genes, contributing to a limited antiviral response. Uncovering the underlying mechanism of innate immune suppression and rescuing the innate antiviral response remain urgent issues in the current pandemic. Here we identified that the dimerization domain of the SARS-CoV-2 nucleocapsid protein (SARS2-NP) is required for SARS2-NP to undergo liquid-liquid phase separation with RNA, which inhibits Lys63-linked poly-ubiquitination and aggregation of MAVS and thereby suppresses the innate antiviral immune response. Mice infected with an RNA virus carrying SARS2-NP exhibited reduced innate immunity, an increased viral load and high morbidity. Notably, we identified SARS2-NP acetylation at Lys375 by host acetyltransferase and reported frequently occurring acetylation-mimicking mutations of Lys375, all of which impaired SARS2-NP liquid-liquid phase separation with RNA. Importantly, a peptide targeting the dimerization domain was screened out to disrupt the SARS2-NP liquid-liquid phase separation and demonstrated to inhibit SARS-CoV-2 replication and rescue innate antiviral immunity both in vitro and in vivo.


Asunto(s)
Proteínas de la Nucleocápside/inmunología , Proteínas de la Nucleocápside/metabolismo , SARS-CoV-2/genética , Animales , Inmunidad Innata/inmunología , Inmunidad Innata/fisiología , Ratones , Proteínas de la Nucleocápside/genética , Virus ARN/genética , SARS-CoV-2/fisiología
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