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1.
Cell ; 185(7): 1172-1188.e28, 2022 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-35303419

RESUMO

Intestinal mucus forms the first line of defense against bacterial invasion while providing nutrition to support microbial symbiosis. How the host controls mucus barrier integrity and commensalism is unclear. We show that terminal sialylation of glycans on intestinal mucus by ST6GALNAC1 (ST6), the dominant sialyltransferase specifically expressed in goblet cells and induced by microbial pathogen-associated molecular patterns, is essential for mucus integrity and protecting against excessive bacterial proteolytic degradation. Glycoproteomic profiling and biochemical analysis of ST6 mutations identified in patients show that decreased sialylation causes defective mucus proteins and congenital inflammatory bowel disease (IBD). Mice harboring a patient ST6 mutation have compromised mucus barriers, dysbiosis, and susceptibility to intestinal inflammation. Based on our understanding of the ST6 regulatory network, we show that treatment with sialylated mucin or a Foxo3 inhibitor can ameliorate IBD.


Assuntos
Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Sialiltransferases/genética , Animais , Homeostase , Humanos , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Camundongos , Muco/metabolismo , Sialiltransferases/metabolismo , Simbiose
2.
Nat Immunol ; 25(2): 282-293, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38172257

RESUMO

Preserving cells in a functional, non-senescent state is a major goal for extending human healthspans. Model organisms reveal that longevity and senescence are genetically controlled, but how genes control longevity in different mammalian tissues is unknown. Here, we report a new human genetic disease that causes cell senescence, liver and immune dysfunction, and early mortality that results from deficiency of GIMAP5, an evolutionarily conserved GTPase selectively expressed in lymphocytes and endothelial cells. We show that GIMAP5 restricts the pathological accumulation of long-chain ceramides (CERs), thereby regulating longevity. GIMAP5 controls CER abundance by interacting with protein kinase CK2 (CK2), attenuating its ability to activate CER synthases. Inhibition of CK2 and CER synthase rescues GIMAP5-deficient T cells by preventing CER overaccumulation and cell deterioration. Thus, GIMAP5 controls longevity assurance pathways crucial for immune function and healthspan in mammals.


Assuntos
Ceramidas , Proteínas de Ligação ao GTP , Animais , Humanos , Longevidade/genética , Células Endoteliais/metabolismo , Mamíferos/metabolismo
3.
Cell ; 171(3): 696-709.e23, 2017 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-28965760

RESUMO

The transcription factor NRF2 is a master regulator of the cellular antioxidant response, and it is often genetically activated in non-small-cell lung cancers (NSCLCs) by, for instance, mutations in the negative regulator KEAP1. While direct pharmacological inhibition of NRF2 has proven challenging, its aberrant activation rewires biochemical networks in cancer cells that may create special vulnerabilities. Here, we use chemical proteomics to map druggable proteins that are selectively expressed in KEAP1-mutant NSCLC cells. Principal among these is NR0B1, an atypical orphan nuclear receptor that we show engages in a multimeric protein complex to regulate the transcriptional output of KEAP1-mutant NSCLC cells. We further identify small molecules that covalently target a conserved cysteine within the NR0B1 protein interaction domain, and we demonstrate that these compounds disrupt NR0B1 complexes and impair the anchorage-independent growth of KEAP1-mutant cancer cells. Our findings designate NR0B1 as a druggable transcriptional regulator that supports NRF2-dependent lung cancers.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/química , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/química , Neoplasias Pulmonares/genética , Proteoma/análise , Transcriptoma , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Cisteína/metabolismo , Receptor Nuclear Órfão DAX-1/metabolismo , Redes Reguladoras de Genes , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Ligantes , Neoplasias Pulmonares/metabolismo
5.
Cell ; 160(4): 619-630, 2015 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-25679758

RESUMO

A central paradigm within virology is that each viral particle largely behaves as an independent infectious unit. Here, we demonstrate that clusters of enteroviral particles are packaged within phosphatidylserine (PS) lipid-enriched vesicles that are non-lytically released from cells and provide greater infection efficiency than free single viral particles. We show that vesicular PS lipids are co-factors to the relevant enterovirus receptors in mediating subsequent infectivity and transmission, in particular to primary human macrophages. We demonstrate that clustered packaging of viral particles within vesicles enables multiple viral RNA genomes to be collectively transferred into single cells. This study reveals a novel mode of viral transmission, where enteroviral genomes are transmitted from cell-to-cell en bloc in membrane-bound PS vesicles instead of as single independent genomes. This has implications for facilitating genetic cooperativity among viral quasispecies as well as enhancing viral replication.


Assuntos
Vesículas Citoplasmáticas/virologia , Infecções por Enterovirus/transmissão , Enterovirus/fisiologia , Macrófagos/virologia , Vesículas Citoplasmáticas/química , Humanos , Macrófagos/citologia , Fosfatidilserinas , Poliovirus/fisiologia , RNA Viral/metabolismo , Rhinovirus/fisiologia , Replicação Viral
6.
Nature ; 592(7856): 712-716, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33911276

RESUMO

Complex concentrated solutions of multiple principal elements are being widely investigated as high- or medium-entropy alloys (HEAs or MEAs)1-11, often assuming that these materials have the high configurational entropy of an ideal solution. However, enthalpic interactions among constituent elements are also expected at normal temperatures, resulting in various degrees of local chemical order12-22. Of the local chemical orders that can develop, chemical short-range order (CSRO) is arguably the most difficult to decipher and firm evidence of CSRO in these materials has been missing thus far16,22. Here we discover that, using an appropriate zone axis, micro/nanobeam diffraction, together with atomic-resolution imaging and chemical mapping via transmission electron microscopy, can explicitly reveal CSRO in a face-centred-cubic VCoNi concentrated solution. Our complementary suite of tools provides concrete information about the degree/extent of CSRO, atomic packing configuration and preferential occupancy of neighbouring lattice planes/sites by chemical species. Modelling of the CSRO order parameters and pair correlations over the nearest atomic shells indicates that the CSRO originates from the nearest-neighbour preference towards unlike (V-Co and V-Ni) pairs and avoidance of V-V pairs. Our findings offer a way of identifying CSRO in concentrated solution alloys. We also use atomic strain mapping to demonstrate the dislocation interactions enhanced by the CSROs, clarifying the effects of these CSROs on plasticity mechanisms and mechanical properties upon deformation.

7.
Nat Immunol ; 15(7): 667-75, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24859450

RESUMO

CD4(+) follicular helper T cells (T(FH) cells) are essential for germinal center (GC) responses and long-lived antibody responses. Here we report that naive CD4(+) T cells deficient in the transcription factor Foxp1 'preferentially' differentiated into T(FH) cells, which resulted in substantially enhanced GC and antibody responses. We found that Foxp1 used both constitutive Foxp1A and Foxp1D induced by stimulation of the T cell antigen receptor (TCR) to inhibit the generation of T(FH) cells. Mechanistically, Foxp1 directly and negatively regulated interleukin 21 (IL-21); Foxp1 also dampened expression of the costimulatory molecule ICOS and its downstream signaling at early stages of T cell activation, which rendered Foxp1-deficient CD4(+) T cells partially resistant to blockade of the ICOS ligand (ICOSL) during T(FH) cell development. Our findings demonstrate that Foxp1 is a critical negative regulator of T(FH) cell differentiation.


Assuntos
Diferenciação Celular , Fatores de Transcrição Forkhead/fisiologia , Proteínas Repressoras/fisiologia , Linfócitos T Auxiliares-Indutores/citologia , Animais , Linfócitos T CD4-Positivos/imunologia , Proteína Coestimuladora de Linfócitos T Induzíveis/genética , Interleucinas/genética , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Antígenos de Linfócitos T/fisiologia
8.
Nat Mater ; 23(6): 755-761, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38605195

RESUMO

The strength-ductility trade-off has long been a Gordian knot in conventional metallic structural materials and it is no exception in multi-principal element alloys. In particular, at ultrahigh yield strengths, plastic instability, that is, necking, happens prematurely, because of which ductility almost entirely disappears. This is due to the growing difficulty in the production and accumulation of dislocations from the very beginning of tensile deformation that renders the conventional dislocation hardening insufficient. Here we propose that premature necking can be harnessed for work hardening in a VCoNi multi-principal element alloy. Lüders banding as an initial tensile response induces the ongoing localized necking at the band front to produce both triaxial stress and strain gradient, which enables the rapid multiplication of dislocations. This leads to forest dislocation hardening, plus extra work hardening due to the interaction of dislocations with the local-chemical-order regions. The dual work hardening combines to restrain and stabilize the premature necking in reverse as well as to facilitate uniform deformation. Consequently, a superior strength-and-ductility synergy is achieved with a ductility of ~20% and yield strength of 2 GPa during room-temperature and cryogenic deformation. These findings offer an instability-control paradigm for synergistic work hardening to conquer the strength-ductility paradox at ultrahigh yield strengths.

9.
PLoS Pathog ; 19(3): e1011295, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36972295

RESUMO

Calcium (Ca2+), a ubiquitous second messenger, plays a crucial role in many cellular functions. Viruses often hijack Ca2+ signaling to facilitate viral processes such as entry, replication, assembly, and egress. Here, we report that infection by the swine arterivirus, porcine reproductive and respiratory syndrome virus (PRRSV), induces dysregulated Ca2+ homeostasis, subsequently activating calmodulin-dependent protein kinase-II (CaMKII) mediated autophagy, and thus fueling viral replication. Mechanically, PRRSV infection induces endoplasmic reticulum (ER) stress and forms a closed ER-plasma membrane (PM) contacts, resulting the opening of store operated calcium entry (SOCE) channel and causing the ER to take up extracellular Ca2+, which is then released into the cytoplasm by inositol trisphosphate receptor (IP3R) channel. Importantly, pharmacological inhibition of ER stress or CaMKII mediated autophagy blocks PRRSV replication. Notably, we show that PRRSV protein Nsp2 plays a dominant role in the PRRSV induced ER stress and autophagy, interacting with stromal interaction molecule 1 (STIM1) and the 78 kDa glucose-regulated protein 78 (GRP78). The interplay between PRRSV and cellular calcium signaling provides a novel potential approach to develop antivirals and therapeutics for the disease outbreaks.


Assuntos
Síndrome Respiratória e Reprodutiva Suína , Vírus da Síndrome Respiratória e Reprodutiva Suína , Animais , Suínos , Vírus da Síndrome Respiratória e Reprodutiva Suína/metabolismo , Sinalização do Cálcio , Cálcio/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Retículo Endoplasmático/metabolismo , Autofagia , Replicação Viral , Síndrome Respiratória e Reprodutiva Suína/metabolismo
10.
Cereb Cortex ; 34(2)2024 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-38342683

RESUMO

Postictal generalized electroencephalographic suppression is a possible electroencephalographic marker for sudden unexpected death in epilepsy. We aimed to investigate the cortical surface area abnormalities in epilepsy patients with postictal generalized electroencephalographic suppression. We retrospectively included 30 epilepsy patients with postictal generalized electroencephalographic suppression (PGES+), 21 epilepsy patients without postictal generalized electroencephalographic suppression (PGES-), and 30 healthy controls. Surface-based analysis on high-resolution T1-weighted images was conducted and cortical surface areas were compared among the three groups, alongside correlation analyses with seizure-related clinical variables. Compared with PGES- group, we identified reduced surface area in the bilateral insula with more extensive distribution in the right hemisphere in PGES+ group. The reduced right insular surface area was associated with younger seizure-onset age. When compared with healthy controls, PGES- group presented reduced surface area in the left caudal middle frontal gyrus; PGES+ group presented more widespread surface area reductions in the right posterior cingulate gyrus, left postcentral gyrus, middle frontal gyrus, and middle temporal gyrus. Our results suggested cortical microstructural impairment in patients with postictal generalized electroencephalographic suppression. The significant surface area reductions in the insular cortex supported the autonomic network involvement in the pathology of postictal generalized electroencephalographic suppression, and its right-sided predominance suggested the potential shared abnormal brain network for postictal generalized electroencephalographic suppression and sudden unexpected death in epilepsy.


Assuntos
Epilepsia , Morte Súbita Inesperada na Epilepsia , Humanos , Estudos Retrospectivos , Epilepsia/diagnóstico por imagem , Eletroencefalografia/métodos , Convulsões , Morte Súbita
11.
Cereb Cortex ; 34(6)2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38847535

RESUMO

Given the widespread use and relapse of methamphetamine (METH), it has caused serious public health burdens globally. However, the neurobiological basis of METH addiction remains poorly understood. Therefore, this study aimed to use magnetic resonance imaging (MRI) to investigate changes in brain networks and their connection to impulsivity and drug craving in abstinent individuals with METH use disorder (MUDs). A total of 110 MUDs and 55 age- and gender-matched healthy controls (HCs) underwent resting-state functional MRI and T1-weighted imaging scans, and completed impulsivity and cue-induced craving measurements. We applied independent component analysis to construct functional brain networks and multivariate analysis of covariance to investigate group differences in network connectivity. Mediation analyses were conducted to explore the relationships among brain-network functional connectivity (FC), impulsivity, and drug craving in the patients. MUDs showed increased connectivity in the salience network (SN) and decreased connectivity in the default mode network compared to HCs. Impulsivity was positively correlated with FC within the SN and played a completely mediating role between METH craving and FC within the SN in MUDs. These findings suggest alterations in functional brain networks underlying METH dependence, with SN potentially acting as a core neural substrate for impulse control disorders.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas , Encéfalo , Fissura , Sinais (Psicologia) , Comportamento Impulsivo , Imageamento por Ressonância Magnética , Metanfetamina , Humanos , Masculino , Transtornos Relacionados ao Uso de Anfetaminas/diagnóstico por imagem , Transtornos Relacionados ao Uso de Anfetaminas/fisiopatologia , Transtornos Relacionados ao Uso de Anfetaminas/psicologia , Adulto , Fissura/fisiologia , Comportamento Impulsivo/fisiologia , Feminino , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Metanfetamina/efeitos adversos , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/fisiopatologia , Vias Neurais/fisiopatologia , Vias Neurais/diagnóstico por imagem , Adulto Jovem
12.
Plant Cell Physiol ; 65(1): 20-34, 2024 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-37758243

RESUMO

Salinity and phosphate (Pi) starvation are the most common abiotic stresses that threaten crop productivity. Salt cress (Eutrema salsugineum) displays good tolerance to both salinity and Pi limitation. Previously, we found several Phosphate Transporter (PHT) genes in salt cress upregulated under salinity. Here, EsPHT1;5 induced by both low Pi (LP) and salinity was further characterized. Overexpression of EsPHT1;5 in salt cress enhanced plant tolerance to LP and salinity, while the knock-down lines exhibited growth retardation. The analysis of phosphorus (P) content and shoot/root ratio of total P in EsPHT1;5-overexpressing salt cress seedlings and the knock-down lines as well as arsenate uptake assays suggested the role of EsPHT1;5 in Pi acquisition and root-shoot translocation under Pi limitation. In addition, overexpression of EsPHT1;5 driven by the native promoter in salt cress enhanced Pi mobilization from rosettes to siliques upon a long-term salt treatment. Particularly, the promoter of EsPHT1;5 outperformed that of AtPHT1;5 in driving gene expression under salinity. We further identified a transcription factor EsANT, which negatively regulated EsPHT1;5 expression and plant tolerance to LP and salinity. Taken together, EsPHT1;5 plays an integral role in Pi acquisition and distribution in plant response to LP and salt stress. Further, EsANT may be involved in the cross-talk between Pi starvation and salinity signaling pathways. This work provides further insight into the mechanism underlying high P use efficiency in salt cress in its natural habitat, and evidence for a link between Pi and salt signaling.


Assuntos
Arabidopsis , Brassicaceae , Brassicaceae/genética , Arabidopsis/genética , Salinidade , Regulação da Expressão Gênica de Plantas , Fosfatos/metabolismo , Raízes de Plantas/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo
13.
Biochem Biophys Res Commun ; 698: 149558, 2024 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-38271832

RESUMO

Molecular breeding has brought about significant transformations in the milk market and production system during the twenty-first century. The primary economic characteristic of dairy production pertains to milk fat content. Our previous transcriptome analyses revealed that serine protease 2 (PRSS2) is a candidate gene that could impact milk fat synthesis in bovine mammary epithelial cells (BMECs) of Chinese Holstein dairy cows. To elucidate the function of the PRSS2 gene in milk fat synthesis, we constructed vectors for PRSS2 overexpression and interference and assessed intracellular triglycerides (TGs), cholesterol (CHOL), and nonesterified fatty acid (NEFA) contents in BMECs. Fatty acid varieties and components were also quantified using gas chromatography‒mass spectrometry (GC‒MS) technology. The regulatory pathway mediated by PRSS2 was validated through qPCR, ELISA, and WB techniques. Based on our research findings, PRSS2 emerges as a pivotal gene that regulates the expression of associated genes, thereby making a substantial contribution to lipid metabolism via the leptin (LEP)/Adenylate-activated protein kinase, alpha 1 catalytic subunit (AMPKα1)/sterol regulatory element binding protein 1(SREBP1) pathway by inhibiting TGs and CHOL accumulation while potentially promoting NEFA synthesis in BMECs. Furthermore, the PRSS2 gene enhances intracellular medium- and long-chain fatty acid metabolism by modulating genes related to the LEP/AMPKα1/SREBP1 pathway, leading to increased contents of unsaturated fatty acids C17:1N7 and C22:4N6. This study provides a robust theoretical framework for further investigation into the underlying molecular mechanisms through which PRSS2 influences lipid metabolism in dairy cows.


Assuntos
Ácidos Graxos não Esterificados , Metabolismo dos Lipídeos , Feminino , Bovinos , Animais , Metabolismo dos Lipídeos/genética , Ácidos Graxos não Esterificados/metabolismo , Leptina/metabolismo , Glândulas Mamárias Animais/metabolismo , Ácidos Graxos/metabolismo , Triglicerídeos/metabolismo , Leite/metabolismo , Colesterol/metabolismo , Células Epiteliais/metabolismo , Serina Proteases/metabolismo
14.
BMC Plant Biol ; 24(1): 482, 2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38822275

RESUMO

Anabasis aphylla (A. aphylla), a species of the Amaranthaceae family, is widely distributed in northwestern China and has high pharmacological value and ecological functions. However, the growth characteristics are poorly understood, impeding its industrial development for biopesticide development. Here, we explored the regenerative capacity of A. aphylla. To this end, different lengths of the secondary branches of perennial branches were mowed at the end of March before sprouting. The four treatments were no mowing (M0) and mowing 1/3, 2/3, and the entire length of the secondary branches of perennial branches (M1-M3, respectively). Next, to evaluate the compensatory growth after mowing, new assimilate branches' related traits were recorded every 30 days, and the final biomass was recorded. The mowed plants showed a greater growth rate of assimilation branches than un-mowed plants. Additionally, with the increasing mowing degree, the growth rate and the final biomass of assimilation branches showed a decreasing trend, with the greatest growth rate and final biomass in response to M1. To evaluate the mechanism of the compensatory growth after mowing, a combination of dynamic (0, 1, 5, and 8 days after mowing) plant hormone-targeted metabolomics and transcriptomics was performed for the M0 and M1 treatment. Overall, 26 plant hormone metabolites were detected, 6 of which significantly increased after mowing compared with control: Indole-3-acetyl-L-valine methyl ester, Indole-3-carboxylic acid, Indole-3-carboxaldehyde, Gibberellin A24, Gibberellin A4, and cis (+)-12-oxo-phytodienoic acid. Additionally, 2,402 differentially expressed genes were detected between the mowed plants and controls. By combining clustering analysis based on expression trends after mowing and gene ontology analysis of each cluster, 18 genes related to auxin metabolism were identified, 6 of which were significantly related to auxin synthesis. Our findings suggest that appropriate mowing can promote A. aphylla growth, regulated by the auxin metabolic pathway, and lays the foundation for the development of the industrial value of A. aphylla.


Assuntos
Ácidos Indolacéticos , Ácidos Indolacéticos/metabolismo , Reguladores de Crescimento de Plantas/metabolismo , Redes e Vias Metabólicas , Regulação da Expressão Gênica de Plantas , Transcriptoma
15.
Mol Carcinog ; 63(4): 663-676, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38197534

RESUMO

Gastric cancer (GC) constitutes substantial cancer mortality worldwide. Several cancer types aberrantly express bone marrow stromal cell antigen 2 (BST2), yet its functional and underlying mechanisms in GC progression remain unknown. In our study, RNA sequencing data revealed that BST2 was transcriptionally activated by homeobox D9 (HOXD9). BST2 was significantly upregulated in GC tissues and promoted epithelial-mesenchymal transition and metastasis of GC. BST2 knockdown reversed HOXD9's oncogenic effect on GC metastasis. Moreover, BST2 messenger RNA stability could be enhanced by poly(A) binding protein cytoplasmic 1 (PABPC1) through the interaction between BST2 3'-UTR and PABPC1 in GC cells. PABPC1 promoted GC metastasis, which BST2 silencing attenuated in vitro and in vivo. In addition, positive correlations among HOXD9, BST2, and PABPC1 were established in clinical samples. Taken together, increased expression of BST2 induced by HOXD9 synergizing with PABPC1 promoted GC cell migration and invasion capacity.


Assuntos
Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Proteínas de Ligação a RNA , Movimento Celular/genética , Transição Epitelial-Mesenquimal/genética , RNA , Proliferação de Células , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Metástase Neoplásica , Proteínas de Neoplasias , Proteínas de Homeodomínio/genética , Antígeno 2 do Estroma da Médula Óssea
16.
J Virol ; 97(10): e0104523, 2023 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-37811994

RESUMO

IMPORTANCE: Senecavirus A (SVA) is an emerging picornavirus associated with vesicular disease, which wide spreads around the world. It has evolved multiple strategies to evade host immune surveillance. The mechanism and pathogenesis of the virus infection remain unclear. In this study, we show that SERPINB1, a member of the SERPINB family, promotes SVA replication, and regulates both innate immunity and the autophagy pathway. SERPINB1 catalyzes K48-linked polyubiquitination of IκB kinase epsilon (IKBKE) and degrades IKBKE through the proteasome pathway. Inhibition of IKBKE expression by SERPINB1 induces autophagy to decrease type I interferon signaling, and ultimately promotes SVA proliferation. These results provide importantly the theoretical basis of SVA replication and pathogenesis. SERPINB1 could be a potential therapeutic target for the control of viral infection.


Assuntos
Quinase I-kappa B , Picornaviridae , Serpinas , Replicação Viral , Autofagia , Quinase I-kappa B/genética , Imunidade Inata , Picornaviridae/fisiologia , Transdução de Sinais , Serpinas/genética , Interferon Tipo I
17.
J Virol ; 97(4): e0018823, 2023 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-37039642

RESUMO

Stimulator of interferon (IFN) genes (STING) was recently pinpointed as an antiviral innate immune factor during the infection of RNA viruses. Porcine reproductive and respiratory syndrome virus (PRRSV), the swine arterivirus, is an enveloped RNA virus which has evolved many strategies to evade innate immunity. To date, the interactive network between PRRSV and STING remains to be fully established. Herein, we report that STING suppresses PRRSV replication through type I interferon signaling. However, PRRSV impedes STING trafficking from the endoplasmic reticulum (ER) to the Golgi apparatus, leading to the decreased phosphorylation of TANK-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3). Furthermore, PRRSV nonstructural protein 2 (Nsp2) colocalizes with STING, blocks STING translocation, and disrupts the STING-TBK1-IRF3 complex. Mechanistically, PRRSV Nsp2 retains STING at the ER by increasing the level of Ca2+ sensor stromal interaction molecule 1 (STIM1) protein. Functional analysis reveals that PRRSV Nsp2 deubiquitinates STIM1 by virtue of its papain-like protease 2 (PLP2) deubiquitinating (DUB) activity. Finally, we demonstrate that loss of STIM1 is associated with an elevated IFN response and restricts PRRSV replication. This work delineates the relationship between PRRSV infection and STING signaling and the importance of papain-like proteases (PLPs) in interfering in this axis. IMPORTANCE Porcine reproductive and respiratory syndrome virus (PRRSV), a member of the family Arteriviridae, is responsible for reproductive disorders in pregnant sows and respiratory problems in piglets, resulting in huge losses in the swine industry worldwide. Of note, PRRSV infection causes immunosuppression, of which the mechanism is not completely understood. Here, we demonstrate for the first time that STING, a protein typically associated with the antiviral response in DNA viruses, plays a critical role in controlling PRRSV infection. However, PRRSV utilizes its encoded protein Nsp2 to inhibit STING activity by blocking its translocation from the ER to the Golgi apparatus. In particular, Nsp2 retains STING at the ER by interacting with and further deubiquitinating STIM1. For this process, the activity of the viral PLP2 DUB enzyme is indispensable. The study describes a novel mechanism by which PLP2 plays a critical role in suppressing the innate immune response against arteriviruses and potentially other viruses that encode similar proteases.


Assuntos
Proteínas de Membrana , Peptídeo Hidrolases , Síndrome Respiratória e Reprodutiva Suína , Vírus da Síndrome Respiratória e Reprodutiva Suína , Molécula 1 de Interação Estromal , Animais , Feminino , Retículo Endoplasmático/metabolismo , Complexo de Golgi/metabolismo , Papaína/metabolismo , Peptídeo Hidrolases/metabolismo , Síndrome Respiratória e Reprodutiva Suína/imunologia , Síndrome Respiratória e Reprodutiva Suína/virologia , Vírus da Síndrome Respiratória e Reprodutiva Suína/metabolismo , Molécula 1 de Interação Estromal/metabolismo , Suínos , Proteínas não Estruturais Virais/metabolismo , Proteínas de Membrana/metabolismo , Imunidade Inata/imunologia , Ubiquitinação/fisiologia
18.
J Transl Med ; 22(1): 363, 2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38632591

RESUMO

Interleukin-33 (IL-33), an emerging cytokine within the IL-1 family, assumes a pivotal function in the control of obesity. However, the specific mechanism of its regulation of obesity formation remains unclear. In this study, we found that the expression level of IL-33 increased in visceral adipose tissue in mice fed with a high-fat diet (HFD) compared with that in mice fed with a normal diet (ND). In vitro, we also found the expression level of IL-33 was upregulated during the adipogenesis of 3T3-L1 cells. Functional test results showed that knockdown of IL-33 in 3T3-L1 cells differentiation could promote the accumulation of lipid droplets, the content of triglyceride and the expression of adipogenic-related genes (i.e. PPAR-γ, C/EBPα, FABP4, LPL, Adipoq and CD36). In contrast, overexpression of IL-33 inhibits adipogenic differentiation. Meanwhile, the above tests were repeated after over-differentiation of 3T3-L1 cells induced by oleic acid, and the results showed that IL-33 played a more significant role in the regulation of adipogenesis. To explore the mechanism, transcriptome sequencing was performed and results showed that IL-33 regulated the PPAR signaling pathway in 3T3-L1 cells. Further, Western blot and confocal microscopy showed that the inhibition of IL-33 could promote PPAR-γ expression by inhibiting the Wnt/ß-catenin signal in 3T3-L1 cells. This study demonstrated that IL-33 was an important regulator of preadipocyte differentiation and inhibited adipogenesis by regulating the Wnt/ß-catenin/PPAR-γ signaling pathway, which provided a new insight for further research on IL-33 as a new intervention target for metabolic disorders.


Assuntos
Adipogenia , Interleucina-33 , Via de Sinalização Wnt , Animais , Camundongos , Adipócitos/metabolismo , Adipogenia/genética , beta Catenina/metabolismo , Diferenciação Celular , Interleucina-33/metabolismo , Obesidade/metabolismo , PPAR gama/genética , PPAR gama/metabolismo
19.
Opt Express ; 32(7): 12816-12823, 2024 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-38571093

RESUMO

A tunable non-polarizing optical bandpass filter structure, comprising a prism pair coupled planar optical waveguide (POW), is demonstrated, by changing the incident angle of the filter. Experimental measurements show that pass bands for both TM and TE polarized waves are present in the filter simultaneously, and the two passbands overlap on each other. The overlapping of the two passbands can be sustainable for the peak wavelength from 623 to 852 nm as the incident angle of the light tuned within 2°. This POW based optical bandpass filter can be potentially applicable in various fields of optical and laser spectroscopies.

20.
Osteoporos Int ; 35(3): 543-549, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37921994

RESUMO

Preoperative bone density assessment is necessary to predict screw loosening. The forearm BMD is a useful predictor of BMD-related complications after lumbar operation. Our results show that the forearm BMD is as effective a predictor of screw loosening as the lumbar average HU value. Measurement of the forearm BMD may be a useful adjunct in predicting screw loosening following lumbar fusion. PURPOSE: To determine the relationship between forearm bone mineral density (BMD) and the risk of pedicle screw loosening in patients with lumbar spondylolisthesis. METHODS: We retrospectively evaluated 270 patients who underwent posterior lumbar interbody fusion for lumbar spondylolisthesis. The patients were divided into two groups on the basis of the with or without loose screws: the loosening group and the non-loosening group. The patient's gender, age, BMI, smoking and diabetes histories, and the operative segment were recorded as the basic information. The Hounsfield unit (HU) value for the BMD of the L1-4 lumbar was measured using computed tomography. The patient's distal one-third of the length of the radius and ulna of the non-dominant forearm was chosen as the site for dual-energy X-ray (DXA) bone density testing. RESULTS: The rate of screw loosening was 13% at a minimum 12 months follow-up. Average forearm BMD (0.461 ± 0.1 vs 0.577 ± 0.1, p < 0.001) and mean HU value (L1-4) (121.1 ± 27.3 vs 155.6 ± 32.2, p < 0.001) were lower in the screw loosening group than those in the non-loosening group. In multivariate logistic regression analysis, the forearm BMD (OR 0.840; 95%CI 0.797-0.886) and HU value (L1-4) (OR 0.952; 95%CI 0.935-0.969) were independent risk factor for screw loosening. The area under the curve (AUC) for the forearm BMD and HU value for prediction of pedicle screw loosening was 0.802 and 0.811. The forearm BMD cut-off for predicting pedicle screw loosening was 0.543 (sensitivity, 0.800; specificity, 0.864). CONCLUSIONS: The forearm BMD was an independent risk factor for loosening of the lumbar pedicle screws. The forearm BMD was a valid predictor of pedicle screw loosening in patients undergoing lumbar fusion, as was the CT HU value.


Assuntos
Parafusos Pediculares , Fusão Vertebral , Espondilolistese , Humanos , Densidade Óssea , Espondilolistese/diagnóstico por imagem , Espondilolistese/cirurgia , Antebraço , Estudos Retrospectivos , Parafusos Pediculares/efeitos adversos , Vértebras Lombares/cirurgia , Fusão Vertebral/efeitos adversos , Fusão Vertebral/métodos
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