RESUMO
Pyrin and hematopoietic expression, interferon-inducible nature, and nuclear localization (HIN) domain family member 1 (PYHIN1), also known as IFIX, belongs to the family of pyrin proteins. This family includes structurally and functionally related mouse (e.g., p202, p203, and p204 proteins) and human (e.g., the interferon-inducible protein 16, absent in melanoma 2 protein, myeloid cell nuclear differentiation antigen, and pyrin and HIN domain family 1 or IFIX) proteins. The IFIX protein belongs to the HIN-200 family of interferon-inducible proteins that have a 200-amino acid signature motif at their C-termini. The increased expression of pyrin proteins in most cell types inhibits cell cycle control and modulates cell survival. Consistent with this role for pyrin proteins, IFIX is a potential antiviral DNA sensor that is essential for immune responses, the detection of viral DNA in the nucleus and cytoplasm, and the binding of foreign DNA via its HIN domain in a sequence non-specific manner. By promoting the ubiquitination and subsequent degradation of MDM2, IFIX acts as a tumor suppressor, thereby leading to p53/TP53 stabilization, HDAC1 regulation via the ubiquitin-proteasome pathway, and tumor-cell-specific silencing of the maspin gene. These data demonstrate that the potential molecular mechanism(s) underlying the action of the IFIX protein might be associated with the development of human diseases, such as viral infections, malignant tumors, and autoimmune diseases. This review summarizes the current insights into IFIX functions and how its regulation affects the outcomes of various human diseases.
Assuntos
Doenças Autoimunes/metabolismo , Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Motivos de Aminoácidos , Animais , Doenças Autoimunes/genética , Humanos , Neoplasias/genética , Proteínas Nucleares/genética , Domínios Proteicos , Proteínas Supressoras de Tumor/genéticaRESUMO
Salmonella enterica is one of the most important food-borne pathogens, whose motility and virulence are highly related to flagella. Flagella alternatively express two kinds of surface antigen flagellin, FliC and FljB, in a phenomenon known as flagellar phase variation. The molecular mechanisms by which the switching orientation of the Hin-composed DNA segment mediates the expression of the fljBA promoter have been thoroughly illustrated. However, the precise regulators that control DNA strand exchange are barely understood. In this study, we found that a putative response regulator, STM0347, contributed to the phase variation of flagellin in S. Typhimurium. With quantitative proteomics and secretome profiling, a lack of STM0347 was confirmed to induce the transformation of flagellin from FliC to FljB. Real-time PCR and in vitro incubation of SMT0347 with the hin DNA segment suggested that STM0347 disturbed Hin-catalyzed DNA reversion via hin degradation, and the overexpression of Hin was sufficient to elicit flagellin variation. Subsequently, the Δstm0347 strain was outcompeted by its parental strain in HeLa cell invasion. Collectively, our results reveal the crucial role of STM0347 in Salmonella virulence and flagellar phase variation and highlight the complexity of the regulatory network of Hin-modulated flagellum phase variation in Salmonella.
Assuntos
Flagelina , Salmonella typhimurium , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Flagelos/genética , Flagelos/metabolismo , Flagelina/genética , Flagelina/metabolismo , Células HeLa , Humanos , Variação de Fase , Salmonella typhimurium/genética , beta-Frutofuranosidase/genéticaRESUMO
BACKGROUND: Circular RNAs (circRNAs) are special noncoding RNA molecules with closed loop structures. Compared with the traditional linear RNA, circRNA is more stable and not easily degraded. Many studies have shown that circRNAs are involved in the regulation of various diseases and cancers. Determining the functions of circRNAs in mammalian cells is of great significance for revealing their mechanism of action in physiological and pathological processes, diagnosis and treatment of diseases. However, determining the functions of circRNAs on a large scale is a challenging task because of the high experimental costs. RESULTS: In this paper, we present a hierarchical deep learning model, DeepciRGO, which can effectively predict gene ontology functions of circRNAs. We build a heterogeneous network containing circRNA co-expressions, protein-protein interactions and protein-circRNA interactions. The topology features of proteins and circRNAs are calculated using a novel representation learning approach HIN2Vec across the heterogeneous network. Then, a deep multi-label hierarchical classification model is trained with the topology features to predict the biological process function in the gene ontology for each circRNA. In particular, we manually curated a benchmark dataset containing 185 GO annotations for 62 circRNAs, namely, circRNA2GO-62. The DeepciRGO achieves promising performance on the circRNA2GO-62 dataset with a maximum F-measure of 0.412, a recall score of 0.400, and an accuracy of 0.425, which are significantly better than other state-of-the-art RNA function prediction methods. In addition, we demonstrate the considerable potential of integrating multiple interactions and association networks. CONCLUSIONS: DeepciRGO will be a useful tool for accurately annotating circRNAs. The experimental results show that integrating multi-source data can help to improve the predictive performance of DeepciRGO. Moreover, The model also can combine RNA structure and sequence information to further optimize predictive performance.
Assuntos
Redes Neurais de Computação , RNA Circular/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , DNA Helicases/genética , Ontologia Genética , Loci Gênicos , Humanos , Mapas de Interação de Proteínas/genética , Ubiquitina-Proteína Ligases/genéticaRESUMO
BACKGROUND: ALRs (AIM2-like Receptors) are germline encoded PRRs that belong to PYHIN gene family of cytokines, which are having signature N-terminal PYD (Pyrin, PAAD or DAPIN) domain and C-terminal HIN-200 (hematopoietic, interferon-inducible nuclear protein with 200 amino acid repeat) domain joined by a linker region. The positively charged HIN-200 domain senses and binds with negatively charged phosphate groups of single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) purely through electrostatic attractions. On the other hand, PYD domain interacts homotypically with a PYD domain of other mediators to pass the signals to effector molecules downwards the pathways for inflammatory responses. There is remarkable inter-specific diversity in the numbers of functional PYHIN genes e.g. one in cow, five in human, thirteen in mice etc., while there is a unique loss of PYHIN genes in the bat genomes which was revealed by Ahn et al. (2016) by studying genomes of ten different bat species belonging to sub-orders yinpterochiroptera and yangochiroptera. The conflicts between host and pathogen interfaces are compared with "Red queen's arms race" which is also described as binding seeking dynamics and binding avoidance dynamics. As a result of this never-ending rivalry, eukaryotes developed PRRs as antiviral mechanism while viruses developed counter mechanisms to evade host immune defense. The PYHIN receptors are directly engaged with pathogenic molecules, so these should have evolved under the influence of selection pressures. In the current study, we investigated the nature of selection pressure on different domain types of IFI16-like (IFI16-L) PYHIN genes in ruminants. RESULTS: Three transcript variants of the IFI16-like gene were found in PBMCs of ruminant animals-water buffalo, zebu cattle, goat, and sheep. The IFI16-like gene has one N-terminal PYD domain and one C-terminal HIN-200 domain, separated by an inter-domain linker region. HIN domain and inter-domain region are positively selected while the PYD domain is under the influence of purifying selection. CONCLUSION: Herein, we conclude that the nature of selection pressure varies on different parts (PYD domain, HIN domain, and inter-domain linker region) of IFI16-like PYHIN genes in the ruminants. This data can be useful to predict the molecular determinants of pathogen interactions.
Assuntos
Proteínas Nucleares/genética , Ruminantes/genética , Seleção Genética , Processamento Alternativo/genética , Animais , Códon/genética , Éxons/genética , Humanos , Funções Verossimilhança , Fosfoproteínas/genética , FilogeniaRESUMO
AIM2 (absent in melanoma 2) is a cytoplasmic sensor of double-stranded DNA from pathogens or damaged cellular organelles. It recruits ASC (apoptosis-associated specklike protein containing a CARD) and caspase-1 to form the AIM2 inflammasome, activate caspase-1, and elicit inflammatory responses via cytokine maturation and pyroptotic cell death. Structural studies from X-ray crystallography, NMR, and cryo-EM have revealed many details in AIM2 inflammasome activation, assembly, and regulation. Many principles learned from AIM2 inflammasome also apply to other inflammasomes. In this chapter, we discuss the interactions between dsDNA and AIM2-like receptors, between AIM2 and adaptor protein ASC, and between ASC and caspase-1 with the focus on helical filament assembly formed by PYD and CARD domains.
Assuntos
Proteínas de Ligação a DNA , Inflamassomos , Transdução de Sinais , Animais , Caspase 1 , DNA/metabolismo , Proteínas de Ligação a DNA/metabolismo , Humanos , Inflamassomos/biossíntese , Inflamassomos/imunologia , Ligação ProteicaRESUMO
Recommender systems (RS) have been increasingly applied to food and health. However, challenges still remain, including the effective incorporation of heterogeneous information and the discovery of meaningful relationships among entities in the context of food and health recommendations. To address these challenges, we propose a novel framework, the Health-aware Food Recommendation System with Dual Attention in Heterogeneous Graphs (HFRS-DA), for unsupervised representation learning on heterogeneous graph-structured data. HFRS-DA utilizes an attention technique to reconstruct node features and edges and employs a dual hierarchical attention mechanism for enhanced unsupervised learning of attributed graph representations. HFRS-DA addresses the challenge of effectively leveraging the heterogeneous information in the graph and discovering meaningful semantic relationships between entities. The framework analyses recipe components and their neighbours in the heterogeneous graph and can discover popular and healthy recipes, thereby promoting healthy eating habits. We compare HFRS-DA using the Allrecipes dataset and find that it outperforms all the related methods from the literature. Our study demonstrates that HFRS-DA enhances the unsupervised learning of attributed graph representations, which is important in scenarios where labelled data is scarce or unavailable. HFRS-DA can generate node embeddings for unused data effectively, enabling both inductive and transductive learning.
Assuntos
Alimentos , SemânticaRESUMO
The hematopoietic interferon-inducible nuclear (HIN) domain of the PYHIN family of proteins recognizes double-stranded DNA (dsDNA) through different dsDNA-binding modes. These modes apparently confer different roles upon these proteins in the regulation of innate immune responses, gene transcription, and apoptosis. Myeloid cell nuclear differentiation antigen (MNDA), a member of the human PYHIN family, binds DNA and regulates gene transcription in monocytes. However, the mechanism of DNA recognition and DNA-binding modes of human MNDA (hMNDA) remain unclear. Here, we determined the crystal structure of the hMNDA-HIN domain in complex with dsDNA at 2.4 Å resolution, and reveal that hMNDA-HIN binds to dsDNA in a sequence-independent manner. Structure and mutation studies indicated that hMNDA-HIN binds to dsDNA through a unique mode, involving two dsDNA-binding interfaces. Interface I exhibits an AIM2-like dsDNA-binding mode, and interface II has a previously unreported mode of dsDNA-binding. These results provide new insights into the DNA-binding modes of this PYHIN protein.
Assuntos
Interferons , Proteínas Nucleares , Humanos , Proteínas Nucleares/genética , Proteínas de Ligação a DNA/metabolismo , DNA/química , Núcleo Celular/metabolismoRESUMO
LncRNA-protein interaction plays an important role in the development and treatment of many human diseases. As the experimental approaches to determine lncRNA-protein interactions are expensive and time-consuming, considering that there are few calculation methods, therefore, it is urgent to develop efficient and accurate methods to predict lncRNA-protein interactions. In this work, a model for heterogeneous network embedding based on meta-path, namely LPIH2V, is proposed. The heterogeneous network is composed of lncRNA similarity networks, protein similarity networks, and known lncRNA-protein interaction networks. The behavioral features are extracted in a heterogeneous network using the HIN2Vec method of network embedding. The results showed that LPIH2V obtains an AUC of 0.97 and ACC of 0.95 in the 5-fold cross-validation test. The model successfully showed superiority and good generalization ability. Compared to other models, LPIH2V not only extracts attribute characteristics by similarity, but also acquires behavior properties by meta-path wandering in heterogeneous networks. LPIH2V would be beneficial in forecasting interactions between lncRNA and protein.
RESUMO
BACKGROUND: Thyroid cancer (TC) is the most common endocrine malignancy, and the incidence is increasing very fast. Surgical resection and radioactive iodine ablation are major therapeutic methods, however, around 10% of differentiated thyroid cancer and all anaplastic thyroid carcinoma (ATC) are failed. Comprehensive understanding the molecular mechanisms may provide new therapeutic strategies for thyroid cancer. Even though genetic heterogeneity is rigorously studied in various cancers, epigenetic heterogeneity in human cancer remains unclear. METHODS: A total of 405 surgical resected thyroid cancer samples were employed (three spatially isolated specimens were obtained from different regions of the same tumor). Twenty-four genes were selected for methylation screening, and frequently methylated genes in thyroid cancer were used for further validation. Methylation specific PCR (MSP) approach was employed to detect the gene promoter region methylation. RESULTS: Five genes (AP2, CDH1, DACT2, HIN1, and RASSF1A) are found frequently methylated (>30%) in thyroid cancer. The five genes panel is used for further epigenetic heterogeneity analysis. AP2 methylation is associated with gender (P < 0.05), DACT2 methylation is associated with age, gender and tumor size (all P < 0.05), HIN1 methylation is associated to tumor size (P < 0.05) and extra-thyroidal extension (P < 0.01). RASSF1A methylation is associated with lymph node metastasis (P < 0.01). For heterogeneity analysis, AP2 methylation heterogeneity is associated with tumor size (P < 0.01), CDH1 methylation heterogeneity is associated with lymph node metastasis (P < 0.05), DACT2 methylation heterogeneity is associated with tumor size (P < 0.01), HIN1 methylation heterogeneity is associated with tumor size and extra-thyroidal extension (all P < 0.01). The multivariable analysis suggested that the risk of lymph node metastasis is 2.5 times in CDH1 heterogeneous methylation group (OR = 2.512, 95% CI 1.135, 5.557, P = 0.023). The risk of extra-thyroidal extension is almost 3 times in HIN1 heterogeneous methylation group (OR = 2.607, 95% CI 1.138, 5.971, P = 0.023). CONCLUSION: Five of twenty-four genes were found frequently methylated in human thyroid cancer. Based on 5 genes panel analysis, epigenetic heterogeneity is an universal event. Epigenetic heterogeneity is associated with cancer development and progression.
RESUMO
Pyroptosis is the process of inflammatory cell death. The primary function of pyroptosis is to induce strong inflammatory responses that defend the host against microbe infection. Excessive pyroptosis, however, leads to several inflammatory diseases, including sepsis and autoimmune disorders. Pyroptosis can be canonical or noncanonical. Upon microbe infection, the canonical pathway responds to pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), while the noncanonical pathway responds to intracellular lipopolysaccharides (LPS) of Gram-negative bacteria. The last step of pyroptosis requires the cleavage of gasdermin D (GsdmD) at D275 (numbering after human GSDMD) into N- and C-termini by caspase 1 in the canonical pathway and caspase 4/5/11 (caspase 4/5 in humans, caspase 11 in mice) in the noncanonical pathway. Upon cleavage, the N-terminus of GsdmD (GsdmD-N) forms a transmembrane pore that releases cytokines such as IL-1ß and IL-18 and disturbs the regulation of ions and water, eventually resulting in strong inflammation and cell death. Since GsdmD is the effector of pyroptosis, promising inhibitors of GsdmD have been developed for inflammatory diseases. This review will focus on the roles of GsdmD during pyroptosis and in diseases.
RESUMO
Absent in melanoma 2 (AIM2) is a cytoplasmic sensor that upon recognizing double-stranded DNA assembles with apoptosis-associated speck-like protein containing a CARD (ASC) and procaspase-1 to form the multi-protein complex AIM2 inflammasome. Double-stranded DNA from bacterial, viral, or host cellular origins triggers AIM2 inflammasome assembly and activation, ultimately resulting in secretion of proinflammatory cytokines and pyroptotic cell death in order to eliminate microbial infection. Many pathogens therefore evade or suppress AIM2 inflammasome to establish infection. On the other hand, AIM2 activation is tightly controlled by multiple cellular factors to prevent autoinflammation. Extensive structural studies have captured the molecular details of multiple steps in AIM2 inflammasome assembly. The structures collectively revealed a nucleated polymerization mechanism that not only pervades each step of AIM2 inflammasome assembly, but also underlies assembly of other inflammasomes and complexes in immune signaling. In this article, we briefly review the identification of AIM2 as a cytoplasmic DNA sensor, summarize the importance of AIM2 inflammasome in infections and diseases, and discuss the molecular mechanisms of AIM2 assembly, activation, and regulation using recent cellular, biochemical, and structural results.
Assuntos
Inflamassomos , Melanoma , Biologia , Caspase 1 , Proteínas de Ligação a DNA , HumanosRESUMO
Inflammation is an immune response that protects against pathogens and cellular stress. The hallmark of inflammatory responses is inflammasome activation in response to various stimuli. This subsequently activates downstream effectors, that is, inflammatory caspases such as caspase-1, 4, 5, 11, and 12. Extensive efforts have been made on developing effective and safe anti-inflammatory therapeutics, and ginseng has long been traditionally used as efficacious and safe herbal medicine in treating various inflammatory and inflammation-mediated diseases. Many studies have successfully shown that ginseng plays an anti-inflammatory role by inhibiting inflammasomes and inflammasome-activated inflammatory caspases. This review discusses the regulatory roles of ginseng on inflammatory caspases in inflammatory responses and also suggests new research areas on the anti-inflammatory function of ginseng, which provides a novel insight into the development of ginseng as an effective and safe anti-inflammatory herbal medicine.
RESUMO
Interferon-inducible protein 204 (p204) binds to microbial DNA to elicit inflammatory responses and induce interferon production. p204 also modulates cell proliferation and differentiation by regulating various transcription factors. The C-terminal HIN domains in p204 are believed to be responsible for DNA binding, but the binding mode is not fully understood. The DNA-binding affinity of the p204 HIN1 domain has been characterized and its crystal structure has been determined, providing insight into its interaction with DNA. Surface-charge distribution together with sequence alignment suggests that the p204 HIN domain uses its L12 and L45 loops for DNA binding.
Assuntos
Interferons/metabolismo , Proteínas Nucleares/química , Proteínas Nucleares/metabolismo , Fosfoproteínas/química , Fosfoproteínas/metabolismo , Sequência de Aminoácidos , Animais , Cristalografia por Raios X , Interferons/química , Camundongos , Modelos Moleculares , Conformação Proteica , Domínios ProteicosRESUMO
Secretoglobins (SCGBs) are cytokine-like small molecular weight secreted proteins with largely unknown biological functions. Three SCGB proteins, SCGB1A1, SCGB3A1, and SCGB3A2, are predominantly expressed in lung airways. To gain insight into the possible functional relationships among the SCGBs, their protein and mRNA expression patterns were examined in lungs during gestation and in adult mice, using Scgb3a1-null and Scgb3a2-null mice as negative controls, by immunohistochemistry and by qRT-PCR analysis, respectively. The three SCGBs exhibited unique spatiotemporal expression patterns during embryogenesis. The lack of Scgb3a1 or Scgb3a2 did not affect expression of the other Scgb genes as determined by mRNA measurements. Moreover, the lack of Scgb3a1 or Scgb3a2 did not affect development of the pulmonary neuroepithelial bodies during embryogenesis, while the lack of Scgb3a2 may have resulted in slightly fewer ciliated cells than in the wild-type. These results suggest that SCGB1A1, SCGB3A1, and SCGB3A2 each may possess its own unique biological function.
Assuntos
Epitélio/metabolismo , Regulação da Expressão Gênica , Pulmão/citologia , Proteínas/genética , Secretoglobinas/genética , Uteroglobina/genética , Animais , Diferenciação Celular , Camundongos , Análise Espaço-TemporalRESUMO
Harpin proteins secreted by plant-pathogenic gram-negative bacteria induce diverse plant defenses against different pathogens. Harpin-induced 1 (HIN1) gene highly induced in tobacco after application of Harpin protein is involved in a common plant defense pathway. However, the role of HIN1 against Tobacco mosaic virus (TMV) remains unknown. In this study, we functionally characterized the Nicotiana benthamiana HIN1 (NbHIN1) gene and generated the transgenic tobacco overexpressing the NbHIN1 gene. In a subcellular localization experiment, we found that NbHIN1 localized in the plasma membrane and cytosol. Overexpression of NbHIN1 did not lead to observed phenotype compared to wild type tobacco plant. However, the NbHIN1 overexpressing tobacco plant exhibited significantly enhanced resistance to TMV infection. Moreover, RNA-sequencing revealed the transcriptomic profiling of NbHIN1 overexpression and highlighted the primary effects on the genes in the processes related to biosynthesis of amino acids, plant-pathogen interaction and RNA transport. We also found that overexpression of NbHIN1 highly induced the expression of NbRAB11, suggesting that jasmonic acid signaling pathway might be involved in TMV resistance. Taken together, for the first time we demonstrated that overexpressing a pathogenesis-related gene NbHIN1 in N. benthamiana significantly enhances the TMV resistance, providing a potential mechanism that will enable us to engineer tobacco with improved TMV resistance in the future.
Assuntos
Ciclopentanos/metabolismo , Resistência à Doença/genética , Nicotiana/genética , Oxilipinas/metabolismo , Doenças das Plantas/virologia , Proteínas de Plantas/genética , Transdução de Sinais , Vírus do Mosaico do Tabaco , Western Blotting , Clonagem Molecular , Genes de Plantas/genética , Genes de Plantas/fisiologia , Microscopia Confocal , Filogenia , Folhas de Planta/metabolismo , Proteínas de Plantas/fisiologia , Plantas Geneticamente Modificadas , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/genética , Nicotiana/metabolismo , Nicotiana/virologia , Técnicas do Sistema de Duplo-HíbridoRESUMO
Glioblastoma multiforme (GBM) is the most common brain tumor in adults. The role of high in normal-1 (HIN-1) as a potential biomarker in combating this disease is being described for the first time in this study. A combination of O6-methylguanine DNA methyltransferase (MGMT) and HIN-1 methylation could be a possible biomarker in therapy choice. Interestingly, survival data shows a similar trend for the methylation of MGMT and for unmethylation of HIN-1 and vice versa. Eighty-eight paraffin-embedded brain tumors were analyzed to screen methylation rates of different genes and evaluate the association between genes methylation and clinicopathologic variables. Our study is the first of its kind to indicate that MGMT and HIN-1 methylation status are inverted (97.7% of methylated ones) and could be new markers in the study of GBM prognosis, especially in the therapy selection.
Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Citocinas/metabolismo , Epigênese Genética , Glioblastoma/genética , Glioblastoma/terapia , Proteínas Supressoras de Tumor/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , Metilação de DNA/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de SobrevidaRESUMO
Ontology is one of the key components in semantic webs. It contains the core knowledge for an effective search. However, building ontology requires the carefully-collected knowledge which is very domain-sensitive. In this work, we present the practice of ontology construction for a case study of health tourism in Thailand. The whole process follows the METHONTOLOGY approach, which consists of phases: information gathering, corpus study, ontology engineering, evaluation, publishing, and the application construction. Different sources of data such as structure web documents like HTML and other documents are acquired in the information gathering process. The tourism corpora from various tourism texts and standards are explored. The ontology is evaluated in two aspects: automatic reasoning using Pellet, and RacerPro, and the questionnaires, used to evaluate by experts of the domains: tourism domain experts and ontology experts. The ontology usability is demonstrated via the semantic web application and via example axioms. The developed ontology is actually the first health tourism ontology in Thailand with the published application.
RESUMO
Interferon gamma-inducible protein 16 (IFI16) senses DNA in the cytoplasm and the nucleus by using two tandem hematopoietic interferon-inducible nuclear (HIN) domains, HINa and HINb, through the cooperative assembly of IFI16 filaments on double-stranded DNA (dsDNA). The role of HINa in sensing DNA is not clearly understood. Here, we describe the crystal structure of the HINa domain in complex with DNA at 2.55 Å resolution and provide the first insight into the mode of DNA binding by the HINa domain. The structure reveals the presence of two oligosaccharide/nucleotide-binding (OB) folds with a unique DNA-binding surface. HINa uses loop L45 of the canonical OB2 fold to bind to the DNA backbone. The dsDNA is recognized as two single strands of DNA. Interestingly, deletion of HINb compromises the ability of IFI16 to induce IFN-ß, while HINa mutants impaired in DNA binding enhance the production of IFN-ß. These results shed light on the roles of IFI16 HIN domains in DNA recognition and innate immune responses.
Assuntos
DNA/metabolismo , Proteínas Nucleares/química , Proteínas Nucleares/metabolismo , Fosfoproteínas/química , Fosfoproteínas/metabolismo , Cristalografia por Raios X , Humanos , Ligação Proteica , Domínios ProteicosRESUMO
The HIN-200 family of proteins play significant roles in inflammation-related processes. Among them, AIM2 (absent in melanoma 2) and IFI16 (γ-interferon-inducible protein 16) recognize double-stranded DNA to initiate inflammatory responses. In contrast, p202, a mouse interferon-inducible protein containing two HIN domains (HINa and HINb), has been reported to inhibit Aim2-mediated inflammatory signalling in mouse. To understand the inhibitory mechanism, the crystal structure of the p202 HINa domain in complex with a 20â bp DNA was determined, in which p202 HINa nonspecifically recognizes both strands of DNA through electrostatic attraction. The p202 HINa domain binds DNA more tightly than does AIM2 HIN, and the DNA-binding mode of p202 HINa is different from that of the AIM2 HIN and IFI16 HINb domains. These results, together with the reported data on p202 HINb, lead to an interaction model for full-length p202 and dsDNA which provides a conceivable mechanism for the negative regulation of Aim2 inflammasome activation by p202.
Assuntos
DNA/metabolismo , Inflamação/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/química , Proteínas Nucleares/metabolismo , Transdução de Sinais , Sequência de Aminoácidos , Animais , Cristalografia por Raios X , DNA/química , Proteínas de Ligação a DNA , Humanos , Inflamassomos/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , Modelos Moleculares , Dados de Sequência Molecular , Mutação , Proteínas Nucleares/química , Ligação Proteica , Estrutura Terciária de Proteína , Relação Estrutura-AtividadeRESUMO
Objective To study the clinical effect of Hin ceruminous injection after uterine lapa-roscopy combined operation in treatment of salpinx obstructive infertility ,which was done under the guidance of color Doppler ultrasound . [ Methods] A series of 160 salpinx obstructive infertility patients were in-cluded and randomly divided into the treatment group ( n=80 , treated with Hin ceruminous injection under the guidance of Color ultrasound 3-7 days after the first Menstrual cycle following hysteroscopy operation ) and the control group ( n=80 , treated by expectant method ) .The pregnancies were compared in the two groups 1 year after operation .The unpregnant patients were given Ioversol check 3 to 7 days after menstrua-tion clean to compare patency conditions of Fallopian tube between the two groups . [ Results] One year after operation the normal intrauterine pregnancy rate was 68.75%,which was higher than 51.25% in the control group .The difference was significant between the two groups (χ2 =5 .104 , P =0 .024 ) .Ectopic pregnancy rates were compared between the two groups and the difference was not significant (P>0.05). The patency rate of bilateral fallopian tubes in unpregnant patients of the observation group was 40 .9%, which was remarkably higher than 14.2%in the control group (P<0.05).And the incidence of impotency was 9.1%,which was markedly lower than 42.8%in the control group(P<0.01).And comparison of the total patency rates showed that the difference between the two groups was not significant ( P>0 .05 ) . [ Conclusion] Hin ceruminous injection after Hysteroscopy operation in treatment of salpinx obstructive infertility is effective and safe .