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1.
Front Immunol ; 14: 942849, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36825005

RESUMO

Secretory pathway kinase or kinase-like proteins (SPKKPs) are effective in the lumen of the endoplasmic reticulum (ER), Golgi apparatus (GA), and extracellular space. These proteins are involved in secretory signaling pathways and are distinctive from typical protein kinases. Various reports have shown that SPKKPs regulate the tumorigenesis and progression of human cancer via the phosphorylation of various substrates, which is essential in physiological and pathological processes. Emerging evidence has revealed that the expression of SPKKPs in human cancers is regulated by multiple factors. This review summarizes the current understanding of the contribution of SPKKPs in tumorigenesis and the progression of immunity. With the epidemic trend of immunotherapy, targeting SPKKPs may be a novel approach to anticancer therapy. This study briefly discusses the recent advances regarding SPKKPs.


Assuntos
Neoplasias , Fosfotransferases , Via Secretória , Humanos , Carcinogênese/imunologia , Neoplasias/imunologia , Fosfotransferases/imunologia , Proteínas/imunologia , Via Secretória/imunologia , Transdução de Sinais/imunologia , Progressão da Doença
2.
Plant Commun ; 1(4): 100084, 2020 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-33367248

RESUMO

Plants perceive various external and internal signals to self-modulate biological processes through members of the receptor-like kinase (RLK) family, among which Catharanthus roseus receptor-like kinase 1-like (CrRLK1L) proteins with their ligands, rapid alkalinization factor (RALF) peptides, have attracted considerable interest. FERONIA (FER), a CrRLK1L member, was initially reported to act as a major plant cell growth modulator in distinct tissues. Subsequently, the RALF-FER pathway was confirmed to function as an essential regulator of plant stress responses, including but not limited to immune responses. Furthermore, the RALF-FER pathway modulates immune responses and cell growth in a context-specific manner, and the vital roles of this pathway are beginning to be appreciated in crop species. The recent remarkable advances in understanding the functions and molecular mechanisms of the RALF-FER pathway have also raised many interesting questions that need to be answered in the future. This review mainly focuses on the roles of FER and other CrRLK1L members in modulating immune responses in the context of cell growth in response to their RALF peptide ligands and presents a brief outlook for future research.


Assuntos
Desenvolvimento Vegetal/genética , Imunidade Vegetal/genética , Proteínas de Plantas/genética , Proteínas de Plantas/imunologia , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/imunologia , Fosfotransferases/genética , Fosfotransferases/imunologia , Transdução de Sinais
3.
Int Immunopharmacol ; 89(Pt B): 107083, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33068860

RESUMO

Acne is a common inflammatory skin disease with the dysregulation of innate and adaptive immunity. However, the underlying mechanism of acne has not been completely elucidated. In this study, we identified gene signatures and the immune-related regulatory network in acne using integrated bioinformatics methods. Here, 303 Differentially expressed genes (DEGs) and 28 Hub genes were identified in acne (GSE53795 and GSE108110), which were associated with the inflammation-related signaling pathway. Subsequently, the CIBERSORT algorithm revealed the increased proinflammatory cells in acne. Moreover, we identified 3 kinases (FGR, HCK and LYN) and 2 transcription factors (TFs) (IRF8 and ZBTB16) from DEGs as the key genes, which regulated immune cell infiltration via targeting immune-related genes in acne. The upregulated 3 kinases (FGR, HCK and LYN) and IRF8, and the downregulated ZBTB16 were also confirmed in GSE6475 and in Acne mice. Based on the expression levels of these key genes, the tissues could be divided into 2 clusters using consensus cluster analysis. GSEA analysis showed that inflammation-related signaling pathways significantly enriched in cluster 2, indicating the important role of kinase and TFs on immune regulation in acne. Finally, we found that isotretinoin and trifarotene (CD5789) treatment repressed the expression of immune genes but not the expression of the kinases and TFs, indicating that kinases and TFs may be novel therapeutic target for acne. In conclusion, 3 kinases and 2 TFs were identified and validated as key regulators in the immune-related regulatory networks in acne, providing a more comprehensive understanding and novel therapeutic targets of acne.


Assuntos
Acne Vulgar/genética , Acne Vulgar/imunologia , Regulação da Expressão Gênica , Acne Vulgar/tratamento farmacológico , Animais , Análise por Conglomerados , Biologia Computacional/métodos , Bases de Dados Genéticas , Fármacos Dermatológicos/administração & dosagem , Fármacos Dermatológicos/farmacologia , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Ontologia Genética , Redes Reguladoras de Genes , Humanos , Isotretinoína/administração & dosagem , Isotretinoína/farmacologia , Camundongos Endogâmicos BALB C , Fosfotransferases/efeitos dos fármacos , Fosfotransferases/genética , Fosfotransferases/imunologia , Mapas de Interação de Proteínas/imunologia , Retinoides/administração & dosagem , Retinoides/farmacologia , Transdução de Sinais , Pele/efeitos dos fármacos , Pele/imunologia , Fatores de Transcrição/efeitos dos fármacos , Fatores de Transcrição/genética , Fatores de Transcrição/imunologia , Transcriptoma/imunologia
4.
Int J Mol Med ; 45(5): 1327-1340, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32323733

RESUMO

Salmonella enterica serovar Typhimurium causes invasive non­typhoidal Salmonella diseases in animals and humans, resulting in a high mortality rate and huge economic losses globally. As the prevalence of antibiotic­resistant Salmonella has been increasing, vaccination is thought to be the most effective and economical strategy to manage salmonellosis. The present study aimed to investigate whether dysfunction in the phosphoenolpyruvate:carbohydrate phosphotransferase system (PTS), which is critical for carbon uptake and survival in macrophages, may be adequate to generate Salmonella­attenuated vaccine strains. A Salmonella strain (KST0555) was generated by deleting the ptsI gene from the PTS and it was revealed that this auxotrophic mutant was unable to efficiently utilize predominant carbon sources during infection (glucose and glycerol), reduced its invasion and replication capacity in macrophages, and significantly (P=0.0065) lowered its virulence in the setting of a mouse colitis model, along with a substantially decreased intestinal colonization and invasiveness compared with its parent strain. The reverse transcription­quantitative PCR results demonstrated that the virulence genes in Salmonella pathogenicity island-1 (SPI-1) and -2 (SPI-2) and the motility of KST0555 were all downregulated compared with its parent strain. Finally, it was revealed that when mice were immunized orally with live KST0555, Salmonella­specific humoral and cellular immune responses were effectively elicited, providing protection against Salmonella infection. Thus, the present promising data provides a strong rationale for the advancement of KST0555 as a live Salmonella vaccine candidate and ptsI as a potential target for developing a live attenuated bacterial vaccine strain.


Assuntos
Proteínas de Bactérias/genética , Proteínas de Bactérias/imunologia , Fosfotransferases/genética , Fosfotransferases/imunologia , Vacinas contra Salmonella/imunologia , Salmonella typhimurium/imunologia , Vacinas Atenuadas/imunologia , Animais , Colite/imunologia , Modelos Animais de Doenças , Regulação para Baixo/imunologia , Imunidade Celular/imunologia , Imunidade Humoral/imunologia , Imunização/métodos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Virulência/imunologia
5.
PLoS Pathog ; 15(7): e1007900, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31269090

RESUMO

The Pseudomonas syringae acetyltransferase HopZ1a is delivered into host cells by the type III secretion system to promote bacterial growth. However, in the model plant host Arabidopsis thaliana, HopZ1a activity results in an effector-triggered immune response (ETI) that limits bacterial proliferation. HopZ1a-triggered immunity requires the nucleotide-binding, leucine-rich repeat domain (NLR) protein, ZAR1, and the pseudokinase, ZED1. Here we demonstrate that HopZ1a can acetylate members of a family of 'receptor-like cytoplasmic kinases' (RLCK family VII; also known as PBS1-like kinases, or PBLs) and promote their interaction with ZED1 and ZAR1 to form a ZAR1-ZED1-PBL ternary complex. Interactions between ZED1 and PBL kinases are determined by the pseudokinase features of ZED1, and mutants designed to restore ZED1 kinase motifs can (1) bind to PBLs, (2) recruit ZAR1, and (3) trigger ZAR1-dependent immunity in planta, all independently of HopZ1a. A ZED1 mutant that mimics acetylation by HopZ1a also triggers immunity in planta, providing evidence that effector-induced perturbations of ZED1 also activate ZAR1. Overall, our results suggest that interactions between these two RLCK families are promoted by perturbations of structural features that distinguish active from inactive kinase domain conformations. We propose that effector-induced interactions between ZED1/ZRK pseudokinases (RLCK family XII) and PBL kinases (RLCK family VII) provide a sensitive mechanism for detecting perturbations of either kinase family to activate ZAR1-mediated ETI.


Assuntos
Proteínas de Arabidopsis/imunologia , Proteínas de Arabidopsis/metabolismo , Arabidopsis/imunologia , Arabidopsis/metabolismo , Fosfotransferases/imunologia , Fosfotransferases/metabolismo , Imunidade Vegetal , Acetilação , Arabidopsis/genética , Proteínas de Arabidopsis/química , Proteínas de Arabidopsis/genética , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Proteínas de Transporte/química , Proteínas de Transporte/imunologia , Proteínas de Transporte/metabolismo , Interações entre Hospedeiro e Microrganismos/genética , Interações entre Hospedeiro e Microrganismos/imunologia , Modelos Imunológicos , Mutação , Fosfotransferases/genética , Domínios e Motivos de Interação entre Proteínas , Proteínas Quinases/química , Proteínas Quinases/metabolismo , Pseudomonas syringae/imunologia , Pseudomonas syringae/metabolismo , Pseudomonas syringae/patogenicidade
6.
Mol Plant ; 12(7): 967-983, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-30947022

RESUMO

Plants utilize intracellular nucleotide-binding leucine-rich repeat domain-containing receptors (NLRs) to recognize pathogen effectors and induce a robust defense response named effector-triggered immunity (ETI). The Arabidopsis NLR protein HOPZ-ACTIVATED RESISTANCE 1 (ZAR1) forms a precomplex with HOPZ-ETI-DEFICIENT 1 (ZED1), a receptor-like cytoplasmic kinase (RLCK) XII-2 subfamily member, to recognize the Pseudomonas syringae effector HopZ1a. We previously described a dominant mutant of Arabidopsis ZED1, zed1-D, which displays temperature-sensitive autoimmunity in a ZAR1-dependent manner. Here, we report that the RLCKs SUPPRESSOR OF ZED1-D1 (SZE1) and SZE2 associate with the ZAR1-ZED1 complex and are required for the ZED1-D-activated autoimmune response and HopZ1a-triggered immunity. We show that SZE1 but not SZE2 has autophosphorylation activity, and that the N-terminal myristoylation of both SZE1 and SZE2 is critical for their plasma membrane localization and ZED1-D-activated autoimmunity. Furthermore, we demonstrate that SZE1 and SZE2 both interact with ZAR1 to form a functional complex and are required for resistance against P. syringae pv. tomato DC3000 expressing HopZ1a. We also provide evidence that SZE1 and SZE2 interact with HopZ1a and function together with ZED1 to change the intramolecular interactions of ZAR1, leading to its activation. Taken together, our results reveal SZE1 and SZE2 as critical signaling components of HopZ1a-triggered immunity.


Assuntos
Proteínas de Arabidopsis/metabolismo , Proteínas de Transporte/metabolismo , Fosfotransferases/metabolismo , Imunidade Vegetal , Transdução de Sinais/imunologia , Arabidopsis/metabolismo , Proteínas NLR/metabolismo , Fosfotransferases/imunologia , Imunidade Vegetal/fisiologia , Pseudomonas syringae/imunologia
7.
Proc Natl Acad Sci U S A ; 114(22): 5749-5754, 2017 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-28507137

RESUMO

Plants detect and respond to pathogen invasion with membrane-localized pattern recognition receptors (PRRs), which recognize pathogen-associated molecular patterns (PAMPs) and activate downstream immune responses. Here we report that Arabidopsis thaliana LORELEI-LIKE GPI-ANCHORED PROTEIN 1 (LLG1), a coreceptor of the receptor-like kinase FERONIA, regulates PRR signaling. In a forward genetic screen for suppressors of enhanced disease resistance 1 (edr1), we identified the point mutation llg1-3, which suppresses edr1 disease resistance but does not affect plant growth and development. The llg1 mutants show enhanced susceptibility to various virulent pathogens, indicating that LLG1 has an important role in plant immunity. LLG1 constitutively associates with the PAMP receptor FLAGELLIN SENSING 2 (FLS2) and the elongation factor-Tu receptor, and forms a complex with BRASSINOSTEROID INSENSITIVE 1-ASSOCIATED RECEPTOR KINASE 1 in a ligand-dependent manner, indicating that LLG1 functions as a key component of PAMP-recognition immune complexes. Moreover, LLG1 contributes to accumulation and ligand-induced degradation of FLS2, and is required for downstream innate immunity responses, including ligand-induced phosphorylation of BOTRYTIS-INDUCED KINASE 1 and production of reactive oxygen species. Taken together, our findings reveal that LLG1 associates with PAMP receptors and modulates their function to regulate disease responses. As LLG1 functions as a coreceptor of FERONIA and plays central roles in plant growth and development, our findings indicate that LLG1 participates in separate pathways, and may suggest a potential connection between development and innate immunity in plants.


Assuntos
Proteínas de Arabidopsis/imunologia , Proteínas de Arabidopsis/metabolismo , Arabidopsis/imunologia , Arabidopsis/metabolismo , Proteínas Ligadas por GPI/imunologia , Proteínas Ligadas por GPI/metabolismo , Glicosilfosfatidilinositóis/metabolismo , Imunidade Vegetal , Proteínas Quinases/imunologia , Proteínas Quinases/metabolismo , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Proteínas Ligadas por GPI/genética , Imunidade Inata/genética , Mutação , Moléculas com Motivos Associados a Patógenos/imunologia , Moléculas com Motivos Associados a Patógenos/metabolismo , Fosfotransferases/imunologia , Fosfotransferases/metabolismo , Doenças das Plantas/genética , Doenças das Plantas/imunologia , Imunidade Vegetal/genética , Plantas Geneticamente Modificadas , Proteínas Serina-Treonina Quinases/imunologia , Proteínas Serina-Treonina Quinases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores de Reconhecimento de Padrão/imunologia , Receptores de Reconhecimento de Padrão/metabolismo
8.
Clin Immunol ; 175: 69-74, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27919819

RESUMO

Patients with common variable immunodeficiency (CVID) constitute a clinically and immunologically heterogeneous group characterized by B-cell dysfunction with hypogammaglobulinemia and defective immunoglobulin class switch of unknown etiology. Current classification systems are insufficient to achieve precise disease management. Characterization of signaling pathways essential for B-cell differentiation and class switch could provide new means to stratify patients. We evaluated constitutive and induced signaling by phospho-specific flow cytometry in 26 CVID patients and 18 healthy blood donors. Strong responses were induced both in CVID and healthy donor B cells upon activation. In contrast, constitutive phosphorylation levels of STAT3,-5,-6, Erk, PLC-γ and Syk were significantly increased in CVID B cells only. Hierarchical clustering revealed a subgroup of CVID patients with elevated constitutive phosphorylation of Syk and PLC-γ. All these patients had non-infectious complications, indicating that a distinct phosphorylation pattern of kinases in B cells identifies a clinically important subgroup of CVID patients.


Assuntos
Subpopulações de Linfócitos B/imunologia , Imunodeficiência de Variável Comum/imunologia , Fosforilação/imunologia , Fosfotransferases/imunologia , Adulto , Idoso , Feminino , Humanos , Switching de Imunoglobulina/imunologia , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Receptores de Antígenos de Linfócitos B/imunologia , Transdução de Sinais/imunologia , Adulto Jovem
9.
Monoclon Antib Immunodiagn Immunother ; 35(5): 267-271, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27788028

RESUMO

The purpose of this study was to detect Streptococcus mutans by using monoclonal antibodies (mAbs) against S. mutans that cause dental caries and compare the levels of the bacterium between the saliva of adolescents undergoing orthodontic treatment (OT) and those not undergoing treatment (NT). Saliva samples, collected from 25 OT adolescents (with a mean age of 12.84 years) and 25 NT adolescents (mean age of 12.4 years), were analyzed by Dentocult-SM and enzyme-linked immunosorbent assay using mAbs against Ag I/II (ckAg I/II) and GTF B (ckGTF B), GTF C (ckGTF C), and GTF D (ckGTF D) of S. mutans. The DMFT index was slightly higher in the OT group (5.12 in OT and 4.96 in NT) and the level of S. mutans (≥105 CFU/mL) was higher in OT (72%) than in NT (56%). The detected levels of ckAg I/II, ckGTF B, ckGTF C, and ckGTF D were slightly higher in OT than in NT. The results of this study indicate that use of mAbs against S. mutans yields sensitive detection for the bacterium in saliva samples and shows that it has a reliable connection to the number of S. mutans and decayed, missing, filled teeth (DMFT), suggesting that the levels of S. mutans in saliva can be defined and compared by the application of the mAbs.


Assuntos
Anticorpos Monoclonais/imunologia , Ortodontia Corretiva/efeitos adversos , Streptococcus mutans/imunologia , Streptococcus mutans/isolamento & purificação , Adolescente , Anticorpos Monoclonais/isolamento & purificação , Cárie Dentária/etiologia , Cárie Dentária/microbiologia , Cárie Dentária/patologia , Ensaio de Imunoadsorção Enzimática , Proteínas de Escherichia coli/imunologia , Proteínas de Escherichia coli/isolamento & purificação , Feminino , Humanos , Masculino , Proteínas de Membrana/imunologia , Proteínas de Membrana/isolamento & purificação , Fosfotransferases/imunologia , Fosfotransferases/isolamento & purificação , Saliva/microbiologia , Streptococcus mutans/patogenicidade
10.
Clin Neuropathol ; 34(6): 359-63, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26365462

RESUMO

AIM: Muscle specific kinase (MuSK) antibody-positive myasthenia gravis(MG) patients might present with clinical and electrophysiological signs of muscle atrophy. In this study, we investigated the potential contribution of mitochondrial dysfunction to muscle atrophy induced by MuSK immunity. METHODS: Mitochondrial enzyme expression was investigated in muscle samples of MuSK-immunized, acetylcholine receptor (AChR)-immunized, and complete Freund's adjuvant (CFA)-immunized C57BL/6 (B6) mice using histochemical methods. Mitochondrial enzyme activity was also investigated in MuSK- and CFA-immunized mice. RESULTS: Histochemical analysis showed normal muscle fiber activity on succinate dehydrogenase (SDH) and cytochrome oxidase (COX) stains in all immunization groups. However, MuSK-immunized mice had more ragged-red fibers on modified Gomori-trichrome (MGT) stain and more pronounced type 1 muscle fiber atrophy. MuSK-immunized mice also showed reduced citrate synthase, SDH, and NADH-cytochrome c-reductase activity. DISCUSSION: Our results suggest that MuSK-immunity might induce muscle atrophy through mitochondrial dysfunction.


Assuntos
Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Mitocôndrias/enzimologia , Doenças Musculares/enzimologia , Miastenia Gravis/enzimologia , Fosfotransferases/imunologia , Succinato Desidrogenase/metabolismo , Animais , Autoanticorpos/imunologia , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL
11.
PLoS One ; 9(10): e109875, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25299686

RESUMO

With the growing availability of genomic sequence information, there is an increasing need for gene function analysis. Antibody-mediated "silencing" represents an intriguing alternative for the precise inhibition of a particular function of biomolecules. Here, we describe a method for selecting recombinant antibodies with a specific purpose in mind, which is to inhibit intrinsic protein-protein interactions in the cytosol of plant cells. Experimental procedures were designed for conveniently evaluating desired properties of recombinant antibodies in consecutive steps. Our selection method was successfully used to develop a recombinant antibody inhibiting the interaction of ARABIDOPSIS HISTIDINE PHOSPHOTRANSFER PROTEIN 3 with such of its upstream interaction partners as the receiver domain of CYTOKININ INDEPENDENT HISTIDINE KINASE 1. The specific down-regulation of the cytokinin signaling pathway in vivo demonstrates the validity of our approach. This selection method can serve as a prototype for developing unique recombinant antibodies able to interfere with virtually any biomolecule in the living cell.


Assuntos
Proteínas de Arabidopsis/genética , Citosol/metabolismo , Fosfotransferases/genética , Mapas de Interação de Proteínas/genética , Proteínas Quinases/genética , Anticorpos/administração & dosagem , Anticorpos/imunologia , Arabidopsis/genética , Proteínas de Arabidopsis/biossíntese , Proteínas de Arabidopsis/imunologia , Citosol/imunologia , Regulação da Expressão Gênica de Plantas , Inativação Gênica/imunologia , Fosfotransferases/biossíntese , Fosfotransferases/imunologia , Mapas de Interação de Proteínas/imunologia , Proteínas Quinases/biossíntese , Proteínas Quinases/imunologia , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/imunologia , Transdução de Sinais
12.
PLoS One ; 9(5): e96456, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24802362

RESUMO

Monitoring protein phosphorylation at the cellular level is important to understand the intracellular signaling. Among the phosphoproteomics methods, phosphokinase antibody arrays have emerged as preferred tools to measure well-characterized phosphorylation in the intracellular signaling. Here, we present a dendron-coated phosphokinase antibody array (DPA) in which the antibodies are immobilized on a dendron-coated glass slide. Self-assembly of conically shaped dendrons well-controlled in size and structure resulted in precisely controlled lateral spacing between the immobilized phosphosite-specific antibodies, leading to minimized steric hindrance and improved antigen-antibody binding kinetics. These features increased sensitivity, selectivity, and reproducibility in measured amounts of protein phosphorylation. To demonstrate the utility of the DPA, we generated the phosphorylation profiles of brain tissue samples obtained from Alzheimer's disease (AD) model mice. The analysis of the profiles revealed signaling pathways deregulated during the course of AD progression.


Assuntos
Antracenos/química , Anticorpos Imobilizados/imunologia , Reações Antígeno-Anticorpo/imunologia , Fosforilação/imunologia , Fosfotransferases/imunologia , Doença de Alzheimer/imunologia , Doença de Alzheimer/patologia , Animais , Encéfalo/imunologia , Encéfalo/patologia , Dendrímeros/química , Modelos Animais de Doenças , Humanos , Imunoensaio/métodos , Masculino , Camundongos , Camundongos Transgênicos/imunologia , Transdução de Sinais/imunologia
13.
Indian J Biochem Biophys ; 51(6): 457-66, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25823217

RESUMO

Hyperactivation of proliferative and growth promoting pathways underlies the progression of vessel remodeling, leading to vascular dysfunction. An upregulation of early growth response protein 1 (Egr-1), a zinc finger transcription factor has been observed in several models of vascular diseases. In the vasculature, Egr-1 expression can be induced by multiple hormonal, metabolic and external stimuli, such as growth factors, cytokines, reactive oxygen species, hyperglycaemia and stretch-induced stress. The structure of the Egr-1 promoter allows both its auto-regulation and its binding with several regulatory transcription cofactors like the serum response factor and the cAMP response element binding protein. Pharmacological and genetic studies have revealed the involvement of several signaling pathways that contribute to the expression of Egr-1. Among them, the mitogen-activated protein kinase pathway has emerged as a predominant signaling cascade that regulates Egr-1 transcription in response to various stimuli. Moreover, targeted deletion of Egr-1 by DNAzymes, antisense oligonucleotides or RNA interference has also helped in defining the importance of Egr-1 in the pathophysiology of vascular diseases. Neointimal formation and expression of genes directly linked with proinflammatory processes have been demonstrated to be enhanced by Egr-1 expression and activity. This review provides an overview on the signaling components implicated in Egr-1 expression and discusses its potential involvement in vascular pathophysiology.


Assuntos
Citocinas/imunologia , Proteína 1 de Resposta de Crescimento Precoce/imunologia , Modelos Cardiovasculares , Fosfotransferases/imunologia , Transdução de Sinais/imunologia , Doenças Vasculares/imunologia , Remodelação Vascular/imunologia , Animais , Humanos , Modelos Imunológicos
14.
Infect Immun ; 81(1): 317-28, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23132496

RESUMO

Mycobacterium tuberculosis persists in the tissues of mammalian hosts despite inducing a robust immune response dominated by the macrophage-activating cytokine gamma interferon (IFN-γ). We identified the M. tuberculosis phosphate-specific transport (Pst) system component PstA1 as a factor required to resist IFN-γ-dependent immunity. A ΔpstA1 mutant was fully virulent in IFN-γ(-/-) mice but attenuated in wild-type (WT) mice and mice lacking specific IFN-γ-inducible immune mechanisms: nitric oxide synthase (NOS2), phagosome-associated p47 GTPase (Irgm1), or phagocyte oxidase (phox). These phenotypes suggest that ΔpstA1 bacteria are sensitized to an IFN-γ-dependent immune mechanism(s) other than NOS2, Irgm1, or phox. In other species, the Pst system has a secondary role as a negative regulator of phosphate starvation-responsive gene expression through an interaction with a two-component signal transduction system. In M. tuberculosis, we found that ΔpstA1 bacteria exhibited dysregulated gene expression during growth in phosphate-rich medium that was mediated by the two-component sensor kinase/response regulator system SenX3-RegX3. Remarkably, deletion of the regX3 gene suppressed the replication and virulence defects of ΔpstA1 bacteria in NOS2(-/-) mice, suggesting that M. tuberculosis requires the Pst system to negatively regulate activity of RegX3 in response to available phosphate in vivo. We therefore speculate that inorganic phosphate is readily available during replication in the lung and is an important signal controlling M. tuberculosis gene expression via the Pst-SenX3-RegX3 signal transduction system. Inability to sense this environmental signal, due to Pst deficiency, results in dysregulation of gene expression and sensitization of the bacteria to the host immune response.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/imunologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/imunologia , Regulação Bacteriana da Expressão Gênica , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/imunologia , Fosfatos/imunologia , Tuberculose/imunologia , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Proteínas de Bactérias/metabolismo , Feminino , Proteínas de Ligação ao GTP/genética , Proteínas de Ligação ao GTP/imunologia , Proteínas de Ligação ao GTP/metabolismo , Expressão Gênica/genética , Expressão Gênica/imunologia , Interferon gama/genética , Interferon gama/imunologia , Interferon gama/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/imunologia , Óxido Nítrico Sintase Tipo II/metabolismo , Oxirredutases/genética , Oxirredutases/imunologia , Oxirredutases/metabolismo , Fagócitos/imunologia , Fagócitos/metabolismo , Fosfatos/metabolismo , Fosfotransferases/genética , Fosfotransferases/imunologia , Fosfotransferases/metabolismo , Tuberculose/genética , Tuberculose/metabolismo , Tuberculose/microbiologia , Virulência
15.
Curr Opin Plant Biol ; 15(4): 358-66, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22658367

RESUMO

An important question in the field of plant-pathogen interactions is how the detection of pathogens is converted into an effective immune response. In recent years, substantial insight has been gained into the identities of both the plant receptors and the microbial molecules they recognize. Likewise, many of the downstream signaling proteins and transcriptions factors that activate defense responses have been characterized. However, the early molecular events that comprise 'recognition' and how defense signaling specificity is achieved are not as well understood. In this review we discuss the significance of non-arginine-aspartate (non-RD) kinases, a subclass of kinases that are often found in association with pattern recognition receptors (PRRs).


Assuntos
Bactérias/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Fosfotransferases/imunologia , Imunidade Vegetal/fisiologia , Plantas/imunologia , Plantas/microbiologia , Resistência à Doença/imunologia , Plantas/enzimologia , Receptores de Reconhecimento de Padrão , Transdução de Sinais
16.
Eur J Immunol ; 42(7): 1843-9, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22585713

RESUMO

Effective CD8(+) T-cell responses against tumor or microbial antigens that are not directly expressed in antigen-presenting cells (APCs) depend on the cross-presentation of these antigens on MHC class I in APCs. To identify signaling molecules that regulate cross-presentation, we used lentiviral-based RNA interference to test the roles of hundreds of kinases and phosphatases in this process. Our study uncovered eight previously unknown genes, consisting of one positive and seven negative regulators of antigen cross-presentation. Depletion of Acvr1c, a type I receptor for TGF-ß family of signaling molecules, led to an increase in CD80 and CD86 co-stimulator surface expression and secreted IL-12 in mouse bone marrow-derived DCs, as well as antigen-specific T-cell proliferation.


Assuntos
Apresentação de Antígeno/imunologia , Células Dendríticas/enzimologia , Células Dendríticas/imunologia , Monoéster Fosfórico Hidrolases/imunologia , Fosfotransferases/imunologia , Receptores de Ativinas Tipo I/genética , Receptores de Ativinas Tipo I/imunologia , Animais , Apresentação de Antígeno/genética , Western Blotting , Apresentação Cruzada/genética , Apresentação Cruzada/imunologia , Citometria de Fluxo , Inativação Gênica/imunologia , Imunidade Inata/genética , Imunidade Inata/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Monoéster Fosfórico Hidrolases/genética , Fosfotransferases/genética , RNA/química , RNA/genética , Interferência de RNA/imunologia
17.
Sci Signal ; 5(220): pl2, 2012 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-22510468

RESUMO

The central roles of kinases in cellular processes and diseases make them highly attractive as indicators of biological responses and as therapeutic targets. Peptide arrays are emerging as an important means of characterizing kinome activity. Currently, the computational tools used to perform high-throughput kinome analyses are not specifically tailored to the nature of the data, which hinders extraction of biological information and overall progress in the field. We have developed a method for kinome analysis, which is implemented as a software pipeline in the R environment. Components and parameters were chosen to address the technical and biological characteristics of kinome microarrays. We performed comparative analysis of kinome data sets that corresponded to stimulation of immune cells with ligands of well-defined signaling pathways: bovine monocytes treated with interferon-γ (IFN-γ), CpG-containing nucleotides, or lipopolysaccharide (LPS). The data sets for each of the treatments were analyzed with our methodology as well as with three other commonly used approaches. The methods were evaluated on the basis of statistical confidence of calculated values with respect to technical and biological variability, and the statistical confidence (P values) by which the known signaling pathways could be independently identified by the pathway analysis of InnateDB (a Web-based resource for innate immunity interactions and pathways). By considering the particular attributes of kinome data, we found that our approach identified more of the peptides involved in the pathways than did the other compared methods and that it did so at a much higher degree of statistical confidence.


Assuntos
Fosfotransferases/imunologia , Proteômica/métodos , Transdução de Sinais/imunologia , Animais , Bovinos , Biologia Computacional/métodos , Imunidade Inata , Métodos
18.
Annu Rev Plant Biol ; 63: 451-82, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22404464

RESUMO

Plants and animals sense conserved microbial signatures through receptors localized to the plasma membrane and cytoplasm. These receptors typically carry or associate with non-arginine-aspartate (non-RD) kinases that initiate complex signaling networks cumulating in robust defense responses. In plants, coregulatory receptor kinases have been identified that not only are critical for the innate immune response but also serve an essential function in other regulatory signaling pathways.


Assuntos
Genes de Plantas/imunologia , Plantas/imunologia , Plantas/microbiologia , Receptores de Superfície Celular/imunologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Animais , Proteínas de Arabidopsis/imunologia , Proteínas de Arabidopsis/metabolismo , Parede Celular/imunologia , Citoplasma/imunologia , Citoplasma/metabolismo , Endocitose/imunologia , Imunidade Inata/imunologia , Fosfotransferases/imunologia , Fosfotransferases/metabolismo , Proteínas de Plantas/imunologia , Proteínas de Plantas/metabolismo , Plantas/metabolismo , Proteínas Quinases/imunologia , Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/imunologia , Proteínas Serina-Treonina Quinases/metabolismo
19.
Dev Comp Immunol ; 36(1): 21-30, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21664929

RESUMO

Complementary (c)DNA encoding selenophosphate synthetase (SPS) messenger (m)RNA of the tiger shrimp Penaeus monodon, designated PmSPS, was obtained from the hepatopancreas by a reverse-transcription polymerase chain reaction (RT-PCR) and rapid amplification of cDNA ends (RACE). The 1582-bp cDNA contained an open reading frame (ORF) of 1248 bp, a 103-bp 5'-untranslated region (UTR), and a 231-bp 3'-UTR, which contained a conserved selenocysteine insertion sequence (SECIS) element, a conventional polyadenylation signal, and a poly A tail. The molecular mass of the deduced amino acid (aa) sequence (416 aa) was 45.5 kDa with an estimated pI of 4.85. It contained a putative selenocysteine residue which was encoded by the unusual stop codon, (275)TGA(277), which formed at the active site with residues Sec(58) and Lys(61). A comparison of amino acid sequences showed that PmSPS was more closely related to invertebrate SPS1, such as those of Heliothis virescens and Drosophila melanogaster a and b. PmSPS cDNA was synthesized in all tested tissues, especially in the hepatopancreas. PmSPS in the hepatopancreas of shrimp significantly increased after an injection with either Photobacterium damsela or white spot syndrome virus (WSSV) in order to protect cells against damage from oxidation, and enhance the recycling of selenocysteine or selenium metabolism, indicating that PmSPS is involved in the disease-resistance response. The PmSPS expression by hemocytes significantly increased in stage C, and then gradually decreased until stage A, suggesting that the cloned PmSPS in hemocytes might play a role in viability by renewing hemocytes and antioxidative stress response for new exoskeleton synthesis during the molt cycle of shrimp.


Assuntos
Hemócitos/metabolismo , Infecções/metabolismo , Penaeidae , Fosfotransferases/metabolismo , Photobacterium/imunologia , Vírus da Síndrome da Mancha Branca 1/imunologia , Animais , Sequência de Bases , Clonagem Molecular , Drosophila melanogaster/genética , Evolução Molecular , Hemócitos/imunologia , Hemócitos/microbiologia , Hemócitos/patologia , Hemócitos/virologia , Imunidade/genética , Infecções/genética , Infecções/imunologia , Dados de Sequência Molecular , Muda/genética , Estresse Oxidativo/genética , Fosfotransferases/genética , Fosfotransferases/imunologia , Photobacterium/patogenicidade , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Ativação Transcricional , Vírus da Síndrome da Mancha Branca 1/patogenicidade
20.
J Dent Res ; 90(4): 417-27, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20940366

RESUMO

UNLABELLED: Toll-like receptors play a critical role in innate immunity by detecting invading pathogens. The ability of TLRs to engage different intracellular signaling molecules and cross-talk with other regulatory pathways is an important factor in shaping the type, magnitude, and duration of the inflammatory response. The present review will cover the fundamental signaling pathways utilized by TLRs and how these pathways regulate the innate immune response to pathogens. ABBREVIATIONS: TLR, Toll-like receptor; PRR, pattern recognition receptor; PAMP, pathogen-associated molecular pattern; LPS, lipopolysaccharide; APC, antigen-presenting cell; IL, interleukin; TIR, Toll/IL-1R homology; MyD88, myeloid differentiation factor 88; IFN, interferon; TRIF, TIR-domain-containing adapter-inducing interferon-ß; IRAK, IL-1R-associated kinase; TAK1, TGF-ß-activated kinase; TAB1, TAK1-binding protein; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B-cells; MAPK, mitogen-activated protein kinase; NLR, NOD-like receptors; LRR, leucine-rich repeats; DC, dendritic cell; PI3K, phosphoinositide 3-kinases; GSK3, glycogen synthase kinase-3; mTOR, mammalian target of rapamycin; DAF, decay-accelerating factor; IKK, IκB kinase; IRF, interferon regulatory factors; TBK1, TANK-binding kinase 1; CARD, caspase activation and recruitment domain; PYD, pyrin N-terminal homology domain; ATF, activating transcription factor; and PTEN, phosphatase and tensin homolog.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/imunologia , Imunidade Inata/imunologia , Fosfotransferases/imunologia , Receptor Cross-Talk/imunologia , Transdução de Sinais/imunologia , Receptores Toll-Like/imunologia , Proteínas do Sistema Complemento/imunologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Fator 88 de Diferenciação Mieloide/imunologia , Proteínas Adaptadoras de Sinalização NOD/imunologia , Fosfatidilinositol 3-Quinases/imunologia , Receptores de Reconhecimento de Padrão/imunologia
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