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1.
Acta Trop ; 199: 105148, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31425673

RESUMO

Toxoplasma gondii, a ubiquitous and obligate intracellular pathogen, belonging to the phylum Apicomplexa, is capable of infecting a broad range of warm-blooded hosts including birds and mammals that is nearly worldwide. Preventive measures for toxoplasmosis are currently lacking and as such, development of novel vaccines is of urgent need. The plant-like calcium-dependent protein kinases (CDPKs) expressed by T. gondii, play important roles in cell invasion, gliding motility, egress and some other developmental processes, in which T. gondii CDPK3 (TgCDPK3) has been implicated as an important virulence factor. In this study, the immune protective function of recombinant TgCDPK3 (rTgCDPK3) against experimental toxoplasmosis in BALB/c were evaluated. We divided the mice into different dose groups of vaccines and all immunizations with purified rTgCDPK3 protein were injected by intramuscular at weeks 0, 2, and 4 in BALB/c mice. The rTgCDPK3 vaccine provided protection was correlated with the development of humoral and cellular immune responses demonstrated through the antigen-specific spleen cell proliferation, release of Th1 cytokines IFN-γ, and the production of the high titers of IgG antibody with a predominance of IgG2a over IgG1. Vaccination with rTgCDPK3 conferred partial protection against acute toxoplasmosis, as demonstrated by prolonged survival rate after lethal challenge. Additionally, the amount of brain tissues cysts in vaccinated mice led to 46.5% reduction compared with non-vaccinated ones. These data demonstrated that rTgCDPK3 inoculation prevents or attenuates the harmful influence of T. gondii infection, and it is a potential vaccine candidate against toxoplasmosis.


Assuntos
Proteínas Quinases/imunologia , Vacinas Protozoárias/imunologia , Toxoplasma/imunologia , Toxoplasmose Animal/prevenção & controle , Animais , Feminino , Interferon gama/análise , Camundongos , Camundongos Endogâmicos BALB C , Vacinação , Vacinas Sintéticas/imunologia
2.
Nature ; 571(7766): 565-569, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31316206

RESUMO

Parkinson's disease is a neurodegenerative disorder with motor symptoms linked to the loss of dopaminergic neurons in the substantia nigra compacta. Although the mechanisms that trigger the loss of dopaminergic neurons are unclear, mitochondrial dysfunction and inflammation are thought to have key roles1,2. An early-onset form of Parkinson's disease is associated with mutations in the PINK1 kinase and PRKN ubiquitin ligase genes3. PINK1 and Parkin (encoded by PRKN) are involved in the clearance of damaged mitochondria in cultured cells4, but recent evidence obtained using knockout and knockin mouse models have led to contradictory results regarding the contributions of PINK1 and Parkin to mitophagy in vivo5-8. It has previously been shown that PINK1 and Parkin have a key role in adaptive immunity by repressing presentation of mitochondrial antigens9, which suggests that autoimmune mechanisms participate in the aetiology of Parkinson's disease. Here we show that intestinal infection with Gram-negative bacteria in Pink1-/- mice engages mitochondrial antigen presentation and autoimmune mechanisms that elicit the establishment of cytotoxic mitochondria-specific CD8+ T cells in the periphery and in the brain. Notably, these mice show a sharp decrease in the density of dopaminergic axonal varicosities in the striatum and are affected by motor impairment that is reversed after treatment with L-DOPA. These data support the idea that PINK1 is a repressor of the immune system, and provide a pathophysiological model in which intestinal infection acts as a triggering event in Parkinson's disease, which highlights the relevance of the gut-brain axis in the disease10.


Assuntos
Infecções por Enterobacteriaceae/microbiologia , Infecções por Enterobacteriaceae/fisiopatologia , Intestinos/microbiologia , Doença de Parkinson/genética , Doença de Parkinson/microbiologia , Proteínas Quinases/deficiência , Proteínas Quinases/genética , Animais , Apresentação do Antígeno/imunologia , Autoantígenos/imunologia , Axônios/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Citrobacter rodentium/imunologia , Citrobacter rodentium/patogenicidade , Modelos Animais de Doenças , Neurônios Dopaminérgicos/imunologia , Neurônios Dopaminérgicos/patologia , Infecções por Enterobacteriaceae/imunologia , Infecções por Enterobacteriaceae/patologia , Feminino , Intestinos/imunologia , Intestinos/patologia , Levodopa/uso terapêutico , Masculino , Camundongos , Mitocôndrias/imunologia , Mitocôndrias/patologia , Neostriado/imunologia , Neostriado/microbiologia , Neostriado/patologia , Neostriado/fisiopatologia , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/fisiopatologia , Proteínas Quinases/imunologia , Ubiquitina-Proteína Ligases/deficiência , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/imunologia
3.
Microb Pathog ; 133: 103560, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31145981

RESUMO

Toxoplasma gondii is an intracellular zoonotic parasite that causes toxoplasmosis, which can cause economic losses and serious public health problems worldwide. A member of the T. gondii calcium-dependent protein kinases family, TgCDPK1 was recently identified as an essential regulator of exocytosis in T. gondii, and participated in direct parasite motility, host-cell invasion and egress. In the present study, the protective immunity of recombinant TgCDPK1 protein (rTgCDPK1) was evaluated against acute toxoplasmosis in mice. rTgCDPK1 were expressed and purified, BABL/c mice were intraperitoneally immunized with rTgCDPK1 and challenged with the highly virulent RH strain of T. gondii. The specific immune responses were analyzed by measuring the cytokine and serum antibody, and lymphocyte proliferation assays, flow cytometry of lymphocytes and the survival curve were employed to evaluate the protective efficacy. From the results we found that special humoral and cellular responses could be elicited in vaccine mice, and higher level of IgG antibody, and the significant increased levels of Th1-type cytokines IFN-γ, IL-12 (p70), IL10 and CD3+CD4+CD8- and CD3+CD8+CD4- T cells could also be detected comparing to control mice (P < 0.05). All vaccinated mice prolonged survival time (14.90 ±â€¯2.89 days) challenge with 1000 tachyzoites of RH, while the control mice died within 8 days. These results indicated that TgCDPK1 protein was a potential vaccine candidate against acute toxoplasmosis.


Assuntos
Imunização , Proteínas Quinases/genética , Proteínas Quinases/imunologia , Toxoplasma/imunologia , Toxoplasmose Animal/prevenção & controle , Animais , Anticorpos Antiprotozoários/sangue , Antígenos de Protozoários/genética , Antígenos de Protozoários/imunologia , Clonagem Molecular , Citocinas/metabolismo , Feminino , Genes de Protozoários/genética , Imunidade Celular , Imunidade Humoral , Imunoglobulina G/sangue , Linfócitos/imunologia , Camundongos , Proteínas de Protozoários/genética , Proteínas de Protozoários/imunologia , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Baço/imunologia , Análise de Sobrevida , Toxoplasma/genética , Toxoplasmose Animal/imunologia , Vacinas de DNA/imunologia
4.
J Virol ; 93(8)2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30728267

RESUMO

Gammaherpesviruses are ubiquitous pathogens that are associated with B cell lymphomas. In the early stages of chronic infection, these viruses infect naive B cells and subsequently usurp the B cell differentiation process through the germinal center response to ensure latent infection of long-lived memory B cells. A unique feature of early gammaherpesvirus chronic infection is a robust differentiation of irrelevant, virus-nonspecific B cells with reactivities against self-antigens and antigens of other species. In contrast, protective, virus-specific humoral responses do not reach peak levels until a much later time. While several host factors are known to either promote or selectively restrict gammaherpesvirus-driven germinal center response, viral mechanisms that contribute to the irrelevant B cell response have not been defined. In this report we show that the expression and the enzymatic activity of the gammaherpesvirus-encoded conserved protein kinase selectively facilitates the irrelevant, but not virus-specific, B cell responses. Further, we show that lack of interleukin-1 (IL-1) receptor attenuates gammaherpesvirus-driven B cell differentiation and viral reactivation. Because germinal center B cells are thought to be the target of malignant transformation during gammaherpesvirus-driven lymphomagenesis, identification of host and viral factors that promote germinal center responses during gammaherpesvirus infection may offer an insight into the mechanism of gammaherpesvirus pathogenesis.IMPORTANCE Gammaherpesviruses are ubiquitous cancer-associated pathogens that usurp the B cell differentiation process to establish life-long latent infection in memory B cells. A unique feature of early gammaherpesvirus infection is the robust increase in differentiation of B cells that are not specific for viral antigens and instead encode antibodies that react with self-antigens and antigens of other species. Viral mechanisms that are involved in driving such irrelevant B cell differentiation are not known. Here, we show that gammaherpesvirus-encoded conserved protein kinase and host IL-1 signaling promote irrelevant B cell responses and gammaherpesvirus-driven germinal center responses, with the latter thought to be the target of viral transformation.


Assuntos
Linfócitos B/imunologia , Diferenciação Celular/imunologia , Gammaherpesvirinae/imunologia , Ativação Linfocitária , Proteínas Quinases/imunologia , Proteínas Virais/imunologia , Animais , Linfócitos B/patologia , Gammaherpesvirinae/genética , Centro Germinativo/imunologia , Centro Germinativo/patologia , Infecções por Herpesviridae/genética , Infecções por Herpesviridae/imunologia , Infecções por Herpesviridae/patologia , Camundongos , Camundongos Knockout , Proteínas Quinases/genética , Receptores de Interleucina-1/genética , Receptores de Interleucina-1/imunologia , Proteínas Virais/genética
5.
Mol Immunol ; 107: 132-141, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30738250

RESUMO

The maintenance of intestinal tissue homeostasis is vital for the resistance against inflammatory bowel diseases (IBDs). Necroptosis is identified as an alternative mode of regulated cell death, which plays a pivotal role in tissue homeostasis. Thus, the roles of RIP3-mediated necroptosis in intestinal inflammation have been extensively studied. However, the biological implications of the mixed lineage kinase-like protein (MLKL), a molecule downstream of RIP3 in gut remain unclear. In this study, the role of MLKL in DSS-induced colitis was examined, and the contribution of gut microbiota was also determined. Compared with non-littermate WT mice, the survival rate, clinical score, intestinal damage and intestinal mucosal barrier integrity of non-littermate MLKL-deficient mice are significantly improved. MLKL deficiency prevents inflammatory cytokines production and MAPK signaling activation. Hence, MLKL deficiency inhibits DSS-induced colitis. Moreover, we proved that DSS susceptibility difference between two genotypes is not driven by intestinal microbiota based on the co-housing of two non-littermate genotypes and qPCR detection of fecal dominant bacterial taxa.


Assuntos
Colite , Sulfato de Dextrana/toxicidade , Microbioma Gastrointestinal/imunologia , Sistema de Sinalização das MAP Quinases/imunologia , Proteínas Quinases/deficiência , Animais , Colite/induzido quimicamente , Colite/genética , Colite/imunologia , Colite/microbiologia , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/imunologia , Inflamação/microbiologia , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Camundongos Knockout , Proteínas Quinases/imunologia , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/imunologia
6.
BMC Complement Altern Med ; 19(1): 14, 2019 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-30630477

RESUMO

BACKGROUND: Coreopsis tinctoria Nutt is an ethnomedicine widely used in Xinjiang, China. It is consumed as a herbal tea by local Uyghur people to treat high blood pressure and diarrhea. Our previous study confirmed that the ethyl acetate extract of Coreopsis tinctoria (AC) had a protective effect on diabetic nephropathy (DN) in an in vivo experiment. Here we aim to elucidate the protective mechanism of AC and marein, the main ingredient in Coreopsis tinctoria on renal fibrosis and inflammation in vitro under high glucose (HG) conditions. METHODS: A HG-induced barrier dysfunction model in rat mesangial cells (HBZY-1) was established. The cells were exposed to AC and marein and/or HG for 24 h. Then, the renal protective effects of AC and marein via transforming growth factor-ß1 (TGF-ß1)/Smads, AMP-activated kinase protein (AMPK), and nuclear factor kappa beta (NF-κB) signaling were assessed. RESULTS: Both AC and marein suppressed rat mesangial cell hyperplasia and significantly attenuated the expression of HG-disrupted fibrotic and inflammatory proteins in HBZY-1 cells. It was also confirmed that AC and marein remarkably attenuated HG-induced renal inflammation and fibrosis by regulating the AMPK, TGF-ß1/Smads, and NF-κB signaling pathways. CONCLUSION: These results indicated that AC and marein may delay the progression of DN, at least in part, by suppressing HG-induced renal inflammation and fibrosis. Marein may be one of the bioactive compounds in AC.


Assuntos
Coreopsis/química , Medicamentos de Ervas Chinesas/farmacologia , Glucose/efeitos adversos , Nefropatias/imunologia , NF-kappa B/imunologia , Proteínas Quinases/imunologia , Proteínas Smad/imunologia , Fator de Crescimento Transformador beta1/imunologia , Animais , Chalconas/farmacologia , Fibrose/tratamento farmacológico , Fibrose/genética , Fibrose/imunologia , Humanos , Nefropatias/induzido quimicamente , Nefropatias/tratamento farmacológico , Células Mesangiais/efeitos dos fármacos , Células Mesangiais/imunologia , NF-kappa B/genética , Proteínas Quinases/genética , Ratos , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/genética , Fator de Crescimento Transformador beta1/genética
7.
Mol Plant ; 12(1): 113-123, 2019 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-30508598

RESUMO

Plants recycle non-activated immune receptors to maintain a functional immune system. The Arabidopsis immune receptor kinase FLAGELLIN-SENSING 2 (FLS2) recognizes bacterial flagellin. However, the molecular mechanisms by which non-activated FLS2 and other non-activated plant PRRs are recycled remain not well understood. Here, we provide evidence showing that Arabidopsis orosomucoid (ORM) proteins, which have been known to be negative regulators of sphingolipid biosynthesis, act as selective autophagy receptors to mediate the degradation of FLS2. Arabidopsis plants overexpressing ORM1 or ORM2 have undetectable or greatly diminished FLS2 accumulation, nearly lack FLS2 signaling, and are more susceptible to the bacterial pathogen Pseudomonas syringae. On the other hand, ORM1/2 RNAi plants and orm1 or orm2 mutants generated by the CRISPR/Cas9-mediated gene editing have increased FLS2 accumulation and enhanced FLS2 signaling, and are more resistant to P. syringae. ORM proteins interact with FLS2 and the autophagy-related protein ATG8. Interestingly, overexpression of ORM1 or ORM2 in autophagy-defective mutants showed FLS2 abundance that is comparable to that in wild-type plants. Moreover, FLS2 levels were not decreased in Arabidopsis plants overexpressing ORM1/2 derivatives that do not interact with ATG8. Taken together, these results suggest that selective autophagy functions in maintaining the homeostasis of a plant immune receptor and that beyond sphingolipid metabolic regulation ORM proteins can also act as selective autophagy receptors.


Assuntos
Proteínas de Arabidopsis/imunologia , Arabidopsis/imunologia , Autofagia , Proteínas de Membrana/imunologia , Proteínas Quinases/imunologia , Arabidopsis/enzimologia , Arabidopsis/genética , Arabidopsis/microbiologia , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Regulação da Expressão Gênica de Plantas , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Doenças das Plantas/imunologia , Doenças das Plantas/microbiologia , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Proteólise , Pseudomonas syringae/fisiologia
8.
Mol Immunol ; 105: 76-85, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30496979

RESUMO

Activation of NLRP3 inflammasomes is crucial in the pathological process of Ulcerative colitis (UC), which could be negatively regulated by PINK1/Parkin-driven mitophagy. Palmatine is a herb derived isoquinoline alkaloid with potent anti-inflammatory and anti-bacteria activities. In present study, we evaluated the effect of palmatine on dextran sulfate sodium (DSS)-induced mice colitis and examined whether its effect is exerted by promoting mitophagy-mediated NLRP3 inflammasome inactivation. The result showed that palmatine (40, 100 mg/kg) significantly prevented bodyweight loss and colonic shortening in DSS mice, and reduced the disease activity index and histopathologic score. The levels of MPO, IL-1ß, TNF-α and the number of F4/80+ cells in colon of DSS mice were remarkably decreased by palmatine. Moreover, palmatine suppressed NLRP3 inflammasomes activation, but enhanced the expression of the mitophagy-related proteins involving LC3, PINK1 and Parkin in colonic tissue of DSS mice. These effects was consistent with the in vitro data revealing that palmatine inhibited the activation of NLRP3 inflammasomes, while promoted the expression and mitochondrial recruitment of PINK1 and Parkin in THP-1 cell differentiated macrophages. Furthermore, the effect of palmatine on THP-1 cells was neutralized by a mitophagy inhibitor Cyclosporin A (CsA) and PINK1-siRNA. In parallel, CsA significantly attenuated the therapeutic effect of palmatine in DSS mice, illustrating that the anti-colitis effect of palmatine is closely related to mitophagy. Taken together, the current results demonstrated that palmatine protected mice against DSS-induced colitis by facilitating PINK1/Parkin-driven mitophagy and thus inactivating NLRP3 inflammasomes in macrophage.


Assuntos
Colite , Sulfato de Dextrana/toxicidade , Inflamassomos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Ácido Palmítico/farmacologia , Animais , Colite/induzido quimicamente , Colite/imunologia , Colite/patologia , Colite/prevenção & controle , Ciclosporina/farmacologia , Modelos Animais de Doenças , Humanos , Masculino , Camundongos Endogâmicos BALB C , Proteínas Quinases/imunologia , Células THP-1 , Ubiquitina-Proteína Ligases/imunologia
9.
Microb Pathog ; 126: 399-406, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30476579

RESUMO

It is well established that the current problem of tuberculosis (TB) can be combated by overcoming the drawbacks of the currently available BCG vaccine. This would involve incorporation of antigens that can control TB at all stages including the dormant phase which is generally ignored. Hence, DosR regulon proteins, which are expressed in latent infection, could prove to be very good vaccine candidates as they can possibly target the silent but most predominant form of TB infection. In the present study, the immune response to two DosR proteins Rv2627 and Rv2628 has been studied in PBMCs derived from normal individuals, TB patients and healthy contacts of TB patients. It was found that these antigens were capable of stimulating a strong IFN-γ+ T cell response along with accentuation of memory T cells and other protective cytokines such as IL-2 and IL-17. At the same time these proteins decreased the frequencies of immune-suppressor regulatory T cells in in vitro stimulation of PBMC from both patients and their contacts. Considering all these facts together, we suggest Rv2627 and Rv2628 to be one of the extremely promising candidates for incorporation into a post exposure subunit vaccine against TB.


Assuntos
Antígenos de Bactérias/imunologia , Proteínas de Bactérias/imunologia , Mycobacterium tuberculosis/metabolismo , Proteínas Quinases/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T/imunologia , Tuberculose/imunologia , Proteínas de Bactérias/genética , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Citocinas/metabolismo , Regulação para Baixo , Vetores Genéticos , Antígenos de Histocompatibilidade Classe II , Humanos , Interferon gama/metabolismo , Interleucina-17/metabolismo , Interleucina-2/metabolismo , Tuberculose Latente/imunologia , Leucócitos Mononucleares/imunologia , Mycobacterium tuberculosis/genética , Proteínas Quinases/genética , Regulon/imunologia , Vacinas contra a Tuberculose/imunologia , Regulação para Cima
10.
Scand J Immunol ; 89(1): e12729, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30372549

RESUMO

There is an urgent need to identify the potential risk factors for activating latent Mycobacterium tuberculosis infection. In this study, we evaluated the immune function of Rv1737c, which is a latency-associated antigen of dormancy survival regulator (DosR) of M. tuberculosis in a mouse model. Our data showed that mice pretreated with recombinant Rv1737c (rRv1737c) exhibited higher levels of antigen-specific antibodies (IgG, IgM and IgA) than sham-treated mice. Following Bacilli Calmette-Guerin (BCG) challenge, rRv1737c adjuvanted with cholera toxin subunit B (CTB) induced diffuse lung inflammation and fibrosis compared to the control mice. The inflammatory pathogenesis due to rRv1737c pre-exposure was associated with a switch in the macrophage phenotype from M1 to activated M2 and was characterized by IL-10 production. Intracellular cytokine analysis further showed that the rRv1737c-pretreated mice exhibited an increased frequency of Th2 cells in the lungs, lymph nodes and spleen after BCG challenge. Furthermore, IFN-γ expression increased in the lungs after rRv1737c pretreatment compared to that in the sham mice. Accordingly, lung cells from rRv1737c-immunized mice stimulated with killed BCG produced higher levels of multiple cytokines, such as IFN-γ, IL-10 and IL-6. The results confirmed that the pathological features of rRv1737c promoted inflammation. Overall, our findings provide direct evidence of the pro-inflammatory function of rRv1737c in a murine model of BCG infection, indicating that Rv1737c is a pathogenic antigen of M. tuberculosis and may be key to the recurrence of latent infection.


Assuntos
Proteínas de Bactérias/imunologia , Inflamação/imunologia , Tuberculose Latente/imunologia , Proteínas Quinases/imunologia , Animais , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis/imunologia
11.
Mol Plant ; 12(1): 59-70, 2019 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-30408577

RESUMO

Plants employ receptor-like kinases (RLKs) and receptor-like proteins for rapid recognition of invading pathogens, and RLKs then transmit signals to receptor-like cytoplasmic kinases (RLCKs) to activate immune responses. RLKs are under fine regulation mediated by subcellular trafficking, which contributes to proper activation of plant immunity. In this study, we show that Arabidopsis thaliana RECEPTOR-LIKE KINASE 902 (RLK902) plays important roles in resistance to the bacterial pathogen Pseudomonas syringae, but not to the fungal powdery mildew pathogen Golovinomyces cichoracearum. RLK902 localizes at the plasma membrane and associates with ENHANCED DISEASE RESISTANCE 4 (EDR4), a protein involved in clathrin-mediated trafficking pathways. EDR4 and CLATHRIN HEAVY CHAIN 2 (CHC2) regulate the subcellular trafficking and accumulation of RLK902 protein. Furthermore, we found that RLK902 directly associates with the RLCK BRASSINOSTEROID-SIGNALING KINASE1 (BSK1), a key component of plant immunity, but not with other members of the FLAGELLIN SENSING 2 immune complex. RLK902 phosphorylates BSK1, and its Ser-230 is a key phosphorylation site critical for RLK902-mediated defense signaling. Taken together, our data indicate that EDR4 regulates plant immunity by modulating the subcellular trafficking and protein accumulation of RLK902, and that RLK902 transmits immune signals by phosphorylating BSK1.


Assuntos
Proteínas de Arabidopsis/imunologia , Arabidopsis/enzimologia , Doenças das Plantas/imunologia , Proteínas Quinases/imunologia , Proteínas Serina-Treonina Quinases/imunologia , Motivos de Aminoácidos , Arabidopsis/genética , Arabidopsis/imunologia , Arabidopsis/microbiologia , Proteínas de Arabidopsis/química , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Ascomicetos/fisiologia , Resistência à Doença , Fosforilação , Doenças das Plantas/microbiologia , Ligação Proteica , Proteínas Quinases/química , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Transporte Proteico , Proteínas Serina-Treonina Quinases/química , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Pseudomonas syringae/fisiologia , Transdução de Sinais
12.
Am J Pathol ; 189(1): 190-199, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30315765

RESUMO

Oral squamous cell carcinoma (OSCC) is the most common malignant cancer, with high mortality rates in advanced stages. Recent studies have shown that the expression of ALPK1 mRNA and its inhibitory differentiation function are associated with cancer progression. However, the expression and clinicopathologic features of ALPK1 in OSCC remain unexplored. Herein, the authors investigated the expression patterns of ALPK1 in 39 matched OSCC patients and examined the relationship between ALPK1 protein expression and clinicopathologic factors using immunohistochemical scores. Using Western blot analysis, ALPK1 expression was found to be significantly higher in tumor tissues than that in nontumor tissues. Through an immunoreactive scoring system, a significantly higher number of advanced-stage tumor size T4 and lymph node metastasis N2 exhibited higher ALPK1 expression levels than that exhibited by T1/T2/T3 tumors and N0/N1. In addition, ALPK1 protein expression was aberrant in malignant oral cancer cell lines compared with that in pre-malignant oral epithelial cells, whereas minimal expression was observed in normal oral epithelial cells. Knockdown of ALPK1 resulted in a significant reduction in cell growth, migration, and invasion capacity in vitro. Consequently, expression of N-cadherin and vimentin decreased in ALPK1-deficient cells. Thus, these results suggest that ALPK1 serves as a potential biomarker and target for OSCC development in late stages.


Assuntos
Biomarcadores Tumorais/biossíntese , Carcinoma de Células Escamosas/enzimologia , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Proteínas de Neoplasias/biossíntese , Proteínas Quinases/biossíntese , Neoplasias da Língua/enzimologia , Adulto , Antígenos CD/genética , Antígenos CD/imunologia , Antígenos CD/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Caderinas/genética , Caderinas/imunologia , Caderinas/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Feminino , Técnicas de Silenciamento de Genes , Humanos , Queratinócitos/imunologia , Queratinócitos/metabolismo , Queratinócitos/patologia , Metástase Linfática/genética , Metástase Linfática/imunologia , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/imunologia , Estadiamento de Neoplasias , Proteínas Quinases/genética , Proteínas Quinases/imunologia , Neoplasias da Língua/genética , Neoplasias da Língua/imunologia , Neoplasias da Língua/patologia , Vimentina/genética , Vimentina/imunologia , Vimentina/metabolismo
13.
FEBS J ; 286(3): 507-522, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30576068

RESUMO

Interleukin-33 (IL-33) is a pro-inflammatory cytokine that plays a significant role in inflammatory diseases by activating immune cells to induce type 2 immune responses upon its release. Although IL-33 is known to be released during tissue damage, its exact release mechanism is not yet fully understood. Previously, we have shown that cleaved IL-33 can be detected in the plasma and epithelium of Ripk1-/- neonates, which succumb to systemic inflammation driven by spontaneous receptor-interacting protein kinase-3 (RIPK3)-dependent necroptotic cell death, shortly after birth. Thus, we hypothesized that necroptosis, a RIPK3/mixed lineage kinase-like protein (MLKL)-dependent, caspase-independent cell death pathway controls IL-33 release. Here, we show that necroptosis directly induces the release of nuclear IL-33 in its full-length form. Unlike the necroptosis executioner protein, MLKL, which was released in its active phosphorylated form in extracellular vesicles, IL-33 was released directly into the supernatant. Importantly, full-length IL-33 released in response to necroptosis was found to be bioactive, as it was able to activate basophils and eosinophils. Finally, the human and murine necroptosis inhibitor, GW806742X, blocked necroptosis and IL-33 release in vitro and reduced eosinophilia in Aspergillus fumigatus extract-induced asthma in vivo, an allergic inflammation model that is highly dependent on IL-33. Collectively, these data establish for the first time, necroptosis as a direct mechanism for IL-33 release, a finding that may have major implications in type 2 immune responses.


Assuntos
Apoptose/imunologia , Asma/imunologia , Interleucina-33/imunologia , Necrose/imunologia , Proteínas Quinases/imunologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Aspergillus fumigatus/química , Aspergillus fumigatus/imunologia , Asma/induzido quimicamente , Asma/tratamento farmacológico , Asma/genética , Basófilos/efeitos dos fármacos , Basófilos/imunologia , Basófilos/patologia , Linhagem Celular , Misturas Complexas/administração & dosagem , Misturas Complexas/química , Misturas Complexas/imunologia , Modelos Animais de Doenças , Eosinófilos/efeitos dos fármacos , Eosinófilos/imunologia , Eosinófilos/patologia , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/imunologia , Fibroblastos/patologia , Regulação da Expressão Gênica , Humanos , Imunidade Inata/efeitos dos fármacos , Interleucina-33/genética , Queratinócitos/efeitos dos fármacos , Queratinócitos/imunologia , Queratinócitos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Necrose/genética , Necrose/patologia , Necrose/prevenção & controle , Cultura Primária de Células , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/imunologia , Transdução de Sinais
14.
Nat Commun ; 9(1): 5185, 2018 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-30518761

RESUMO

Detection of conserved microbial patterns by host cell surface pattern recognition receptors (PRRs) activates innate immunity. The FLAGELLIN-SENSITIVE 2 (FLS2) receptor perceives bacterial flagellin and recruits another PRR, BAK1 and the cytoplasmic-kinase BIK1 to form an active co-receptor complex that initiates antibacterial immunity in Arabidopsis. Molecular mechanisms that transmit flagellin perception from the plasma-membrane FLS2-associated receptor complex to intracellular events are less well understood. Here, we show that flagellin induces the conjugation of the SMALL UBIQUITIN-LIKE MODIFIER (SUMO) protein to FLS2 to trigger release of BIK1. Disruption of FLS2 SUMOylation can abolish immune responses, resulting in susceptibility to bacterial pathogens in Arabidopsis. We also identify the molecular machinery that regulates FLS2 SUMOylation and demonstrate a role for the deSUMOylating enzyme, Desi3a in innate immunity. Flagellin induces the degradation of Desi3a and enhances FLS2 SUMOylation to promote BIK1 dissociation and trigger intracellular immune signalling.


Assuntos
Proteínas de Arabidopsis/imunologia , Arabidopsis/imunologia , Cisteína Endopeptidases/imunologia , Doenças das Plantas/imunologia , Proteínas Quinases/imunologia , Pseudomonas syringae/imunologia , Receptores de Reconhecimento de Padrão/imunologia , Arabidopsis/genética , Arabidopsis/microbiologia , Proteínas de Arabidopsis/genética , Proteínas de Bactérias/imunologia , Cisteína Endopeptidases/genética , Flagelina/imunologia , Imunidade Inata , Doenças das Plantas/microbiologia , Proteínas Quinases/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/imunologia , Pseudomonas syringae/genética , Pseudomonas syringae/fisiologia , Receptores de Reconhecimento de Padrão/genética , Transdução de Sinais , Sumoilação
15.
PLoS Biol ; 16(12): e2005956, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30540739

RESUMO

Plant protein kinases form redundant signaling pathways to perceive microbial pathogens and activate immunity. Bacterial pathogens repress cellular immune responses by secreting effectors, some of which bind and inhibit multiple host kinases. To understand how broadly bacterial effectors may bind protein kinases and the function of these kinase interactors, we first tested kinase-effector (K-E) interactions using the Pseudomonas syringae pv. tomato-tomato pathosystem. We tested interactions between five individual effectors (HopAI1, AvrPto, HopA1, HopM1, and HopAF1) and 279 tomato kinases in tomato cells. Over half of the tested kinases interacted with at least one effector, and 48% of these kinases interacted with more than three effectors, suggesting a role in the defense. Next, we characterized the role of select multi-effector-interacting kinases and revealed their roles in basal resistance, effector-triggered immunity (ETI), or programmed cell death (PCD). The immune function of several of these kinases was only detectable in the presence of effectors, suggesting that these kinases are critical when particular cell functions are perturbed or that their role is typically masked. To visualize the kinase networks underlying the cellular responses, we derived signal-specific networks. A comparison of the networks revealed a limited overlap between ETI and basal immunity networks. In addition, the basal immune network complexity increased when exposed to some of the effectors. The networks were used to successfully predict the role of a new set of kinases in basal immunity. Our work indicates the complexity of the larger kinase-based defense network and demonstrates how virulence- and avirulence-associated bacterial effectors alter sectors of the defense network.


Assuntos
Lycopersicon esculentum/imunologia , Proteínas Quinases/fisiologia , Fatores de Virulência/imunologia , Proteínas de Bactérias/metabolismo , Interações Hospedeiro-Patógeno , Lycopersicon esculentum/genética , Doenças das Plantas/microbiologia , Imunidade Vegetal/fisiologia , Proteínas de Plantas/metabolismo , Proteínas Quinases/imunologia , Pseudomonas syringae/patogenicidade , Transdução de Sinais , Virulência
16.
PLoS One ; 13(11): e0207438, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30440039

RESUMO

Cysteine-rich receptor-like kinases (CRKs) are transmembrane proteins that exhibit ectodomains containing the domain of unknown function 26 (DUF26). The CRKs form a large subfamily of receptor-like kinases in plants, and their possible functions remain to be elucidated. Several lines of evidence suggest that CRKs play important roles in plant defense responses to environmental stress, including plant immunity. We performed a genome-wide analysis of CRK encoding genes in soybean (Glycine max). We found 91 GmCRKs distributed in 16 chromosomes, and identified several tandem and segmental duplications, which influenced the expansion of this gene family. According to our phylogenetic analysis, GmCRKs are grouped in four clades. Furthermore, 12% of the members exhibited GmCRKs with a duplicated bi-modular organization of the ectodomains, containing four DUF26 domains. Expression analysis of GmCRKs was performed by exploring publicly available databases, and by RT-qPCR analysis of selected genes in soybean leaves responding to biotic stress signals. GmCRKs exhibited diverse expression patterns in leaves, stems, roots, and other tissues. Some of them were highly expressed in only one type of tissue, suggesting predominant roles in specific tissues. Furthermore, several GmCRKs were induced with PAMPs, DAMPs and the pathogens Phakopsora pachyrhizi and Phytophthora sojae. Expression profiles of several GmCRKs encoding highly similar proteins exhibited antagonist modes of regulation. The results suggest a fine-tuning control of GmCRKs transcriptional regulation in response to external stimuli, including PAMPs and DAMPs. This study offers a comprehensive view of the GmCRKs family in soybean, and provides a foundation for evolutionary and functional analysis of this family of plant proteins involved in the perception of pathogens and activation of plant immunity.


Assuntos
Filogenia , Imunidade Vegetal/genética , Proteínas Quinases/genética , Soja/genética , Arabidopsis/genética , Regulação da Expressão Gênica de Plantas/genética , Regulação da Expressão Gênica de Plantas/imunologia , Genoma de Planta/genética , Genoma de Planta/imunologia , Proteínas de Plantas/genética , Raízes de Plantas/genética , Raízes de Plantas/imunologia , Proteínas Quinases/imunologia , Soja/crescimento & desenvolvimento , Estresse Fisiológico/genética , Estresse Fisiológico/imunologia
17.
Cell Host Microbe ; 24(4): 461-463, 2018 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-30308148

RESUMO

Early detection of microbial patterns is a hallmark of innate immunity and essential for clearance of invading pathogens. A recent Nature publication by Zhou et al. (2018) has uncovered ALPK1 as a pattern recognition receptor for Gram-negative bacteria triggering NF-κB activation and identified the bacterial sugar ADP-Hep as its ligand.


Assuntos
Imunidade Inata/imunologia , Proteínas Quinases/imunologia , Receptores de Reconhecimento de Padrão/imunologia , Açúcares/imunologia , Animais , Proteínas de Transporte , Bactérias Gram-Negativas/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Inflamação , Camundongos , Camundongos Knockout , NF-kappa B/metabolismo , Proteínas Quinases/genética , Transdução de Sinais/fisiologia , Sistemas de Secreção Tipo III
18.
Front Immunol ; 9: 2047, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30319601

RESUMO

The role of autoimmunity in Parkinson's disease (PD), as one of the most popular research subjects, has been intensively investigated in recent years. Although the ultimate cause of PD is unknown, one major area of interest remains identifying new therapeutic targets and options for patients suffering from PD. Herein, we present a comprehensive review of the impacts of autoimmunity in neurodegenerative diseases, especially PD, and we have composed a logical argument to substantiate that autoimmunity is actively involved in the pathogenesis of PD through several proteins, including α-synuclein, DJ-1, PINK1, and Parkin, as well as immune cells, such as dendritic cells, microglia, T cells, and B cells. Furthermore, a detailed analysis of the relevance of autoimmunity to the clinical symptoms of PD provides strong evidence for the close correlation of autoimmunity with PD. In addition, the previously identified relationships between other autoimmune diseases and PD help us to better understand the disease pattern, laying the foundation for new therapeutic solutions to PD. In summary, this review aims to integrate and present currently available data to clarify the pathogenesis of PD and discuss some controversial but innovative research perspectives on the involvement of autoimmunity in PD, as well as possible novel diagnostic methods and treatments based on autoimmunity targets.


Assuntos
Autoantígenos/genética , Autoimunidade/genética , Encéfalo/imunologia , Doença de Parkinson/imunologia , Animais , Autoantígenos/imunologia , Linfócitos B/imunologia , Encéfalo/citologia , Células Dendríticas/imunologia , Modelos Animais de Doenças , Humanos , Microglia/imunologia , Mutação , Doença de Parkinson/diagnóstico , Doença de Parkinson/genética , Doença de Parkinson/terapia , Proteína Desglicase DJ-1/genética , Proteína Desglicase DJ-1/imunologia , Proteínas Quinases/genética , Proteínas Quinases/imunologia , Linfócitos T/imunologia , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/imunologia , alfa-Sinucleína/genética , alfa-Sinucleína/imunologia
19.
Proc Natl Acad Sci U S A ; 115(45): 11573-11578, 2018 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-30337484

RESUMO

Invasive microbes causing diseases such as sudden oak death negatively affect ecosystems and economies around the world. The deployment of resistant genotypes for combating introduced diseases typically relies on breeding programs that can take decades to complete. To demonstrate how this process can be accelerated, we employed a genome-wide association mapping of ca 1,000 resequenced Populus trichocarpa trees individually challenged with Sphaerulina musiva, an invasive fungal pathogen. Among significant associations, three loci associated with resistance were identified and predicted to encode one putative membrane-bound L-type receptor-like kinase and two receptor-like proteins. A susceptibility-associated locus was predicted to encode a putative G-type D-mannose-binding receptor-like kinase. Multiple lines of evidence, including allele analysis, transcriptomics, binding assays, and overexpression, support the hypothesized function of these candidate genes in the P. trichocarpa response to S. musiva.


Assuntos
Regulação da Expressão Gênica de Plantas , Interações Hospedeiro-Patógeno/genética , Doenças das Plantas/genética , Proteínas de Plantas/genética , Populus/genética , Saccharomycetales/patogenicidade , Transcriptoma , Alelos , Mapeamento Cromossômico , Cromossomos de Plantas/química , Resistência à Doença/genética , Perfilação da Expressão Gênica , Loci Gênicos , Interações Hospedeiro-Patógeno/imunologia , Lectina de Ligação a Manose/genética , Lectina de Ligação a Manose/imunologia , Doenças das Plantas/imunologia , Doenças das Plantas/microbiologia , Imunidade Vegetal/genética , Proteínas de Plantas/imunologia , Populus/imunologia , Populus/microbiologia , Proteínas Quinases/genética , Proteínas Quinases/imunologia , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/imunologia , Saccharomycetales/fisiologia
20.
Nat Commun ; 9(1): 3797, 2018 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-30228258

RESUMO

Inflammatory bowel disease (IBD) are heterogenous disorders of the gastrointestinal tract caused by a spectrum of genetic and environmental factors. In mice, overlapping regions of chromosome 3 have been associated with susceptibility to IBD-like pathology, including a locus called Hiccs. However, the specific gene that controls disease susceptibility remains unknown. Here we identify a Hiccs locus gene, Alpk1 (encoding alpha kinase 1), as a potent regulator of intestinal inflammation. In response to infection with the commensal pathobiont Helicobacter hepaticus (Hh), Alpk1-deficient mice display exacerbated interleukin (IL)-12/IL-23 dependent colitis characterized by an enhanced Th1/interferon(IFN)-γ response. Alpk1 controls intestinal immunity via the hematopoietic system and is highly expressed by mononuclear phagocytes. In response to Hh, Alpk1-/- macrophages produce abnormally high amounts of IL-12, but not IL-23. This study demonstrates that Alpk1 promotes intestinal homoeostasis by regulating the balance of type 1/type 17 immunity following microbial challenge.


Assuntos
Colite/imunologia , Infecções por Helicobacter/imunologia , Doenças Inflamatórias Intestinais/imunologia , Interleucina-12/imunologia , Proteínas Quinases/metabolismo , Células Th1/imunologia , Animais , Células da Medula Óssea , Transplante de Medula Óssea , Colite/microbiologia , Colite/patologia , Colo , Modelos Animais de Doenças , Feminino , Infecções por Helicobacter/microbiologia , Infecções por Helicobacter/patologia , Helicobacter hepaticus/imunologia , Humanos , Doenças Inflamatórias Intestinais/microbiologia , Doenças Inflamatórias Intestinais/patologia , Interleucina-12/metabolismo , Interleucina-23/imunologia , Interleucina-23/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Cultura Primária de Células , Proteínas Quinases/genética , Proteínas Quinases/imunologia , Quimera por Radiação , Células Th1/metabolismo
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