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1.
Signal Transduct Target Ther ; 5(1): 221, 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-33024073
2.
Nat Commun ; 11(1): 4382, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32873802

RESUMO

Fusarium graminearum is a causal agent of Fusarium head blight (FHB) and a deoxynivalenol (DON) producer. In this study, OSP24 is identified as an important virulence factor in systematic characterization of the 50 orphan secreted protein (OSP) genes of F. graminearum. Although dispensable for growth and initial penetration, OSP24 is important for infectious growth in wheat rachis tissues. OSP24 is specifically expressed during pathogenesis and its transient expression suppresses BAX- or INF1-induced cell death. Osp24 is translocated into plant cells and two of its 8 cysteine-residues are required for its function. Wheat SNF1-related kinase TaSnRK1α is identified as an Osp24-interacting protein and shows to be important for FHB resistance in TaSnRK1α-overexpressing or silencing transgenic plants. Osp24 accelerates the degradation of TaSnRK1α by facilitating its association with the ubiquitin-26S proteasome. Interestingly, TaSnRK1α also interacts with TaFROG, an orphan wheat protein induced by DON. TaFROG competes against Osp24 for binding with the same region of TaSnRKα and protects it from degradation. Overexpression of TaFROG stabilizes TaSnRK1α and increases FHB resistance. Taken together, Osp24 functions as a cytoplasmic effector by competing against TaFROG for binding with TaSnRK1α, demonstrating the counteracting roles of orphan proteins of both host and fungal pathogens during their interactions.


Assuntos
Proteínas Fúngicas/metabolismo , Fusarium/patogenicidade , Doenças das Plantas/imunologia , Proteínas de Plantas/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Triticum/microbiologia , Fatores de Virulência/metabolismo , Resistência à Doença , Fusarium/imunologia , Fusarium/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Doenças das Plantas/microbiologia , Proteínas de Plantas/genética , Proteínas de Plantas/imunologia , Plantas Geneticamente Modificadas , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/imunologia , Proteólise , Tricotecenos/metabolismo , Triticum/imunologia
3.
PLoS Pathog ; 16(5): e1008569, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32463840

RESUMO

Mycobacterial infection leads to activation of the RIG-I/MAVS/TBK1 RNA sensing pathway in macrophages but the consequences of this activation remains poorly defined. In this study, we determined that activation of this RNA sensing pathway stimulates ICAM-1 expression in M.avium-infected macrophage through the inhibition of the E3 ubiquitin ligase CRL4COP1/DET1. CRL4 when active targets the transcription factor ETV5 for degradation by the ubiquitin-proteasome system. In the absence of the ETV5 transcription factor, ICAM-1 expression is significantly decreased. The M.avium-induced ICAM-1 production is required for the formation of immune synapse between infected macrophages and antigen-specific CD4+ T lymphocytes, and is essential for CD4+ T lymphocyte-mediated mycobacterial killing in vitro and in mice. This study demonstrates a previously undefined mechanism by which a host cytosolic RNA sensing pathway contributes to the interplay between mycobacteria infected macrophages and antigen-specific T lymphocytes.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/imunologia , Linfócitos T CD4-Positivos/imunologia , Proteína DEAD-box 58/imunologia , Macrófagos , Mycobacterium avium/imunologia , Proteínas Serina-Treonina Quinases/imunologia , Tuberculose/imunologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Linfócitos T CD4-Positivos/microbiologia , Linfócitos T CD4-Positivos/patologia , Proteína DEAD-box 58/genética , Macrófagos/imunologia , Macrófagos/microbiologia , Macrófagos/patologia , Camundongos , Camundongos Knockout , Proteínas Serina-Treonina Quinases/genética , Tuberculose/genética , Tuberculose/patologia
4.
Mol Immunol ; 121: 195-203, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32298923

RESUMO

Cells recognize virus nucleic acid by pattern recognition receptors (PRRs), virus involve in the activation of signaling cascade of variable adaptor proteins, TANK-binding kinase1(TBK1)/ inhibitor of nuclear factor kappa-B kinase subunit epsilon(IKKi) complex, IκB kinase(IKKs) to trigger activation of transcription factor, interferon regulatory factor 3/7(IRF3/7), ultimately, leading to the production of type I interferon and exert anti-viral effects. In this study, E3 ubiquitin ligase ankyrin repeat and SOCS box-containing 8(ASB8) interacted with TBK1/IKKi and phosphorylation modification of ASB8 at site of Ser17 to further strengthen its ubiquitination activity were verified. Conversely, phosphorylated ASB8 accelerate K48-linked ubiquitination and degradation of TBK1/IKKi, which further reduces phosphorylation level of IRF3 and inhibits production of IFN-ß. At the same time, a new bridge molecule Leucine-rich repeat containing protein 10B(LRRC10B) upregulated after viral infection are involved in the formation and interaction with ASB8-TBK1/IKKi complex was reported. Our study reveals a new mechanism of ubiquitin ligase ASB8 modulating antiviral innate immunity by altering stability of TBK1/IKKi kinase complex.


Assuntos
Quinase I-kappa B/metabolismo , Interferon beta/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Células HEK293 , Células HeLa , Humanos , Quinase I-kappa B/imunologia , Imunidade Inata , Fator Regulador 3 de Interferon/metabolismo , Fator Regulador 7 de Interferon/metabolismo , Interferon beta/imunologia , Fosforilação/imunologia , Proteínas Serina-Treonina Quinases/imunologia , RNA Interferente Pequeno/metabolismo , Serina/metabolismo , Transdução de Sinais/imunologia , Proteínas Supressoras da Sinalização de Citocina/genética , Proteínas Supressoras da Sinalização de Citocina/imunologia , Ubiquitina-Proteína Ligases/imunologia , Ubiquitinação/imunologia
5.
Nat Commun ; 11(1): 1632, 2020 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-32242021

RESUMO

Co-stimulatory signals, cytokines and transcription factors regulate the balance between effector and memory cell differentiation during T cell activation. Here, we analyse the role of the TRAF2-/NCK-interacting kinase (TNIK), a signaling molecule downstream of the tumor necrosis factor superfamily receptors such as CD27, in the regulation of CD8+ T cell fate during acute infection with lymphocytic choriomeningitis virus. Priming of CD8+ T cells induces a TNIK-dependent nuclear translocation of ß-catenin with consecutive Wnt pathway activation. TNIK-deficiency during T cell activation results in enhanced differentiation towards effector cells, glycolysis and apoptosis. TNIK signaling enriches for memory precursors by favouring symmetric over asymmetric cell division. This enlarges the pool of memory CD8+ T cells and increases their capacity to expand after re-infection in serial re-transplantation experiments. These findings reveal that TNIK is an important regulator of effector and memory T cell differentiation and induces a population of stem cell-like memory T cells.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Coriomeningite Linfocítica/imunologia , Proteínas Serina-Treonina Quinases/imunologia , Animais , Apoptose , Linfócitos T CD8-Positivos/citologia , Diferenciação Celular , Humanos , Memória Imunológica , Ativação Linfocitária , Coriomeningite Linfocítica/genética , Coriomeningite Linfocítica/fisiopatologia , Coriomeningite Linfocítica/virologia , Vírus da Coriomeningite Linfocítica/fisiologia , Camundongos , Camundongos Knockout , Proteínas Serina-Treonina Quinases/genética , Transdução de Sinais , Via de Sinalização Wnt
6.
Neuron ; 106(5): 789-805.e5, 2020 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-32220666

RESUMO

DNA sequence variants in the TBK1 gene associate with or cause sporadic or familial amyotrophic lateral sclerosis (ALS). Here we show that mice bearing human ALS-associated TBK1 missense loss-of-function mutations, or mice in which the Tbk1 gene is selectively deleted in motor neurons, do not display a neurodegenerative disease phenotype. However, loss of TBK1 function in motor neurons of the SOD1G93A mouse model of ALS impairs autophagy, increases SOD1 aggregation, and accelerates early disease onset without affecting lifespan. By contrast, point mutations that decrease TBK1 kinase activity in all cells also accelerate disease onset but extend the lifespan of SOD1 mice. This difference correlates with the failure to activate high levels of expression of interferon-inducible genes in glia. We conclude that loss of TBK1 kinase activity impacts ALS disease progression through distinct pathways in different spinal cord cell types and further implicate the importance of glia in neurodegeneration.


Assuntos
Esclerose Amiotrófica Lateral/genética , Autofagia/genética , Microglia/imunologia , Neurônios Motores/metabolismo , Proteínas Serina-Treonina Quinases/genética , Superóxido Dismutase-1/genética , Idade de Início , Esclerose Amiotrófica Lateral/imunologia , Animais , Autofagia/imunologia , Modelos Animais de Doenças , Progressão da Doença , Técnicas de Introdução de Genes , Inflamação , Mutação com Perda de Função , Camundongos , Camundongos Knockout , Mutação de Sentido Incorreto , Junção Neuromuscular/genética , Proteínas Serina-Treonina Quinases/imunologia , Taxa de Sobrevida
7.
Microbiol Immunol ; 64(4): 270-279, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31909489

RESUMO

Anaplasma phagocytophilum, an obligate intracellular bacterium that propagates within host granulocytes, is considered to modify the host intracellular environment for pathogenesis. However, the mechanism(s) underlying such host modifications remain unclear. Here, we aimed to investigate the relation between A. phagocytophilum and endoplasmic reticulum (ER) stress in THP-1 cells. A. phagocytophilum activated the three ER stress sensors: inositol-requiring enzyme-1 (IRE1), protein kinase RNA-like endoplasmic reticulum kinase (PERK), and activating transcription factor-6 (ATF6). IRE1 activation occurred immediately after host cell invasion by A. phagocytophilum; however, the activated IRE1-induced splicing of X-box-binding protein 1 was not promoted during A. phagocytophilum infection. This suppression was sustained even after the doxycycline-mediated elimination of intracellular A. phagocytophilum. IRE1 knockdown accelerated A. phagocytophilum-induced apoptosis and decreased intracellular A. phagocytophilum. These data suggest that A. phagocytophilum utilizes IRE1 activation to promote its own intracellular proliferation. Moreover, PERK and ATF6 partially mediated A. phagocytophilum-induced apoptosis by promoting the expression of CCAAT/enhancer-binding protein homologous protein, which induces the transcription of several proapoptotic genes. Thus, A. phagocytophilum possibly manipulates the host ER stress signals to facilitate intracellular proliferation and infection of surrounding cells before/after host cell apoptosis.


Assuntos
Anaplasma phagocytophilum/patogenicidade , Apoptose/imunologia , Ehrlichiose/imunologia , Estresse do Retículo Endoplasmático/imunologia , Interações entre Hospedeiro e Microrganismos/imunologia , Fator 6 Ativador da Transcrição/imunologia , Linhagem Celular , Ehrlichiose/microbiologia , Endorribonucleases/imunologia , Humanos , Proteínas Serina-Treonina Quinases/imunologia , Proteína 1 de Ligação a X-Box/imunologia , eIF-2 Quinase/imunologia
8.
Rheumatology (Oxford) ; 59(6): 1416-1425, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31899518

RESUMO

OBJECTIVE: Clinical diagnosis of SLE is currently challenging due to its heterogeneity. Many autoantibodies are associated with SLE and are considered potential diagnostic markers, but systematic screening and validation of such autoantibodies is lacking. This study aimed to systematically discover new autoantibodies that may be good biomarkers for use in SLE diagnosis. METHODS: Sera from 15 SLE patients and 5 healthy volunteers were analysed using human proteome microarrays to identify candidate SLE-related autoantibodies. The results were validated by screening of sera from 107 SLE patients, 94 healthy volunteers and 60 disease controls using focussed arrays comprised of autoantigens corresponding to the identified candidate antibodies. Logistic regression was used to derive and validate autoantibody panels that can discriminate SLE disease. Extensive ELISA screening of sera from 294 SLE patients and 461 controls was performed to validate one of the newly discovered autoantibodies. RESULTS: A total of 31, 11 and 18 autoantibodies were identified to be expressed at significantly higher levels in the SLE group than in the healthy volunteers, disease controls and healthy volunteers plus disease control groups, respectively, with 25, 7 and 13 of these differentially expressed autoantibodies being previously unreported. Diagnostic panels comprising anti-RPLP2, anti-SNRPC and anti-PARP1, and anti-RPLP2, anti-PARP1, anti-MAK16 and anti- RPL7A were selected. Performance of the newly discovered anti-MAK16 autoantibody was confirmed by ELISA. Some associations were seen with clinical characteristics of SLE patients, such as disease activity with the level of anti-PARP1 and rash with the level of anti-RPLP2, anti-MAK16 and anti- RPL7A. CONCLUSION: The combined autoantibody panels identified here show promise for the diagnosis of SLE and for differential diagnosis of other major rheumatic immune diseases.


Assuntos
Autoanticorpos/sangue , Lúpus Eritematoso Sistêmico/diagnóstico , Análise Serial de Proteínas/métodos , Adulto , Autoanticorpos/imunologia , Biomarcadores/sangue , Estudos de Casos e Controles , Diagnóstico Diferencial , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Fosfoproteínas/imunologia , Poli(ADP-Ribose) Polimerase-1/imunologia , Proteínas Serina-Treonina Quinases/imunologia , Proteoma , Reprodutibilidade dos Testes , Ribonucleoproteínas Nucleares Pequenas/imunologia , Proteínas Ribossômicas/imunologia
9.
J Immunol ; 204(4): 832-843, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31915260

RESUMO

IL-1R-associated kinases (IRAK) are important regulators in the TLR/IL-1R pathways, but their function appears inconsistent between Drosophila, bony fishes, and vertebrates. This causes a difficulty to understand the IRAK functions. As a step to reveal the evolution of IRAKs, in this study, we performed comparative and functional analysis of IRAKs by exploiting the amphioxus, a pivotal taxon connecting invertebrates and vertebrates. Sequence and phylogenetic analysis indicated three major IRAK lineages: IRAK1/2/3 is a vertebrate-specific lineage, IRAK4 is an ancient lineage conserved between invertebrate and vertebrates, and Pelle is another ancient lineage that is preserved in protostomes and invertebrate deuterostomes but lost in vertebrate deuterostomes. Pelle is closer neither to IRAK4 nor to IRAK1/2/3, hence suggesting no clear functional analogs to IRAK1/2/3 in nonvertebrates. Functional analysis showed that both amphioxus IRAK4 and Pelle could suppress NF-κB activation induced by MyD88 and TRAF6, which are unlike mammalian and Drosophila IRAKs, but, surprisingly, similar to bony fish IRAK4. Also unlike Drosophila IRAKs, no interaction was detected between amphioxus IRAK4 and Pelle, although both of them were shown capable of binding MyD88. These findings, together with previous reports, show that unlike other signal transducers in the TLR/IL-1R pathways, such as MyD88 and TRAF6, the functions of IRAKs are highly variable during evolution and very specialized in different major animal taxa. Indeed, we suggest that the functional variability of IRAKs might confer plasticity to the signal transduction of the TLR/IL-1R pathways, which in return helps the species to evolve against the pathogens.


Assuntos
Evolução Biológica , Fator 88 de Diferenciação Mieloide/imunologia , Proteínas Serina-Treonina Quinases/imunologia , Transdução de Sinais/imunologia , Fator 6 Associado a Receptor de TNF/imunologia , Animais , Anfioxos , Filogenia
10.
Cancer Immunol Immunother ; 69(1): 81-94, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31844909

RESUMO

Amino acid deprivation is a strategy that malignancies utilize to blunt anti-tumor T-cell immune responses. It has been proposed that amino acid insufficiency in T-cells is detected by GCN2 kinase, which through phosphorylation of EIF2α, shuts down global protein synthesis leading to T-cell arrest. The role of this amino acid stress sensor in the context of malignant brain tumors has not yet been studied, and may elucidate important insights into the mechanisms of T-cell survival in this harsh environment. Using animal models of glioblastoma and animals with deficiency in GCN2, we explored the importance of this pathway in T-cell function within brain tumors. Our results show that GCN2 deficiency limited CD8+ T-cell activation and expression of cytotoxic markers in two separate murine models of glioblastoma in vivo. Importantly, adoptive transfer of antigen-specific T-cells from GCN2 KO mice did not control tumor burden as well as wild-type CD8+ T-cells. Our in vitro and in vivo data demonstrated that reduction in amino acid availability caused GCN2 deficient CD8+ T-cells to become rapidly necrotic. Mechanistically, reduced CD8+ T-cell activation and necrosis was due to a disruption in TCR signaling, as we observed reductions in PKCθ and phoshpo-PKCθ on CD8+ T-cells from GCN2 KO mice in the absence of tryptophan. Validating these observations, treatment of wild-type CD8+ T-cells with a downstream inhibitor of GCN2 activation also triggered necrosis of CD8+ T-cells in the absence of tryptophan. In conclusion, our data demonstrate the vital importance of intact GCN2 signaling on CD8+ T-cell function and survival in glioblastoma.


Assuntos
Neoplasias Encefálicas/imunologia , Linfócitos T CD8-Positivos/imunologia , Glioblastoma/imunologia , Proteínas Serina-Treonina Quinases/metabolismo , Evasão Tumoral/imunologia , Transferência Adotiva , Animais , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Linfócitos T CD8-Positivos/patologia , Linfócitos T CD8-Positivos/transplante , Linhagem Celular Tumoral/transplante , Sobrevivência Celular/imunologia , Modelos Animais de Doenças , Glioblastoma/patologia , Glioblastoma/terapia , Humanos , Ativação Linfocitária , Camundongos , Camundongos Knockout , Necrose/genética , Necrose/imunologia , Fosforilação/imunologia , Biossíntese de Proteínas/imunologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/imunologia
11.
Eur J Histochem ; 63(4)2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31833327

RESUMO

Serine-arginine protein kinase (SRPK) belongs to a class of cell cycle regulating kinases that can phosphorylate proteins containing serine/arginine-Rich (SR) regions. SR proteins are a family of RNA binding phosphoproteins that control both constitutive and alternative pre-mRNA splicing events. However, little is known about their role in non-small cell lung cancer (NSCLC). In the present study, we found that serine-arginine protein kinase 2 (SRPK2) expression was upregulated in NSCLC tissues compared with adjacent normal tissues. Kaplan-Meier curve analyses showed that the overall survival time of NSCLC patients with high SRPK2 expression was shorter than those with low SRPK2 expression. Overexpression of SRPK2 promoted NSCLC cell proliferation and cell cycle arrest, while knockdown of SRPK2 inhibited proliferation and promoted cell cycle arrest in NSCLC cell lines. SRPK2 promoted the transcriptional regulation of E2F1 on downstream cell cycle related genes through phosphorylation of SC35. Xenograft model showed that SRPK2 promoted tumor growth in vivo. SRPK2 phosphorylated SC35 and phosphorylated SC35 activated E2F1 transcription of cyclin-related proteins, thereby promoting the cycle progression of NSCLC. Our findings demonstrated that SRPK2 may be a potential therapeutic target for NSCLC clinical therapy, which plays an important role in the progression of NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Pontos de Checagem do Ciclo Celular/fisiologia , Regulação para Baixo/fisiologia , Fator de Transcrição E2F1/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Anticorpos/imunologia , Carcinoma Pulmonar de Células não Pequenas/genética , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/genética , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/imunologia
12.
Cell Rep ; 29(13): 4509-4524.e5, 2019 12 24.
Artigo em Inglês | MEDLINE | ID: mdl-31875557

RESUMO

Group 2 innate lymphoid cells (ILC2s) can initiate pathologic inflammation in allergic asthma by secreting copious amounts of type 2 cytokines, promoting lung eosinophilia and airway hyperreactivity (AHR), a cardinal feature of asthma. We discovered that the TNF/TNFR2 axis is a central immune checkpoint in murine and human ILC2s. ILC2s selectively express TNFR2, and blocking the TNF/TNFR2 axis inhibits survival and cytokine production and reduces ILC2-dependent AHR. The mechanism of action of TNFR2 in ILC2s is through the non-canonical NF-κB pathway as an NF-κB-inducing kinase (NIK) inhibitor blocks the costimulatory effect of TNF-α. Similarly, human ILC2s selectively express TNFR2, and using hILC2s, we show that TNFR2 engagement promotes AHR through a NIK-dependent pathway in alymphoid murine recipients. These findings highlight the role of the TNF/TNFR2 axis in pulmonary ILC2s, suggesting that targeting TNFR2 or relevant signaling is a different strategy for treating patients with ILC2-dependent asthma.


Assuntos
Linfócitos/imunologia , Proteínas Serina-Treonina Quinases/genética , Receptores Tipo II do Fator de Necrose Tumoral/genética , Hipersensibilidade Respiratória/imunologia , Transdução de Sinais/imunologia , Transferência Adotiva , Animais , Sobrevivência Celular , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Humanos , Pulmão/imunologia , Pulmão/patologia , Transfusão de Linfócitos , Linfócitos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , NF-kappa B/genética , NF-kappa B/imunologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/imunologia , Proteínas Serina-Treonina Quinases/imunologia , Receptores Tipo II do Fator de Necrose Tumoral/imunologia , Hipersensibilidade Respiratória/genética , Hipersensibilidade Respiratória/patologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
13.
Cell Rep ; 29(13): 4525-4539.e4, 2019 12 24.
Artigo em Inglês | MEDLINE | ID: mdl-31875558

RESUMO

LACC1 genetic variants are associated with multiple immune-mediated diseases. However, laccase domain containing-1 (LACC1) functions are incompletely defined. We find that upon stimulation of the pattern-recognition receptor (PRR) NOD2, LACC1 localizes to the endoplasmic reticulum (ER) and forms a complex with ER-stress sensors. All three ER-stress branches, PERK, IRE1α, and ATF6, are required for NOD2-induced signaling, cytokines, and antimicrobial pathways in human macrophages. LACC1, and its localization to the ER, is required for these outcomes. Relative to wild-type (WT) LACC1, transfection of the common Val254 and rare Arg284 immune-mediated disease-risk LACC1 variants into HeLa cells and macrophages, as well as macrophages from LACC1 Val254 carriers, shows reduced NOD2-induced ER stress-associated outcomes; these downstream outcomes are restored by rescuing ER stress. Therefore, we identify ER stress to be essential in PRR-induced outcomes in macrophages, define a critical role for LACC1 in these ER stress-dependent events, and elucidate how LACC1 disease-risk variants mediate these outcomes.


Assuntos
Estresse do Retículo Endoplasmático/imunologia , Interações Hospedeiro-Patógeno/imunologia , Imunidade Inata , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Macrófagos/imunologia , Proteína Adaptadora de Sinalização NOD2/imunologia , Fator 6 Ativador da Transcrição/genética , Fator 6 Ativador da Transcrição/imunologia , Retículo Endoplasmático/imunologia , Retículo Endoplasmático/microbiologia , Estresse do Retículo Endoplasmático/genética , Endorribonucleases/genética , Endorribonucleases/imunologia , Enterococcus faecalis/crescimento & desenvolvimento , Enterococcus faecalis/imunologia , Escherichia coli/crescimento & desenvolvimento , Escherichia coli/imunologia , Regulação da Expressão Gênica , Células HeLa , Interações Hospedeiro-Patógeno/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Macrófagos/microbiologia , Proteína Adaptadora de Sinalização NOD2/genética , Fagocitose , Cultura Primária de Células , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/imunologia , Risco , Transdução de Sinais , eIF-2 Quinase/genética , eIF-2 Quinase/imunologia
14.
Artigo em Inglês | MEDLINE | ID: mdl-31867288

RESUMO

Toxoplasma gondii ROP16 and ROP18 proteins have been identified as important virulence factors for this parasite. Here, we describe the effect of ROP16 and ROP18 proteins on peripheral blood mononuclear cells (PBMCs) from individuals with different clinical status of infection. We evaluated IFN-γ, IL-10, and IL-1ß levels in supernatants from PBMCs cultures infected with tachyzoites of the T. gondii wild-type RH strain or with knock-out mutants of the rop16 and rop18 encoding genes (RHΔrop16 and RHΔrop18). Cytokine secretion was compared between PBMCs obtained from seronegative individuals (n = 10), with those with chronic asymptomatic (n = 8), or ocular infection (n = 12). We also evaluated if polymorphisms in the genes encoding for IFN-γ, IL-10, IL-1ß, Toll-like receptor 9 (TLR9), and purinoreceptor P2RX7 influenced the production of the encoded proteins after ex vivo stimulation. In individuals with chronic asymptomatic infection, only a moderate effect on IL-10 levels was observed when PBMCs were infected with RHΔrop16, whereas a significant difference in the levels of inflammatory cytokines IFN-γ and IL-1ß was observed in seronegative individuals, but this was also dependent on the host's cytokine gene polymorphisms. Infection with ROP16-deficient parasites had a significant effect on IFN-γ production in previously non-infected individuals, suggesting that ROP16 which is considered as a virulence factor plays a role during the primary infection in humans, but not in the secondary immune response.


Assuntos
Leucócitos Mononucleares/imunologia , Proteínas Serina-Treonina Quinases/imunologia , Proteínas Tirosina Quinases/imunologia , Proteínas de Protozoários/imunologia , Toxoplasma/imunologia , Toxoplasmose/imunologia , Toxoplasmose/parasitologia , Citocinas/metabolismo , Fibroblastos , Interações Hospedeiro-Parasita/genética , Interações Hospedeiro-Parasita/imunologia , Humanos , Leucócitos Mononucleares/metabolismo , Polimorfismo Genético , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT6/metabolismo , Toxoplasma/patogenicidade , Toxoplasmose/genética , Virulência , Fatores de Virulência/imunologia
15.
Nat Commun ; 10(1): 5755, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31848340

RESUMO

Autophagy perturbation represents an emerging therapeutic strategy in cancer. Although LATS1 and LATS2 kinases, core components of the mammalian Hippo pathway, have been shown to exert tumor suppressive activities, here we report a pro-survival role of LATS1 but not LATS2 in hepatocellular carcinoma (HCC) cells. Specifically, LATS1 restricts lethal autophagy in HCC cells induced by sorafenib, the standard of care for advanced HCC patients. Notably, autophagy regulation by LATS1 is independent of its kinase activity. Instead, LATS1 stabilizes the autophagy core-machinery component Beclin-1 by promoting K27-linked ubiquitination at lysine residues K32 and K263 on Beclin-1. Consequently, ubiquitination of Beclin-1 negatively regulates autophagy by promoting inactive dimer formation of Beclin-1. Our study highlights a functional diversity between LATS1 and LATS2, and uncovers a scaffolding role of LATS1 in mediating a cross-talk between the Hippo signaling pathway and autophagy.


Assuntos
Autofagia/imunologia , Carcinoma Hepatocelular/patologia , Sobrevivência Celular/imunologia , Neoplasias Hepáticas/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Autofagia/efeitos dos fármacos , Proteína Beclina-1/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/mortalidade , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular/efeitos dos fármacos , Conjuntos de Dados como Assunto , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos/imunologia , Humanos , Estimativa de Kaplan-Meier , Fígado/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/mortalidade , Lisina/metabolismo , Camundongos , Camundongos Knockout , Organoides , Estabilidade Proteica , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/imunologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Proteínas Supressoras de Tumor/imunologia , Ubiquitinação , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Nat Commun ; 10(1): 4996, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31676803

RESUMO

Plants deploy various immune receptors to recognize pathogens and defend themselves. Crosstalk may happen among receptor-mediated signal transduction pathways in the same host during simultaneous infection of different pathogens. However, the related function of the receptor-like kinases (RLKs) in thwarting different pathogens remains elusive. Here, we report that NIK1, which positively regulates plant antiviral immunity, acts as an important negative regulator of antibacterial immunity. nik1 plants exhibit dwarfed morphology, enhanced disease resistance to bacteria and increased PAMP-triggered immunity (PTI) responses, which are restored by NIK1 reintroduction. Additionally, NIK1 negatively regulates the formation of the FLS2/BAK1 complex. The interaction between NIK1 and FLS2/BAK1 is enhanced upon flg22 perception, revealing a novel PTI regulatory mechanism by an RLK. Furthermore, flg22 perception induces NIK1 and RPL10A phosphorylation in vivo, activating antiviral signalling. The NIK1-mediated inverse modulation of antiviral and antibacterial immunity may allow bacteria and viruses to activate host immune responses against each other.


Assuntos
Proteínas de Arabidopsis/genética , Arabidopsis/genética , Imunidade Vegetal/genética , Proteínas Quinases/genética , Proteínas Serina-Treonina Quinases/genética , Arabidopsis/microbiologia , Arabidopsis/virologia , Proteínas de Arabidopsis/imunologia , Proteínas de Arabidopsis/metabolismo , Regulação da Expressão Gênica de Plantas/imunologia , Interações Hospedeiro-Patógeno/imunologia , Complexos Multiproteicos/imunologia , Complexos Multiproteicos/metabolismo , Doenças das Plantas/imunologia , Doenças das Plantas/microbiologia , Doenças das Plantas/virologia , Imunidade Vegetal/imunologia , Vírus de Plantas/imunologia , Vírus de Plantas/fisiologia , Plantas Geneticamente Modificadas , Ligação Proteica , Proteínas Quinases/imunologia , Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/imunologia , Proteínas Serina-Treonina Quinases/metabolismo , Pseudomonas syringae/imunologia , Pseudomonas syringae/fisiologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia
17.
Int Immunopharmacol ; 77: 105900, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31644963

RESUMO

Via promoting synovitis, pannus growth and cartilage/bone destruction, fibroblast-like synovial cells (FLSs) play a significant role in the pathogenesis of rheumatoid arthritis (RA). In our study, rats were induced with complete freund's adjuvant (CFA) to be animal models for studying the RA pathogenesis. Microtubule-associated Serine/Threonine-protein kinase 3 (MAST3) has been documented to play a critical role in regulating the immune response of IBD (Inflammatory bowel disease) and involved in the process of cytoskeleton organization, intracellular signal transduction and peptidyl-serine phosphorylation, but its role in the progression of RA remains unknown and is warranted for investigation. So, we tried our best to investigate the mechanism and signaling pathway of MAST3 in RA progression. In the synovial tissue and FLSs of AA rats, we have found that MAST3 was significantly up-regulated than normal. Furthermore, MAST3 overexpression could promote proliferation and inflammatory response of FLSs. In the aspect of mechanism, we discovered that the expression of MAST3 might involve in NF-κB signaling pathway in RA. On the whole, our results suggested that MAST3 might promote the proliferation and inflammation of FLSs by regulating NF-κB signaling pathway.


Assuntos
Artrite Experimental/imunologia , Artrite Reumatoide/imunologia , Proteínas Associadas aos Microtúbulos/imunologia , Proteínas Serina-Treonina Quinases/imunologia , Sinoviócitos/imunologia , Animais , Artrite Experimental/genética , Artrite Experimental/patologia , Artrite Reumatoide/genética , Artrite Reumatoide/patologia , Proliferação de Células , Células Cultivadas , Feminino , Inflamação/genética , Inflamação/imunologia , Articulação do Joelho/imunologia , Articulação do Joelho/patologia , Proteínas Associadas aos Microtúbulos/genética , NF-kappa B/imunologia , Proteínas Serina-Treonina Quinases/genética , Ratos Sprague-Dawley
18.
Nat Commun ; 10(1): 4810, 2019 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-31641112

RESUMO

Systemic acquired resistance (SAR) is a long-lasting broad-spectrum plant immunity induced by mobile signals produced in the local leaves where the initial infection occurs. Although multiple structurally unrelated signals have been proposed, the mechanisms responsible for perception of these signals in the systemic leaves are unknown. Here, we show that exogenously applied nicotinamide adenine dinucleotide (NAD+) moves systemically and induces systemic immunity. We demonstrate that the lectin receptor kinase (LecRK), LecRK-VI.2, is a potential receptor for extracellular NAD+ (eNAD+) and NAD+ phosphate (eNADP+) and plays a central role in biological induction of SAR. LecRK-VI.2 constitutively associates with BRASSINOSTEROID INSENSITIVE1-ASSOCIATED KINASE1 (BAK1) in vivo. Furthermore, BAK1 and its homolog BAK1-LIKE1 are required for eNAD(P)+ signaling and SAR, and the kinase activities of LecR-VI.2 and BAK1 are indispensable to their function in SAR. Our results indicate that eNAD+ is a putative mobile signal, which triggers SAR through its receptor complex LecRK-VI.2/BAK1 in Arabidopsis thaliana.


Assuntos
Proteínas de Arabidopsis/imunologia , Arabidopsis/imunologia , NAD/imunologia , Doenças das Plantas/imunologia , Proteínas Serina-Treonina Quinases/imunologia , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Resistência à Doença , Regulação da Expressão Gênica de Plantas , Doenças das Plantas/microbiologia , Imunidade Vegetal , Ligação Proteica , Proteínas Serina-Treonina Quinases/genética , Pseudomonas syringae/fisiologia
19.
Blood ; 134(20): 1730-1744, 2019 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-31434702

RESUMO

Heterozygous deletions within chromosome 20q, or del(20q), are frequent cytogenetic abnormalities detected in hematologic malignancies. To date, identification of genes in the del(20q) common deleted region that contribute to disease development have remained elusive. Through assessment of patient gene expression, we have identified STK4 (encoding Hippo kinase MST1) as a 20q gene that is downregulated below haploinsufficient amounts in myelodysplastic syndrome (MDS) and myeloproliferative neoplasm (MPN). Hematopoietic-specific gene inactivation in mice revealed Hippo kinase loss to induce splenomegaly, thrombocytopenia, megakaryocytic dysplasia, and a propensity for chronic granulocytosis; phenotypes that closely resemble those observed in patients harboring del(20q). In a JAK2-V617F model, heterozygous Hippo kinase inactivation led to accelerated development of lethal myelofibrosis, recapitulating adverse MPN disease progression and revealing a novel genetic interaction between these 2 molecular events. Quantitative serum protein profiling showed that myelofibrotic transformation in mice was associated with cooperative effects of JAK2-V617F and Hippo kinase inactivation on innate immune-associated proinflammatory cytokine production, including IL-1ß and IL-6. Mechanistically, MST1 interacted with IRAK1, and shRNA-mediated knockdown was sufficient to increase IRAK1-dependent innate immune activation of NF-κB in human myeloid cells. Consistent with this, treatment with a small molecule IRAK1/4 inhibitor rescued the aberrantly elevated IL-1ß production in the JAK2-V617F MPN model. This study identified Hippo kinase MST1 (STK4) as having a central role in the biology of del(20q)-associated hematologic malignancies and revealed a novel molecular basis of adverse MPN progression that may be therapeutically exploitable via IRAK1 inhibition.


Assuntos
Neoplasias Hematológicas/genética , Síndromes Mielodisplásicas/genética , Transtornos Mieloproliferativos/genética , Proteínas Serina-Treonina Quinases/genética , Animais , Deleção Cromossômica , Cromossomos Humanos Par 20/genética , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Neoplasias Hematológicas/imunologia , Humanos , Imunidade Inata , Camundongos , Síndromes Mielodisplásicas/imunologia , Transtornos Mieloproliferativos/imunologia , Proteínas Serina-Treonina Quinases/imunologia
20.
Proc Natl Acad Sci U S A ; 116(37): 18544-18549, 2019 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-31451663

RESUMO

The detection of microbes and damaged host cells by the innate immune system is essential for host defense against infection and tissue homeostasis. However, how distinct positive and negative regulatory signals from immune receptors are integrated to tailor specific responses in complex scenarios remains largely undefined. Clec12A is a myeloid cell-expressed inhibitory C-type lectin receptor that can sense cell death under sterile conditions. Clec12A detects uric acid crystals and limits proinflammatory pathways by counteracting the cell-activating spleen tyrosine kinase (Syk). Here, we surprisingly find that Clec12A additionally amplifies type I IFN (IFN-I) responses in vivo and in vitro. Using retinoic acid-inducible gene I (RIG-I) signaling as a model, we demonstrate that monosodium urate (MSU) crystal sensing by Clec12A enhances cytosolic RNA-induced IFN-I production and the subsequent induction of IFN-I-stimulated genes. Mechanistically, Clec12A engages Src kinase to positively regulate the TBK1-IRF3 signaling module. Consistently, Clec12A-deficient mice exhibit reduced IFN-I responses upon lymphocytic choriomeningitis virus (LCMV) infection, which affects the outcomes of these animals in acute and chronic virus infection models. Thus, our results uncover a previously unrecognized connection between an MSU crystal-sensing receptor and the IFN-I response, and they illustrate how the sensing of extracellular damage-associated molecular patterns (DAMPs) can shape the immune response.


Assuntos
Alarminas/imunologia , Interferon Tipo I/imunologia , Lectinas Tipo C/metabolismo , Coriomeningite Linfocítica/imunologia , Receptores Mitogênicos/metabolismo , Ácido Úrico/imunologia , Animais , Citosol/imunologia , Citosol/metabolismo , Proteína DEAD-box 58/imunologia , Proteína DEAD-box 58/metabolismo , Modelos Animais de Doenças , Humanos , Imunidade Inata , Fator Regulador 3 de Interferon/imunologia , Fator Regulador 3 de Interferon/metabolismo , Interferon Tipo I/metabolismo , Lectinas Tipo C/genética , Lectinas Tipo C/imunologia , Coriomeningite Linfocítica/virologia , Vírus da Coriomeningite Linfocítica/imunologia , Camundongos , Camundongos Knockout , Padrões Moleculares Associados a Patógenos/imunologia , Proteínas Serina-Treonina Quinases/imunologia , Proteínas Serina-Treonina Quinases/metabolismo , RNA/imunologia , RNA/metabolismo , Receptores Mitogênicos/genética , Receptores Mitogênicos/imunologia , Transdução de Sinais/imunologia
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