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1.
Fish Shellfish Immunol ; 99: 442-451, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32084540

RESUMEN

The homeostasis of immune cells during immune response is vital for hosts to defend against invaders. Activating transcription factor 6 (ATF6) is an important transcription factor in the unfolded protein response (UPR) to maintaining cellular homeostasis. In the present study, one ATF6 homologue was identified from Pacific oyster Crassostrea gigas (designated as CgATF6ß). The full length cDNA of CgATF6ß was of 2645 bp with a 1596 bp open reading frame (ORF) encoding a polypeptide of 531 amino acids. The deduced amino acid sequence of CgATF6ß was predicted to contain a transmembrane region, a conserved basic leucine zipper (bZIP) domain, a site 1 protease cleavage site, a site 2 protease cleavage site, and a Golgi localization signal. CgATF6ß mRNA was constitutively expressed in hemocytes, gill, mantle, gonad, hepatopancreas and labial palp, with a slightly higher expression level in muscle (2.45-fold of that in gill, p < 0.05). After oysters were challenged with Vibrio splendidus, the mRNA expression levels of CgATF6ß in hemocytes were significantly up-regulated at 3 h (2.68-fold of that in seawater group, p < 0.01) and peaked at 12 h (3.14-fold of that in seawater group, p < 0.01). The endogenic CgATF6ß protein was mainly located in the cytoplasm of oyster hemocytes, and it was significantly transported into the nuclei of hemocytes at 1.5 h after the challenge with V. splendidus. After an injection with CgATF6ß dsRNA, the mRNA expression of CgATF6ß was knocked down to 0.26-fold of that in dsGFP group (p < 0.01). In CgATF6ß dsRNA-injected oysters, the mRNA expressions of glucose-regulated protein 78 (GRP78), calnexin (CNX) and anti-apoptotic B-cell lymphoma-2 (Bcl-2) in hemocytes were significantly decreased at 12 h after V. splendidus challenge, which were 0.65-fold (p < 0.01), 0.54-fold (p < 0.01) and 0.17-fold (p < 0.01) of that in dsGFP-injected oysters, while the apoptotic rate of hemocytes was significantly up-regulated (1.97-fold of that in dsGFP group, p < 0.05). Collectively, these results suggested that CgATF6ß was involved in apoptosis inhibition of oyster hemocytes upon V. splendidus challenge by regulating the expression of CgGRP78, CgCNX and CgBcl-2.


Asunto(s)
Factor de Transcripción Activador 6/inmunología , Apoptosis , Crassostrea/inmunología , Hemocitos/inmunología , Vibriosis/veterinaria , Factor de Transcripción Activador 6/genética , Animales , Clonación Molecular , Crassostrea/genética , ADN Complementario/genética , Regulación de la Expresión Génica , Hemocitos/citología , Homeostasis , Inmunidad Innata , Sistemas de Lectura Abierta , ARN Mensajero/genética , Respuesta de Proteína Desplegada , Vibrio , Vibriosis/inmunología
2.
Microbiol Immunol ; 64(4): 270-279, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-31909489

RESUMEN

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.


Asunto(s)
Anaplasma phagocytophilum/patogenicidad , Apoptosis/inmunología , Ehrlichiosis/inmunología , Estrés del Retículo Endoplásmico/inmunología , Interacciones Microbiota-Huesped/inmunología , Factor de Transcripción Activador 6/inmunología , Línea Celular , Ehrlichiosis/microbiología , Endorribonucleasas/inmunología , Humanos , Proteínas Serina-Treonina Quinasas/inmunología , Proteína 1 de Unión a la X-Box/inmunología , eIF-2 Quinasa/inmunología
3.
Cell Rep ; 29(13): 4525-4539.e4, 2019 12 24.
Artículo en Inglés | MEDLINE | ID: mdl-31875558

RESUMEN

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.


Asunto(s)
Estrés del Retículo Endoplásmico/inmunología , Interacciones Huésped-Patógeno/inmunología , Inmunidad Innata , Péptidos y Proteínas de Señalización Intracelular/inmunología , Macrófagos/inmunología , Proteína Adaptadora de Señalización NOD2/inmunología , Factor de Transcripción Activador 6/genética , Factor de Transcripción Activador 6/inmunología , Retículo Endoplásmico/inmunología , Retículo Endoplásmico/microbiología , Estrés del Retículo Endoplásmico/genética , Endorribonucleasas/genética , Endorribonucleasas/inmunología , Enterococcus faecalis/crecimiento & desarrollo , Enterococcus faecalis/inmunología , Escherichia coli/crecimiento & desarrollo , Escherichia coli/inmunología , Regulación de la Expresión Génica , Células HeLa , Interacciones Huésped-Patógeno/genética , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Macrófagos/microbiología , Proteína Adaptadora de Señalización NOD2/genética , Fagocitosis , Cultivo Primario de Células , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/inmunología , Riesgo , Transducción de Señal , eIF-2 Quinasa/genética , eIF-2 Quinasa/inmunología
4.
Cell Chem Biol ; 26(7): 913-925.e4, 2019 07 18.
Artículo en Inglés | MEDLINE | ID: mdl-31105062

RESUMEN

Activation of the unfolded protein response (UPR)-associated transcription factor ATF6 has emerged as a promising strategy to reduce the secretion and subsequent toxic aggregation of destabilized, amyloidogenic proteins implicated in systemic amyloid diseases. However, the molecular mechanism by which ATF6 activation reduces the secretion of amyloidogenic proteins remains poorly defined. We employ a quantitative interactomics platform to define how ATF6 activation reduces secretion of a destabilized, amyloidogenic immunoglobulin light chain (LC) associated with light-chain amyloidosis (AL). Using this platform, we show that ATF6 activation increases the targeting of this destabilized LC to a subset of pro-folding ER proteostasis factors that retains the amyloidogenic LC within the ER, preventing its secretion. Our results define a molecular basis for the ATF6-dependent reduction in destabilized LC secretion and highlight the advantage for targeting this UPR-associated transcription factor to reduce secretion of destabilized, amyloidogenic proteins implicated in AL and related systemic amyloid diseases.


Asunto(s)
Factor de Transcripción Activador 6/metabolismo , Proteínas Amiloidogénicas/metabolismo , Respuesta de Proteína Desplegada/fisiología , Factor de Transcripción Activador 6/inmunología , Proteínas Amiloidogénicas/fisiología , Amiloidosis/inmunología , Amiloidosis/metabolismo , Retículo Endoplásmico/metabolismo , Estrés del Retículo Endoplásmico , Células HEK293 , Humanos , Chaperonas Moleculares , Proteómica/métodos , Factores de Transcripción/metabolismo
5.
Fish Shellfish Immunol ; 75: 223-230, 2018 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-29427718

RESUMEN

Activating transcription factor 6 (ATF6) pathway is the key branch of unfolded protein response (UPR). In this study, a homolog of ATFα from Marsupenaeus japonicus (MjATF6) was identified using genome sequencing and characterized, so as to investigate the role of ATF6 pathway in anti-viral immunity of M. japonicus. The cDNA of MjATF6 obtained was 1008 bp in length, with an open reading frame (ORF) of 849bp, which had encoded a putative of 283 amino acid proteins. Results of qRT-PCR showed that MjATF6 was distributed in all the six tested tissues, with the higher expression level being seen in hemocytes and hepatopancreas. Furthermore, MjATF6 expression would be up-regulated from 1 day to 7 day under white spot syndrome virus (WSSV) challenge. In comparison, RNA interference-induced MjATF6 knockdown had resulted in a lower 7-day cumulative mortality of M. japonicus in the presence of WSSV infection. Additionally, our results also revealed that less VP28 mRNA was extracted from hemocytes or hepatopancreas of MjATF6 knockdown shrimp than that from the control. Taken together, these results have confirmed that ATF6 pathway is vital for WSSV replication, and that UPR in M. japonicus may facilitate WSSV infection.


Asunto(s)
Factor de Transcripción Activador 6/genética , Factor de Transcripción Activador 6/inmunología , Regulación de la Expresión Génica/inmunología , Inmunidad Innata/genética , Penaeidae/genética , Penaeidae/inmunología , Factor de Transcripción Activador 6/química , Secuencia de Aminoácidos , Animales , Proteínas de Artrópodos/química , Proteínas de Artrópodos/genética , Proteínas de Artrópodos/inmunología , Secuencia de Bases , Perfilación de la Expresión Génica , Filogenia , Alineación de Secuencia , Virus del Síndrome de la Mancha Blanca 1/fisiología
6.
J Immunother Cancer ; 5: 5, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28105371

RESUMEN

Established tumors build a stressful and hostile microenvironment that blocks the development of protective innate and adaptive immune responses. Different subsets of immunoregulatory myeloid populations, including dendritic cells, myeloid-derived suppressor cells (MDSCs) and macrophages, accumulate in the stressed tumor milieu and represent a major impediment to the success of various forms of cancer immunotherapy. Specific conditions and factors within tumor masses, including hypoxia, nutrient starvation, low pH, and increased levels of free radicals, provoke a state of "endoplasmic reticulum (ER) stress" in both malignant cells and infiltrating myeloid cells. In order to cope with ER stress, cancer cells and tumor-associated myeloid cells activate an integrated signaling pathway known as the Unfolded Protein Response (UPR), which promotes cell survival and adaptation under adverse environmental conditions. However, the UPR can also induce cell death under unresolved levels of ER stress. Three branches of the UPR have been described, including the activation of the inositol-requiring enzyme 1 (IRE1), the pancreatic ER kinase (PKR)-like ER kinase (PERK), and the activating transcription factor 6 (ATF6). In this minireview, we briefly discuss the role of ER stress and specific UPR mediators in tumor development, growth and metastasis. In addition, we describe how sustained ER stress responses operate as key mediators of chronic inflammation and immune suppression within tumors. Finally, we discuss multiple pharmacological approaches that overcome the immunosuppressive effect of the UPR in tumors, and that could potentially enhance the efficacy of cancer immunotherapies by reprogramming the function of tumor-infiltrating myeloid cells.


Asunto(s)
Factor de Transcripción Activador 6/genética , Endorribonucleasas/genética , Neoplasias/inmunología , Proteínas Serina-Treonina Quinasas/genética , Respuesta de Proteína Desplegada/inmunología , eIF-2 Quinasa/genética , Factor de Transcripción Activador 6/inmunología , Animales , Estrés del Retículo Endoplásmico/genética , Estrés del Retículo Endoplásmico/inmunología , Endorribonucleasas/inmunología , Humanos , Células Mieloides/inmunología , Células Mieloides/patología , Neoplasias/genética , Neoplasias/patología , Proteínas Serina-Treonina Quinasas/inmunología , Transducción de Señal/genética , Transducción de Señal/inmunología , eIF-2 Quinasa/inmunología
7.
J Autoimmun ; 75: 68-81, 2016 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-27461470

RESUMEN

Salivary gland (SG) acinar-cells are susceptible to endoplasmic reticulum (ER) stress related to their secretory activity and the complexity of synthesized secretory products. SGs of Sjögren's syndrome patients (SS)-patients show signs of inflammation and altered proteostasis, associated with low IRE1α/XBP-1 pathway activity without avert increases in apoptosis. Acinar-cells may avoid apoptosis by activation of the ATF6α pathway and ER-associated protein degradation (ERAD). The aim of this study was to evaluate the role of pro-inflammatory cytokines in ATF6α pathway/ERAD activation and cell viability in labial salivary glands (LSG) of SS-patients. In biopsies from SS-patients increased ATF6α signaling pathway activity, as evidenced by generation of the ATF6f cleavage fragment, and increased expression of ERAD machinery components, such as EDEM1, p97, SEL1L, gp78, UBE2J1, UBE2G2, HERP and DERLIN1, were observed compared to controls. Alternatively, for pro- (active-caspase-3) and anti-apoptotic (cIAP2) markers no significant difference between the two experimental groups was detected. Increased presence of ATF6f and ERAD molecules correlated significantly with increased expression of pro-inflammatory cytokines. These observations were corroborated in vitro in 3D-acini treated with TNF-α and/or IFN-γ, where an increase in the expression and activation of the ATF6α sensor and ERAD machinery components was detected under ER stress conditions, while changes in cell viability and caspase-3 activation were not observed. Cytokine stimulation protected cells from death when co-incubated with an ERAD machinery inhibitor. Alternatively, when cytokines were eliminated from the medium prior to ERAD inhibition, cell death increased, suggesting that the presence of pro-inflammatory cytokines in the medium is essential to maintain cell viability. In conclusion, the ATF6α pathway and the ERAD machinery are active in LSG of SS-patients. Both were also activated by TNF-α and IFN-γ in vitro in 3D-acini and aided in preventing apoptosis. IFN-γ levels were elevated in SS-patients and UPR responses triggered in vitro by this cytokine closely matched those observed in LSG from SS-patients, suggesting that cytokines may induce ER stress.


Asunto(s)
Factor de Transcripción Activador 6/inmunología , Citocinas/inmunología , Degradación Asociada con el Retículo Endoplásmico/inmunología , Glándulas Salivales/inmunología , Síndrome de Sjögren/inmunología , Factor de Transcripción Activador 6/genética , Factor de Transcripción Activador 6/metabolismo , Adolescente , Adulto , Apoptosis/inmunología , Apoptosis/efectos de la radiación , Western Blotting , Caspasa 3/inmunología , Caspasa 3/metabolismo , Citocinas/metabolismo , Citocinas/farmacología , Degradación Asociada con el Retículo Endoplásmico/genética , Activación Enzimática/efectos de los fármacos , Activación Enzimática/inmunología , Femenino , Expresión Génica/inmunología , Humanos , Inmunohistoquímica , Mediadores de Inflamación/inmunología , Mediadores de Inflamación/metabolismo , Mediadores de Inflamación/farmacología , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/inmunología , Proteínas de la Membrana/metabolismo , Microscopía Fluorescente , Persona de Mediana Edad , Proteínas/genética , Proteínas/inmunología , Proteínas/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Glándulas Salivales/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Transducción de Señal/inmunología , Síndrome de Sjögren/genética , Síndrome de Sjögren/metabolismo , Adulto Joven
8.
Nat Immunol ; 17(3): 323-30, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26779600

RESUMEN

Plasma cell differentiation requires silencing of B cell transcription, while it establishes antibody-secretory function and long-term survival. The transcription factors Blimp-1 and IRF4 are essential for the generation of plasma cells; however, their function in mature plasma cells has remained elusive. We found that while IRF4 was essential for the survival of plasma cells, Blimp-1 was dispensable for this. Blimp-1-deficient plasma cells retained their transcriptional identity but lost the ability to secrete antibody. Blimp-1 regulated many components of the unfolded protein response (UPR), including XBP-1 and ATF6. The overlap in the functions of Blimp-1 and XBP-1 was restricted to that response, with Blimp-1 uniquely regulating activity of the kinase mTOR and the size of plasma cells. Thus, Blimp-1 was required for the unique physiological ability of plasma cells that enables the secretion of protective antibody.


Asunto(s)
Diferenciación Celular/inmunología , Inmunoglobulinas/inmunología , Factores Reguladores del Interferón/inmunología , Células Plasmáticas/inmunología , Factores de Transcripción/inmunología , Respuesta de Proteína Desplegada/inmunología , Factor de Transcripción Activador 6/genética , Factor de Transcripción Activador 6/inmunología , Animales , Tamaño de la Célula , Inmunoprecipitación de Cromatina , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/inmunología , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Inmunoglobulinas/metabolismo , Factores Reguladores del Interferón/genética , Ratones , Ratones Noqueados , Microscopía Electrónica de Transmisión , Células Plasmáticas/metabolismo , Factor 1 de Unión al Dominio 1 de Regulación Positiva , Factores de Transcripción del Factor Regulador X , Análisis de Secuencia de ADN , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/inmunología , Factores de Transcripción/genética , Respuesta de Proteína Desplegada/genética , Proteína 1 de Unión a la X-Box
9.
J Immunol ; 195(3): 801-5, 2015 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-26109639

RESUMEN

Multiple pathogen-associated molecular pattern-induced TLR pathway cross-talk provokes proinflammatory cytokine synergy in macrophages, which is important for pathogen resistance and immune homeostasis. However, the detailed mechanisms are unclear. In this article, we demonstrate viral RNA analog-induced transcription synergy of Il6 and Il12b via IFN regulatory factor (IRF)1 (TLR3-TIR domain-containing adaptor inducing IFN-ß [TRIF] responsive), C/EBPß (TLR7-MyD88 responsive), and JunB (all responsive). Coactivation of the TLR3 and TLR7 pathways synchronizes the interaction of IRF1, JunB, and C/EBPß with the Il6 and Il12b promoters, facilitating maximal gene expression. MyD88 pathway activation suppresses TRIF-induced IRF1 in a delayed manner, controlling the magnitude and timing of cytokine expression. Our findings provide novel mechanisms of cooperation of different TLR pathways to achieve optimal immune responses, with the potential for immunomodulatory strategies.


Asunto(s)
Inflamación/inmunología , Subunidad p40 de la Interleucina-12/inmunología , Interleucina-6/inmunología , Glicoproteínas de Membrana/inmunología , Receptor Toll-Like 3/inmunología , Receptor Toll-Like 7/inmunología , Factor de Transcripción Activador 6/inmunología , Proteínas Adaptadoras del Transporte Vesicular/inmunología , Animales , Células Cultivadas , Factor 1 Regulador del Interferón/inmunología , Subunidad p40 de la Interleucina-12/genética , Interleucina-6/genética , Macrófagos/inmunología , Ratones , Factor 88 de Diferenciación Mieloide/inmunología , Regiones Promotoras Genéticas , ARN Mensajero/genética , Receptor Cross-Talk/inmunología , Transducción de Señal/inmunología , Factores de Transcripción/inmunología
10.
J Leukoc Biol ; 97(2): 425-33, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25516752

RESUMEN

Abnormal regulation of ER stress and apoptosis has been implicated in autoimmune disorders. Particularly, ER stress-induced autophagy and the role of GRP78, or BiP in T lymphocyte survival and death in SLE are poorly understood. This study investigated the pathogenic roles of ER stress-induced autophagy and GRP78/BiP in apoptosis of T lymphocytes. We compared spontaneous and induced autophagy and apoptosis of T lymphocytes in healthy donors and patients with SLE. The molecular mechanism of altered autophagy and apoptosis was investigated in T lymphocytes transfected with siRNA for beclin 1 and CHOP and T lymphocytes overexpressing GRP78. Decreased autophagy and increased apoptosis in response to TG-induced ER stress were observed in lupus T lymphocytes. GRP78 and ER stress-signaling molecules, such as PERK, p-eIF2α, IRE1, and ATF6 decreased, whereas CHOP levels increased in lupus T cells in response to TG. The levels antiapoptotic molecules, Bcl-2 and Bcl-XL decreased, whereas the proapoptotic molecules, Bax and caspase 6, increased in lupus T cells. The TG-induced ER stress altered autophagy and apoptosis, which in turn, led to abnormal T cell homeostasis with increased apoptotic T cell death. We hypothesize that aberrant autophagy of T lymphocytes as a result of ER stress and decreased GRP78 expression is involved in the pathogenesis of SLE and might serve as important therapeutic targets.


Asunto(s)
Autofagia/inmunología , Estrés del Retículo Endoplásmico/inmunología , Proteínas de Choque Térmico/inmunología , Lupus Eritematoso Sistémico/inmunología , Linfocitos T/inmunología , Factor de Transcripción Activador 6/genética , Factor de Transcripción Activador 6/inmunología , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/inmunología , Autofagia/genética , Beclina-1 , Caspasa 6/genética , Caspasa 6/inmunología , Chaperón BiP del Retículo Endoplásmico , Estrés del Retículo Endoplásmico/genética , Endorribonucleasas/genética , Endorribonucleasas/inmunología , Factor 2 Eucariótico de Iniciación/genética , Factor 2 Eucariótico de Iniciación/inmunología , Femenino , Regulación de la Expresión Génica/genética , Regulación de la Expresión Génica/inmunología , Proteínas de Choque Térmico/genética , Humanos , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/patología , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/inmunología , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/inmunología , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/inmunología , Linfocitos T/patología , Factor de Transcripción CHOP/genética , Factor de Transcripción CHOP/inmunología , Proteína X Asociada a bcl-2/genética , Proteína X Asociada a bcl-2/inmunología , Proteína bcl-X/genética , Proteína bcl-X/inmunología , eIF-2 Quinasa/genética , eIF-2 Quinasa/inmunología
11.
Eur J Immunol ; 44(12): 3758-67, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25209846

RESUMEN

NK cells play important roles in anti-tumor immunity. CD226 is a major NK-cell activating receptor, which transduces activating signals after binding ligands CD155 and CD112. Here, we demonstrated that activated unfolded protein response (UPR) attenuated the sensitivity of human hepatocellular carcinoma cell (HCC) to NK-cell cytotoxicity by decreasing the expression level of CD226 ligand CD155 in HCC. The decreased expression level of CD155 was due to the involvement of the activating transcription factor 6 (ATF6) and inositol-requiring enzyme 1α (IRE1α) pathways. In addition, the IRE1α pathway contributed to the increased expression level of the ER-associated degradation (ERAD)-related molecule HRD1 and facilitated the degradation of CD155. Moreover, we found that low levels of CD155 expression were significantly associated with poor prognosis in patients with HCC. Thus, our results provide molecular, cellular, and clinical evidence demonstrating a novel NK cell-associated immune evasion mechanism, and indicate that targeting this immune evasion pathway may be meaningful in treating patients with HCC.


Asunto(s)
Antígenos de Diferenciación de Linfocitos T/inmunología , Carcinoma Hepatocelular/inmunología , Degradación Asociada con el Retículo Endoplásmico/inmunología , Regulación Neoplásica de la Expresión Génica/inmunología , Inmunidad Celular , Células Asesinas Naturales/inmunología , Neoplasias Hepáticas/inmunología , Proteínas de Neoplasias/inmunología , Receptores Virales/inmunología , Factor de Transcripción Activador 6/inmunología , Carcinoma Hepatocelular/patología , Endorribonucleasas/inmunología , Células Hep G2 , Humanos , Células Asesinas Naturales/patología , Neoplasias Hepáticas/patología , Proteínas Serina-Treonina Quinasas/inmunología , Escape del Tumor , Ubiquitina-Proteína Ligasas/inmunología
12.
Mol Immunol ; 51(3-4): 347-55, 2012 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-22555069

RESUMEN

B lymphocytes, like all mammalian cells, are equipped with the unfolded protein response (UPR), a complex signaling system allowing for both pro- and mal-adaptive responses to increased demands on the endoplasmic reticulum (ER). The UPR is comprised of three signaling pathways initiated by the ER transmembrane stress sensors, IRE1α/ß, PERK and ATF6α/ß. Activation of IRE1 yields XBP1(S), a transcription factor that directs expansion of the ER and enhances protein biosynthetic and secretory machinery. XBP1(S) is essential for the differentiation of B lymphocytes into antibody-secreting cells. In contrast, the PERK pathway, a regulator of translation and transcription, is dispensable for the generation of antibody-secreting cells. Functioning as a transcription factor, ATF6α can augment ER quality control processes and drive ER expansion, but the potential role of this UPR pathway in activated B cells has not been investigated. Here, we report studies of ATF6α-deficient B cells demonstrating that ATF6α is not required for the development of antibody-secreting cells. Thus, when B cells are stimulated to secrete antibody, a specialized UPR relies exclusively on the IRE1-XBP1 pathway to remodel the ER and expand cellular secretory capacity.


Asunto(s)
Factor de Transcripción Activador 6/metabolismo , Células Productoras de Anticuerpos/inmunología , Linfocitos B/inmunología , Factor de Transcripción Activador 6/genética , Factor de Transcripción Activador 6/inmunología , Animales , Linfocitos B/metabolismo , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Células Cultivadas , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/inmunología , Proteínas de Unión al ADN/metabolismo , Retículo Endoplásmico/genética , Retículo Endoplásmico/inmunología , Retículo Endoplásmico/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/inmunología , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/inmunología , Proteínas Serina-Treonina Quinasas/metabolismo , Factores de Transcripción del Factor Regulador X , Transducción de Señal , Factores de Transcripción/genética , Factores de Transcripción/inmunología , Factores de Transcripción/metabolismo , Respuesta de Proteína Desplegada , Proteína 1 de Unión a la X-Box , eIF-2 Quinasa/genética , eIF-2 Quinasa/inmunología , eIF-2 Quinasa/metabolismo
13.
Adv Exp Med Biol ; 738: 153-68, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22399379

RESUMEN

This chapter provides an overview of our present understanding of mechanisms of sensing protein folding status and endoplasmic reticulum (ER) stress in eukaryotic cells. The ER folds and matures most secretory and transmembrane proteins. Mis- or unfolded proteins are sensed by specialized ER stress sensors, such as IRE1, PERK and ATF6, which initiate several cellular responses and signaling pathways to restore ER homeostasis. These intracellular signaling events are called the unfolded protein response (UPR). Here we focus on how ER stress and protein folding status in the ER are sensed by the ER stress sensors by summarizing results from recent structural, biochemical and genetic approaches.


Asunto(s)
Estrés del Retículo Endoplásmico/inmunología , Retículo Endoplásmico/inmunología , Pliegue de Proteína , Respuesta de Proteína Desplegada/inmunología , Factor de Transcripción Activador 6/genética , Factor de Transcripción Activador 6/inmunología , Animales , Retículo Endoplásmico/genética , Estrés del Retículo Endoplásmico/genética , Endorribonucleasas/genética , Endorribonucleasas/inmunología , Humanos , Proteínas de la Membrana/genética , Proteínas de la Membrana/inmunología , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/inmunología , Respuesta de Proteína Desplegada/genética , eIF-2 Quinasa/genética , eIF-2 Quinasa/inmunología
14.
Virulence ; 3(1): 77-80, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22286708

RESUMEN

Toxoplasma gondii (T. gondii) secretes various effector molecules, which co-opt host cells and enable parasite proliferation. Of these, the rhoptry protein, ROP18, is a parasite-derived factor that determines acute virulence. ROP18 is injected into the host cytoplasm during infection and, eventually, localizes to parasitophorous vacuole (PV) membranes. ROP18 is predicted to be a serine/threonine kinase; however, the molecular mechanism by which ROP18 mediates its pathological effects remains unclear. At the end of 2010, two groups reported that ROP18 targets and phosphorylates interferon-inducible p47 small GTPases (IRGs), demonstrating the parasite's strategy for disarming the innate defense system. Recently, we described a mechanism by which ROP18 mediates degradation of the host endoplasmic reticulum-localizing transcription factor, ATF6ß, to downregulate CD8 T cell-mediated type I adaptive immune responses. Taken together, these results suggest that T. gondii inactivates host innate and adaptive immune responses by targeting different host immunity-related molecules: IRGs and ATF6ß.


Asunto(s)
Factor de Transcripción Activador 6/inmunología , Inmunidad Adaptativa , Regulación hacia Abajo , Proteínas Serina-Treonina Quinasas/inmunología , Toxoplasma/enzimología , Toxoplasmosis/inmunología , Factores de Virulencia/inmunología , Factor de Transcripción Activador 6/genética , Animales , Interacciones Huésped-Parásitos , Humanos , Inmunidad Innata , Ratones , Proteínas Serina-Treonina Quinasas/genética , Proteínas Protozoarias , Toxoplasma/genética , Toxoplasma/inmunología , Toxoplasmosis/parasitología , Factores de Virulencia/genética
15.
J Exp Med ; 208(7): 1533-46, 2011 Jul 04.
Artículo en Inglés | MEDLINE | ID: mdl-21670204

RESUMEN

The ROP18 kinase has been identified as a key virulence determinant conferring a high mortality phenotype characteristic of type I Toxoplasma gondii strains. This major effector molecule is secreted by the rhoptries into the host cells during invasion; however, the molecular mechanisms by which this kinase exerts its pathogenic action remain poorly understood. In this study, we show that ROP18 targets the host endoplasmic reticulum-bound transcription factor ATF6ß. Disruption of the ROP18 gene severely impairs acute toxoplasmosis by the type I RH strain. Because another virulence factor ROP16 kinase modulates immune responses through its N-terminal portion, we focus on the role of the N terminus of ROP18 in the subversion of host cellular functions. The N-terminal extension of ROP18 contributes to ATF6ß-dependent pathogenicity by interacting with ATF6ß and destabilizing it. The kinase activity of ROP18 is essential for proteasome-dependent degradation of ATF6ß and for parasite virulence. Consistent with a key role for ATF6ß in resistance against this intracellular pathogen, ATF6ß-deficient mice exhibit a high susceptibility to infection by ROP18-deficient parasites. The results reveal that interference with ATF6ß-dependent immune responses is a novel pathogenic mechanism induced by ROP18.


Asunto(s)
Factor de Transcripción Activador 6/metabolismo , Proteínas Serina-Treonina Quinasas/toxicidad , Toxoplasma/patogenicidad , Factores de Virulencia/toxicidad , Factor de Transcripción Activador 6/deficiencia , Factor de Transcripción Activador 6/genética , Factor de Transcripción Activador 6/inmunología , Animales , Animales Modificados Genéticamente , Técnicas de Inactivación de Genes , Genes Protozoarios , Interacciones Huésped-Parásitos/inmunología , Interacciones Huésped-Parásitos/fisiología , Hipersensibilidad Inmediata/etiología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos ICR , Ratones Noqueados , Proteínas Serina-Treonina Quinasas/genética , Proteínas Protozoarias , Toxoplasma/enzimología , Toxoplasma/genética , Toxoplasmosis Animal/etiología , Toxoplasmosis Animal/inmunología , Virulencia/fisiología , Factores de Virulencia/genética
16.
Egypt J Immunol ; 16(1): 83-93, 2009.
Artículo en Inglés | MEDLINE | ID: mdl-20726325

RESUMEN

We genotyped and identified the asthma and atopic status and related phenotypes of 154 nuclear families (453 individuals) each containing at least two affected children with physician-diagnosed asthma (PDA) in order to confirm or refute the possible relevance of known single nucleotide polymorphisms (SNPs) in the gene coding for the CCR3 receptor. Allelic quantification for each SNP by DNA pooling identified -17/TC as the only allele with a clinically relevant frequency in this population with a frequencies of 0.142 in cases of PDA and 0.035 in asymptomatic controls. The whole population frequency of the -17/TC polymorphism was 13.9% and the functional binding site analyses by MatInd and MatInspector programs found that it belonged to the same family as activating transcription factor 6 (ATF-6). The pedigree disequilibrium test (PDT) was applied in 34 informative families and the mutant allele was preferentially transmitted with PDA (P = 0.0001) with methacholine bronchial hyperresponsiveness (BHR) (0.002) but not with markers of atopy as assessed by allergen skin prick tests (SPT) or elevated serum IgE. Case-control analyses in 303 unrelated parents (34-61y [median 43y]) revealed a significant association with both atopic and non atopic asthma (P = 0.001), and in 150 unrelated child probands for non-atopic asthma (P = 0.001). The mutant allele was associated with BHR, with baseline Forced Expiratory Volume in the first second (FEV1) below the population median value but not with atopy defined SPT or elevated serum IgE (>100 IU/ml). The T17C chemokine receptor 3 polymorphism appears to be associated with asthma BHR and disease severity but not with atopy.


Asunto(s)
Asma/genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Receptores CCR3/genética , Factor de Transcripción Activador 6/genética , Factor de Transcripción Activador 6/inmunología , Adolescente , Alelos , Asma/inmunología , Estudios de Casos y Controles , Niño , Femenino , Humanos , Masculino , Mutación , Linaje , Receptores CCR3/inmunología , Índice de Severidad de la Enfermedad , Adulto Joven
17.
PLoS Pathog ; 4(10): e1000176, 2008 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-18846208

RESUMEN

Pore-forming toxins (PFTs) constitute the single largest class of proteinaceous bacterial virulence factors and are made by many of the most important bacterial pathogens. Host responses to these toxins are complex and poorly understood. We find that the endoplasmic reticulum unfolded protein response (UPR) is activated upon exposure to PFTs both in Caenorhabditis elegans and in mammalian cells. Activation of the UPR is protective in vivo against PFTs since animals that lack either the ire-1-xbp-1 or the atf-6 arms of the UPR are more sensitive to PFT than wild-type animals. The UPR acts directly in the cells targeted by the PFT. Loss of the UPR leads to a normal response against unrelated toxins or a pathogenic bacterium, indicating its PFT-protective role is specific. The p38 mitogen-activated protein (MAPK) kinase pathway has been previously shown to be important for cellular defenses against PFTs. We find here that the UPR is one of the key downstream targets of the p38 MAPK pathway in response to PFT since loss of a functional p38 MAPK pathway leads to a failure of PFT to properly activate the ire-1-xbp-1 arm of the UPR. The UPR-mediated activation and response to PFTs is distinct from the canonical UPR-mediated response to unfolded proteins both in terms of its activation and functional sensitivities. These data demonstrate that the UPR, a fundamental intracellular pathway, can operate in intrinsic cellular defenses against bacterial attack.


Asunto(s)
Infecciones Bacterianas/inmunología , Proteínas Bacterianas/toxicidad , Caenorhabditis elegans/inmunología , Endotoxinas/toxicidad , Proteínas Hemolisinas/toxicidad , Inmunidad Innata , Pliegue de Proteína , Factor de Transcripción Activador 6/genética , Factor de Transcripción Activador 6/inmunología , Factor de Transcripción Activador 6/metabolismo , Animales , Toxinas de Bacillus thuringiensis , Infecciones Bacterianas/genética , Infecciones Bacterianas/metabolismo , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/inmunología , Proteínas de Unión al ADN/metabolismo , Retículo Endoplásmico/genética , Retículo Endoplásmico/inmunología , Retículo Endoplásmico/metabolismo , Endorribonucleasas/genética , Endorribonucleasas/inmunología , Endorribonucleasas/metabolismo , Escherichia coli , Células HeLa , Humanos , Inmunidad Innata/genética , Proteínas de la Membrana/genética , Proteínas de la Membrana/inmunología , Proteínas de la Membrana/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/inmunología , Proteínas Serina-Treonina Quinasas/metabolismo , Factores de Transcripción del Factor Regulador X , Factores de Transcripción/genética , Factores de Transcripción/inmunología , Factores de Transcripción/metabolismo , Proteína 1 de Unión a la X-Box , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Proteínas Quinasas p38 Activadas por Mitógenos/inmunología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
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