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1.
J Cell Sci ; 137(5)2024 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-38084966

RESUMEN

Elimination of virally infected or tumoral cells is mediated by cytotoxic T cells (CTL). Upon antigen recognition, CTLs assemble a specialized signaling and secretory domain at the interface with their target, the immune synapse (IS). During IS formation, CTLs acquire a transient polarity, marked by re-orientation of the centrosome and microtubule cytoskeleton toward the IS, thus directing the transport and delivery of the lytic granules to the target cell. Based on the implication that the kinase Aurora A has a role in CTL function, we hypothesized that its substrate, the mitotic regulator Polo-like kinase 1 (PLK1), might participate in CTL IS assembly. We demonstrate that PLK1 is phosphorylated upon TCR triggering and polarizes to the IS. PLK1 silencing or inhibition results in impaired IS assembly and function, as witnessed by defective synaptic accumulation of T cell receptors (TCRs), as well as compromised centrosome and lytic granule polarization to the IS, resulting in impaired target cell killing. This function is achieved by coupling early signaling to microtubule dynamics, a function pivotal for CTL-mediated cytotoxicity. These results identify PLK1 as a new player in CTL IS assembly and function.


Asunto(s)
Quinasa Tipo Polo 1 , Linfocitos T Citotóxicos , Linfocitos T Citotóxicos/metabolismo , Centrosoma/metabolismo , Transducción de Señal , Microtúbulos/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo
2.
Trends Immunol ; 44(6): 424-434, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-37137805

RESUMEN

The COVID-19 pandemic, caused by SARS-CoV-2, has caused an estimated 5 billion infections and 20 million deaths by respiratory failure. In addition to the respiratory disease, SARS-CoV-2 infection has been associated with many extrapulmonary complications not easily explainable by the respiratory infection. A recent study showed that the SARS-CoV-2 spike protein, which mediates cell entry by binding to the angiotensin-converting enzyme 2 (ACE2) receptor, signals through ACE2 to change host cell behavior. In CD8+ T cells, spike-dependent ACE2-mediated signaling suppresses immunological synapse (IS) formation and impairs their killing ability, leading to immune escape of virus-infected cells. In this opinion article, we discuss the consequences of ACE2 signaling on the immune response and propose that it contributes to the extrapulmonary manifestations of COVID-19.


Asunto(s)
COVID-19 , Humanos , Enzima Convertidora de Angiotensina 2/metabolismo , Linfocitos T CD8-positivos/metabolismo , Evasión Inmune , Pandemias , Unión Proteica , SARS-CoV-2/metabolismo
3.
J Cell Sci ; 134(16)2021 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-34423835

RESUMEN

Components of the intraflagellar transport (IFT) system that regulates the assembly of the primary cilium are co-opted by the non-ciliated T cell to orchestrate polarized endosome recycling and to sustain signaling during immune synapse formation. Here, we investigated the potential role of Bardet-Biedl syndrome 1 protein (BBS1), an essential core component of the BBS complex that cooperates with the IFT system in ciliary protein trafficking, in the assembly of the T cell synapse. We demonstrated that BBS1 allows for centrosome polarization towards the immune synapse. This function is achieved through the clearance of centrosomal F-actin and its positive regulator WASH1 (also known as WASHC1), a process that we demonstrated to be dependent on the proteasome. We show that BBS1 regulates this process by coupling the 19S proteasome regulatory subunit to the microtubule motor dynein for its transport to the centrosome. Our data identify the ciliopathy-related protein BBS1 as a new player in T cell synapse assembly that functions upstream of the IFT system to set the stage for polarized vesicular trafficking and sustained signaling. This article has an associated First Person interview with the first author of the paper.


Asunto(s)
Síndrome de Bardet-Biedl , Cilios , Síndrome de Bardet-Biedl/genética , Polaridad Celular , Endosomas , Humanos , Proteínas Asociadas a Microtúbulos/genética , Sinapsis , Linfocitos T
4.
Int J Mol Sci ; 23(20)2022 Oct 12.
Artículo en Inglés | MEDLINE | ID: mdl-36292997

RESUMEN

Initially discovered as the smallest component of the intraflagellar transport (IFT) system, the IFT20 protein has been found to be implicated in several unconventional mechanisms beyond its essential role in the assembly and maintenance of the primary cilium. IFT20 is now considered a key player not only in ciliogenesis but also in vesicular trafficking of membrane receptors and signaling proteins. Moreover, its ability to associate with a wide array of interacting partners in a cell-type specific manner has expanded the function of IFT20 to the regulation of intracellular degradative and secretory pathways. In this review, we will present an overview of the multifaceted role of IFT20 in both ciliated and non-ciliated cells.


Asunto(s)
Proteínas Portadoras , Fenómenos Fisiológicos Celulares , Proteínas Portadoras/metabolismo , Transporte Biológico/fisiología
5.
J Cell Sci ; 130(6): 1110-1121, 2017 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-28154159

RESUMEN

Sustained signalling at the immune synapse (IS) requires the synaptic delivery of recycling endosome-associated T cell antigen receptors (TCRs). IFT20, a component of the intraflagellar transport system, controls TCR recycling to the IS as a complex with IFT57 and IFT88. Here, we used quantitative mass spectrometry to identify additional interaction partners of IFT20 in Jurkat T cells. In addition to IFT57 and IFT88, the analysis revealed new binding partners, including IFT54 (also known as TRAF3IP1), GMAP-210 (also known as TRIP11), Arp2/3 complex subunit-3 (ARPC3), COP9 signalosome subunit-1 (CSN1, also known as GPS1) and ERGIC-53 (also known as LMAN1). A direct interaction between IFT20 and both IFT54 and GMAP-210 was confirmed in pulldown assays. Confocal imaging of antigen-specific conjugates using T cells depleted of these proteins by RNA interference showed that TCR accumulation and phosphotyrosine signalling at the IS were impaired in the absence of IFT54, ARPC3 or ERGIC-53. Similar to in IFT20-deficient T cells, this defect resulted from a reduced ability of endosomal TCRs to polarize to the IS despite a correct translocation of the centrosome towards the antigen-presenting cell contact. Our data underscore the traffic-related role of an IFT20 complex that includes components of the intracellular trafficking machinery in IS assembly.


Asunto(s)
Proteínas Portadoras/metabolismo , Sinapsis Inmunológicas/metabolismo , Mapas de Interacción de Proteínas , Linfocitos T/metabolismo , Complejo 2-3 Proteico Relacionado con la Actina/metabolismo , Proteínas del Citoesqueleto , Endocitosis , Células HEK293 , Humanos , Células Jurkat , Activación de Linfocitos/inmunología , Lectinas de Unión a Manosa/metabolismo , Espectrometría de Masas , Proteínas de la Membrana/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Centro Organizador de los Microtúbulos/metabolismo , Proteínas Nucleares/metabolismo , Unión Proteica , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores de Transferrina/metabolismo
6.
Traffic ; 16(3): 241-9, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25393976

RESUMEN

The signals that orchestrate the process of T cell activation are coordinated at the specialized interface that forms upon contact with an antigen presenting cell displaying a specific MHC-associated peptide ligand, known as the immune synapse. The central role of vesicular traffic in the assembly of the immune synapse has emerged only in recent years with the finding that sustained T-cell receptor (TCR) signaling involves delivery of TCR/CD3 complexes from an intracellular pool associated with recycling endosomes. A number of receptors as well as membrane-associated signaling mediators have since been demonstrated to exploit this process to localize to the immune synapse. Here, we will review our current understanding of the mechanisms responsible for TCR recycling, with a focus on the intraflagellar transport system, a multimolecular complex that is responsible for the assembly and function of the primary cilium which we have recently implicated in polarized endosome recycling to the immune synapse.


Asunto(s)
Cilios/inmunología , Sinapsis Inmunológicas/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Vesículas Sinápticas/inmunología , Linfocitos T/inmunología , Animales , Transporte Biológico/inmunología , Endosomas/inmunología , Humanos , Transducción de Señal/inmunología
7.
J Cell Sci ; 127(Pt 9): 1924-37, 2014 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-24554435

RESUMEN

T cell activation requires sustained signaling at the immune synapse, a specialized interface with the antigen-presenting cell (APC) that assembles following T cell antigen receptor (TCR) engagement by major histocompatibility complex (MHC)-bound peptide. Central to sustained signaling is the continuous recruitment of TCRs to the immune synapse. These TCRs are partly mobilized from an endosomal pool by polarized recycling. We have identified IFT20, a component of the intraflagellar transport (IFT) system that controls ciliogenesis, as a central regulator of TCR recycling to the immune synapse. Here, we have investigated the interplay of IFT20 with the Rab GTPase network that controls recycling. We found that IFT20 forms a complex with Rab5 and the TCR on early endosomes. IFT20 knockdown (IFT20KD) resulted in a block in the recycling pathway, leading to a build-up of recycling TCRs in Rab5(+) endosomes. Recycling of the transferrin receptor (TfR), but not of CXCR4, was disrupted by IFT20 deficiency. The IFT components IFT52 and IFT57 were found to act together with IFT20 to regulate TCR and TfR recycling. The results provide novel insights into the mechanisms that control TCR recycling and immune synapse assembly, and underscore the trafficking-related function of the IFT system beyond ciliogenesis.


Asunto(s)
Sinapsis/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Células Presentadoras de Antígenos/metabolismo , Transporte Biológico/fisiología , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Línea Celular , Células Cultivadas , Citometría de Flujo , Humanos , Immunoblotting , Inmunoprecipitación , Células Jurkat , Microscopía Fluorescente , Unión Proteica/genética , Transporte de Proteínas/genética , Transporte de Proteínas/fisiología , Receptores de Antígenos de Linfocitos T/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/genética , Transducción de Señal/fisiología , Proteínas de Unión al GTP rab/genética , Proteínas de Unión al GTP rab/metabolismo , Proteínas de Unión al GTP rab5/genética , Proteínas de Unión al GTP rab5/metabolismo
8.
BMC Cancer ; 15: 668, 2015 Oct 09.
Artículo en Inglés | MEDLINE | ID: mdl-26453442

RESUMEN

BACKGROUND: The oncogenic transcription factor MYC is pathologically activated in many human malignancies. A paradigm for MYC dysregulation is offered by Burkitt lymphoma, where chromosomal translocations leading to Immunoglobulin gene-MYC fusion are the crucial initiating oncogenic events. However, Burkitt lymphoma cases with no detectable MYC rearrangement but maintaining MYC expression have been identified and alternative mechanisms can be involved in MYC dysregulation in these cases. METHODS: We studied the microRNA profile of MYC translocation-positive and MYC translocation-negative Burkitt lymphoma cases in order to uncover possible differences at the molecular level. Data was validated at the mRNA and protein level by quantitative Real-Time polymerase chain reaction and immunohistochemistry, respectively. RESULTS: We identified four microRNAs differentially expressed between the two groups. The impact of these microRNAs on the expression of selected genes was then investigated. Interestingly, in MYC translocation-negative cases we found over-expression of DNA-methyl transferase family members, consistent to hypo-expression of the hsa-miR-29 family. This finding suggests an alternative way for the activation of lymphomagenesis in these cases, based on global changes in methylation landscape, aberrant DNA hypermethylation, lack of epigenetic control on transcription of targeted genes, and increase of genomic instability. In addition, we observed an over-expression of another MYC family gene member, MYCN that may therefore represent a cooperating mechanism of MYC in driving the malignant transformation in those cases lacking an identifiable MYC translocation but expressing the gene at the mRNA and protein levels. CONCLUSIONS: Collectively, our results showed that MYC translocation-positive and MYC translocation-negative Burkitt lymphoma cases are slightly different in terms of microRNA and gene expression. MYC translocation-negative Burkitt lymphoma, similarly to other aggressive B-cell non Hodgkin's lymphomas, may represent a model to understand the intricate molecular pathway responsible for MYC dysregulation in cancer.


Asunto(s)
Linfoma de Burkitt/genética , Metilasas de Modificación del ADN/genética , Regulación Neoplásica de la Expresión Génica , Genes myc , Translocación Genética , Linfoma de Burkitt/metabolismo , Análisis por Conglomerados , Metilación de ADN , Metilasas de Modificación del ADN/metabolismo , Amplificación de Genes , Perfilación de la Expresión Génica , Humanos , MicroARNs/genética , Familia de Multigenes , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reproducibilidad de los Resultados , Transcriptoma
9.
Blood ; 117(13): 3596-608, 2011 Mar 31.
Artículo en Inglés | MEDLINE | ID: mdl-21245480

RESUMEN

Burkitt lymphoma (BL) is classified into 3 clinical subsets: endemic, sporadic, and immunodeficiency-associated BL. So far, possible differences in their gene expression profiles (GEPs) have not been investigated. We studied GEPs of BL subtypes, other B-cell lymphomas, and B lymphocytes; first, we found that BL is a unique molecular entity, distinct from other B-cell malignancies. Indeed, by unsupervised analysis all BLs clearly clustered apart of other lymphomas. Second, we found that BL subtypes presented slight differences in GEPs. Particularly, they differed for genes involved in cell cycle control, B-cell receptor signaling, and tumor necrosis factor/nuclear factor κB pathways. Notably, by reverse engineering, we found that endemic and sporadic BLs diverged for genes dependent on RBL2 activity. Furthermore, we found that all BLs were intimately related to germinal center cells, differing from them for molecules involved in cell proliferation, immune response, and signal transduction. Finally, to validate GEP, we applied immunohistochemistry to a large panel of cases and showed that RBL2 can cooperate with MYC in inducing a neoplastic phenotype in vitro and in vivo. In conclusion, our study provided substantial insights on the pathobiology of BLs, by offering novel evidences that may be relevant for its classification and possibly future treatment.


Asunto(s)
Linfoma de Burkitt/clasificación , Linfoma de Burkitt/genética , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Animales , Linfoma de Burkitt/metabolismo , Línea Celular Tumoral , Análisis por Conglomerados , Humanos , Ratones , Ratones Desnudos , Análisis por Micromatrices , Trasplante de Neoplasias , Fenotipo , Trasplante Heterólogo
10.
J Exp Med ; 220(2)2023 02 06.
Artículo en Inglés | MEDLINE | ID: mdl-36378226

RESUMEN

CTL-mediated killing of virally infected or malignant cells is orchestrated at the immune synapse (IS). We hypothesized that SARS-CoV-2 may target lytic IS assembly to escape elimination. We show that human CD8+ T cells upregulate the expression of ACE2, the Spike receptor, during differentiation to CTLs. CTL preincubation with the Wuhan or Omicron Spike variants inhibits IS assembly and function, as shown by defective synaptic accumulation of TCRs and tyrosine phosphoproteins as well as defective centrosome and lytic granule polarization to the IS, resulting in impaired target cell killing and cytokine production. These defects were reversed by anti-Spike antibodies interfering with ACE2 binding and reproduced by ACE2 engagement by angiotensin II or anti-ACE2 antibodies, but not by the ACE2 product Ang (1-7). IS defects were also observed ex vivo in CTLs from COVID-19 patients. These results highlight a new strategy of immune evasion by SARS-CoV-2 based on the Spike-dependent, ACE2-mediated targeting of the lytic IS to prevent elimination of infected cells.


Asunto(s)
COVID-19 , Glicoproteína de la Espiga del Coronavirus , Humanos , Enzima Convertidora de Angiotensina 2 , SARS-CoV-2 , Peptidil-Dipeptidasa A/metabolismo , Sinapsis/metabolismo , Unión Proteica
11.
J Cell Physiol ; 227(4): 1771-5, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-21702048

RESUMEN

Notch3 is a single pass transmembrane protein belonging to the Notch receptor family. Notch proteins are involved in a very conserved signaling system (Notch signaling) with a broad spectrum of functions, from cell proliferation and differentiation to apoptosis. Mutations in Notch3 gene are linked to cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a disorder characterized by stroke and dementia in young adults. Studies evaluating Notch3 expression in human differentiated cells and adult tissues have shown high Notch3 levels only in vascular smooth muscle cells (VSMC). However, it has been hypothesized that Notch3 is ubiquitously expressed in adult human tissues. Our aim was to evaluate Notch3 expression in human peripheral blood lymphocytes (PBLs) and fibroblasts from normal healthy subjects. In both cell types, we examined the expression of Notch3 by reverse transcriptase-polymerase chain reaction (RT-PCR) and quantitative real-time polymerase chain reaction (qRT-PCR). Moreover, we assessed Notch3 protein expression by Western blot analysis. RT-PCR and qRT-PCR analysis showed the presence of Notch3 mRNA in both cell types. Western blot analysis confirmed Notch3 protein expression in PBLs and fibroblasts though showing different profiles. Our data support the expression of Notch3 in adult human cell types, and suggests that PBLs and fibroblasts could provide readily available cells for the study of the role of Notch3 expression in the pathogenetic mechanisms leading to different human disease.


Asunto(s)
Fibroblastos/metabolismo , Linfocitos/metabolismo , Receptores Notch/genética , Receptores Notch/metabolismo , Adulto , Secuencia de Bases , Western Blotting , Femenino , Perfilación de la Expresión Génica , Humanos , Técnicas In Vitro , Células Jurkat , Masculino , Persona de Mediana Edad , Modelos Biológicos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptor Notch3 , Receptores Notch/química , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
12.
Cell Death Differ ; 29(1): 65-81, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34294890

RESUMEN

Ciliogenesis proteins orchestrate vesicular trafficking pathways that regulate immune synapse (IS) assembly in the non-ciliated T-cells. We hypothesized that ciliogenesis-related genes might be disease candidates for common variable immunodeficiency with impaired T-cell function (T-CVID). We identified a heterozygous, predicted pathogenic variant in the ciliogenesis protein CCDC28B present with increased frequency in a large CVID cohort. We show that CCDC28B participates in IS assembly by regulating polarized T-cell antigen receptor (TCR) recycling. This involves the CCDC28B-dependent, FAM21-mediated recruitment of the actin regulator WASH to retromer at early endosomes to promote actin polymerization. The CVID-associated CCDC28BR25W variant failed to interact with FAM21, leading to impaired synaptic TCR recycling. CVID T cells carrying the ccdc28b 211 C > T allele displayed IS defects mapping to this pathway that were corrected by overexpression of the wild-type allele. These results identify a new disease gene in T-CVID and pinpoint CCDC28B as a new player in IS assembly.


Asunto(s)
Inmunodeficiencia Variable Común , Actinas/genética , Inmunodeficiencia Variable Común/genética , Proteínas del Citoesqueleto , Humanos , Receptores de Antígenos de Linfocitos T/metabolismo , Sinapsis/metabolismo , Linfocitos T
13.
Semin Cancer Biol ; 19(6): 401-6, 2009 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19619656

RESUMEN

Since its discovery as the first human tumor virus, Epstein-Barr virus (EBV) has been implicated in the development of a wide range of B-cell lymphoproliferative disorders, the first being Burkitt lymphoma. However, the exact mechanism by which EBV promotes oncogenesis is still matter of discussion. A role in EBV-mediated transformation has been proposed for a novel described class of small non-coding RNAs, the microRNAs (miRNAs). EBV encodes viral miRNAs, through which it may interfere with the physiological regulation exterted by cellular miRNAs. In addition, EBV-coded proteins may also disturb the well-orchestrated mechanisms of regulation of cellular function. In this review, we will focus on the role of EBV in malignant transformation of Burkitt lymphoma, with a particular insight in the interplay between the virus and cellular miRNAs.


Asunto(s)
Linfoma de Burkitt/virología , Infecciones por Virus de Epstein-Barr/virología , Herpesvirus Humano 4/fisiología , MicroARNs/metabolismo , Animales , Humanos
14.
Front Cell Dev Biol ; 9: 634003, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33829015

RESUMEN

Lymphocyte homeostasis, activation and differentiation crucially rely on basal autophagy. The fine-tuning of this process depends on autophagy-related (ATG) proteins and their interaction with the trafficking machinery that orchestrates the membrane rearrangements leading to autophagosome biogenesis. The underlying mechanisms are as yet not fully understood. The intraflagellar transport (IFT) system, known for its role in cargo transport along the axonemal microtubules of the primary cilium, has emerged as a regulator of autophagy in ciliated cells. Growing evidence indicates that ciliogenesis proteins participate in cilia-independent processes, including autophagy, in the non-ciliated T cell. Here we investigate the mechanism by which IFT20, an integral component of the IFT system, regulates basal T cell autophagy. We show that IFT20 interacts with the core autophagy protein ATG16L1 and that its CC domain is essential for its pro-autophagic activity. We demonstrate that IFT20 is required for the association of ATG16L1 with the Golgi complex and early endosomes, both of which have been identified as membrane sources for phagophore elongation. This involves the ability of IFT20 to interact with proteins that are resident at these subcellular localizations, namely the golgin GMAP210 at the Golgi apparatus and Rab5 at early endosomes. GMAP210 depletion, while leading to a dispersion of ATG16L1 from the Golgi, did not affect basal autophagy. Conversely, IFT20 was found to recruit ATG16L1 to early endosomes tagged for autophagosome formation by the BECLIN 1/VPS34/Rab5 complex, which resulted in the local accumulation of LC3. Hence IFT20 participates in autophagosome biogenesis under basal conditions by regulating the localization of ATG16L1 at early endosomes to promote autophagosome biogenesis. These data identify IFT20 as a new regulator of an early step of basal autophagy in T cells.

15.
J Cell Physiol ; 223(1): 143-50, 2010 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-20039270

RESUMEN

RB loss has long been recognized as the causative genetic alteration underlying retinoblastoma but it is increasingly evident that other alterations are required for the tumor to develop. Therefore, we set out to identify additional inheritable susceptibility markers and new potential preventive and therapeutic targets for retinoblastoma. We focused on the p16INK4A tumor suppressor gene because of its possible role in retinoblastoma pathogenesis and its involvement in predisposition to familial cancer. p16INK4A expression was analyzed in tumor samples from retinoblastoma patients by immunohistochemistry and in peripheral blood cells from both patients and their parents by real-time quantitative reverse transcription-PCR (qRT-PCR). Since promoter methylation is a common mechanism regulating p16INK4A expression, the methylation status of its promoter was also analyzed in blood samples from patients and their parents by methylation-specific PCR. A downregulation of p16INK4A was observed in 55% of retinoblastoma patients. Interestingly, in 56% of the cases showing p16INK4A downregulation at least one of the patients' parents bore the same alteration in blood cells. Analysis of p16INK4A promoter methylation showed hypermethylation in most patients with p16INK4A downregulation and in the parents with the same alteration in p16INK4A expression. The finding that p16INK4A was downregulated both in patients and their parents suggests that this alteration could be a novel inheritable susceptibility marker to retinoblastoma. The observation that p16INK4A downregulation seems to be due to its promoter hypermethylation opens the way for the development of new preventive and therapeutic strategies using demethylating agents.


Asunto(s)
Biomarcadores de Tumor/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Metilación de ADN , Regulación Neoplásica de la Expresión Génica , Regiones Promotoras Genéticas , Neoplasias de la Retina/genética , Retinoblastoma/genética , Biomarcadores de Tumor/análisis , Niño , Preescolar , Inhibidor p16 de la Quinasa Dependiente de Ciclina/análisis , Regulación hacia Abajo , Femenino , Predisposición Genética a la Enfermedad , Humanos , Inmunohistoquímica , Lactante , Masculino , Linaje , Fosforilación , ARN/análisis , Neoplasias de la Retina/química , Neoplasias de la Retina/patología , Retinoblastoma/química , Retinoblastoma/patología , Proteína de Retinoblastoma/análisis , Proteína p130 Similar a la del Retinoblastoma/análisis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Riesgo
16.
Int J Cancer ; 126(6): 1316-26, 2010 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-19530237

RESUMEN

Endemic, sporadic and HIV-associated Burkitt lymphoma (BL) all have a B-cell phenotype and a MYC translocation, but a variable association with the Epstein-Barr virus (EBV). However, there is still no satisfactory explanation of how EBV participates in the pathogenesis of BL. A recent investigation suggested that EBV-positive and EBV-negative BL have different cells of origin. In particular, according to immunoglobulin gene mutation analysis, EBV-negative BLs may originate from early centroblasts, whereas EBV-positive BLs seem to arise from postgerminal center B cells or memory B cells. The appearance of a germinal center phenotype in EBV-positive cells might thus derive from a block in B-cell differentiation. The exit from the germinal center involves a complex series of events, which require the activation of BLIMP-1, and the consequent downregulation of several target genes. Here, we investigated the expression of specific miRNAs predicted to be involved in B-cell differentiation and found that hsa-miR-127 is differentially expressed between EBV-positive and EBV-negative BLs. In particular, it was strongly upregulated only in EBV-positive BL samples, whereas EBV-negative cases showed levels of expression similar to normal controls, including microdissected germinal centers (GC) cells. In addition, we found evidence that hsa-miR-127 is involved in B-cell differentiation process through posttranscriptional regulation of BLIMP1 and XBP1. The overexpression of this miRNA may thus represent a key event in the lymphomagenesis of EBV positive BL, by blocking the B-cell differentiation process.


Asunto(s)
Linfocitos B/metabolismo , Linfoma de Burkitt/genética , Diferenciación Celular , MicroARNs/genética , Procesamiento Postranscripcional del ARN , Adolescente , Adulto , Linfocitos B/patología , Linfocitos B/virología , Western Blotting , Linfoma de Burkitt/metabolismo , Linfoma de Burkitt/patología , Línea Celular Tumoral , Niño , Preescolar , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Herpesvirus Humano 4/crecimiento & desarrollo , Humanos , Masculino , Persona de Mediana Edad , Factor 1 de Unión al Dominio 1 de Regulación Positiva , Factores de Transcripción del Factor Regulador X , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteína 1 de Unión a la X-Box , Adulto Joven
17.
Hematol Oncol ; 28(1): 20-6, 2010 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-19728399

RESUMEN

A particular extra-nodal lymphoma type arises from B cells of the marginal zone (MZ) of mucosa-associated lymphoid tissue (MALT). The aetiology of MZ lymphomas suggests that they are associated with chronic antigenic stimulation by microbial pathogens, among which Helicobacter pylori-associated gastric MALT lymphoma is the best studied. Recently, MALT lymphomas have been described in the context of chronic conjunctivitis, which can be associated with Chlamydia spp. infection. Studies from Italy showed the presence of Chlamydia psittaci in 87% of ocular adnexal lymphomas (OAL), and C. psittaci has been described in a large part of samples from Austria and Korea as well. However, this finding was not always confirmed by other studies, suggesting that the association with C. psittaci may depend on geographic heterogeneity. Interestingly, none of the studies up to now has been carried out in the African population, where a strong association between infectious agents and the occurrence of human neoplasms has been reported. This study was designed to investigate the possible association of Chlamydia psittaci in cases retrieved from Kenya, compared to cases from Italy. Our results showed that there was a marked variation between the two geographical areas in terms of association with C. psittaci, as 17% (5/30) of the samples from Italy were positive for C. psittaci, whereas no association with this pathogen was observed in any of the African samples (0/9), suggesting that other cofactors may determine the OAL occurrence in those areas. OAL cases are often characterized by down-regulation of p16/INK4a expression and promoter hypermethylation of the p16/INK4a gene. Our results showed a partial methylation of p16/INK4a promoter in C. psittaci-negative cases, whereas no hypermethylation of this gene was found in C. psittaci-positive cases, suggesting that mechanisms other than promoter hypermethylation lead to p16/INK4a silencing in C. psittaci-positive cases. We may conclude that the role of epidemiologic, environmental and genetic factors, must be considered in the aetiology of this disease.


Asunto(s)
Chlamydophila psittaci/genética , Chlamydophila psittaci/aislamiento & purificación , Infecciones Bacterianas del Ojo/microbiología , Neoplasias del Ojo/microbiología , Linfoma de Células B de la Zona Marginal/microbiología , Psitacosis/microbiología , Adulto , Anciano , Anciano de 80 o más Años , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , ADN Bacteriano/análisis , Regulación hacia Abajo , Ensayo de Cambio de Movilidad Electroforética , Femenino , Humanos , Inmunofenotipificación , Hibridación Fluorescente in Situ , Italia , Kenia , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Regiones Promotoras Genéticas
18.
Front Cell Dev Biol ; 8: 193, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32274384

RESUMEN

p66SHC is a pro-oxidant member of the SHC family of protein adaptors that acts as a negative regulator of cell survival. In lymphocytes p66SHC exploits both its adaptor and its reactive oxygen species (ROS)-elevating function to antagonize mitogenic and survival signaling and promote apoptosis. As a result, p66SHC deficiency leads to the abnormal expansion of peripheral T and B cells and lupus-like autoimmunity. Additionally, a defect in p66SHC expression is a hallmark of B cell chronic lymphocytic leukemia, where it contributes to the accumulation of long-lived neoplastic cells. We have recently provided evidence that p66SHC exerts a further layer of control on B cell homeostasis by acting as a new mitochondrial LC3-II receptor to promote the autophagic demise of dysfunctional mitochondria. Here we discuss this finding in the context of the autophagic control of B cell homeostasis, development, and differentiation in health and disease.

19.
Cell Death Differ ; 27(1): 310-328, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31142807

RESUMEN

The assembly and function of the primary cilium depends on multimolecular intraflagellar transport (IFT) complexes that shuttle their cargo along the axonemal microtubules through their interaction with molecular motors. The IFT system has been moreover recently implicated in a reciprocal interplay between autophagy and ciliogenesis. We have previously reported that IFT20 and other components of the IFT complexes participate in the assembly of the immune synapse in the non-ciliated T cell, suggesting that other cellular processes regulated by the IFT system in ciliated cells, including autophagy, may be shared by cells lacking a cilium. Starting from the observation of a defect in autophagic clearance and an accumulation of lipid droplets in IFT20-deficient T cells, we show that IFT20 is required for lysosome biogenesis and function by controlling the lysosomal targeting of acid hydrolases. This function involves its ability to regulate the retrograde traffic of the cation-independent mannose-6-phosphate receptor (CI-MPR) to the trans-Golgi network, which is achieved by coupling recycling CI-MPRs to the microtubule motor dynein. Consistent with the lysosomal defect, an upregulation of the TFEB-dependent expression of the lysosomal gene network can be observed in IFT20-deficient cells, which is associated with defective tonic T-cell antigen receptor signaling and mTOR activity. We additionally show that the lysosome-related function of IFT20 extends to non-ciliated cells other than T cells, as well as to ciliated cells. Our findings provide the first evidence that a component of the IFT system that controls ciliogenesis is implicated in the biogenesis of lysosomes.


Asunto(s)
Proteínas Portadoras/fisiología , Lisosomas/enzimología , Péptido Hidrolasas/metabolismo , Autofagia , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Línea Celular , Cilios , Dineínas/metabolismo , Humanos , Células Jurkat , Lisosomas/metabolismo , Lisosomas/ultraestructura , Biogénesis de Organelos , Transporte de Proteínas , Receptor IGF Tipo 2/metabolismo , Linfocitos T/metabolismo , Red trans-Golgi/metabolismo
20.
Front Cell Dev Biol ; 7: 110, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31334230

RESUMEN

Ligation of the T-cell antigen receptor (TCR) by cognate peptide bound to the Major Histocompatibility Complex on the surface of an antigen-presenting cell (APC) leads to the spatial reorganization of the TCR and accessory receptors to form a specialized area of intimate contact between T cell and APC, known as the immunological synapse (IS), where signals are deciphered, coordinated, and integrated to promote T cell activation. With the discovery that an endosomal TCR pool contributes to IS assembly and function by undergoing polarized recycling to the IS, recent years have witnessed a shift from a plasma membrane-centric view of the IS to the vesicular trafficking events that occur at this location following the TCR-dependent translocation of the centrosome toward the synaptic membrane. Here we will summarize our current understanding of the trafficking pathways that are responsible for the steady delivery of endosomal TCRs, kinases, and adapters to the IS to sustain signaling, as well as of the endocytic pathways responsible for signal termination. We will also discuss recent evidence highlighting a role for endosomes in sustaining TCR signaling after its internalization at the IS and identifying the IS as a site of formation and release of extracellular vesicles that allow for transcellular communication with the APC.

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