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1.
Science ; : eadk4898, 2024 05 23.
Artículo en Inglés | MEDLINE | ID: mdl-38781354

RESUMEN

Following infection of B cells, Epstein Barr virus (EBV) engages host pathways that mediate cell proliferation and transformation, contributing to the propensity of the virus to drive immune dysregulation and lymphomagenesis. We found that the EBV protein EBNA2 initiates NAD de novo biosynthesis by driving expression of the metabolic enzyme IDO1 in infected B cells. Virus-enforced NAD production sustained mitochondrial complex I activity, to match ATP-production with bioenergetic requirements of proliferation and transformation. In transplant patients, IDO1 expression in EBV-infected B cells, and a serum signature of increased IDO1 activity, preceded development of lymphoma. In humanized mice infected with EBV, IDO1 inhibition reduced both viremia and lymphomagenesis. Virus-orchestrated NAD biosynthesis is, thus, a druggable metabolic vulnerability of EBV-driven B cell transformation-opening therapeutic possibilities for EBV-related diseases.

2.
Int J Mol Sci ; 21(14)2020 Jul 11.
Artículo en Inglés | MEDLINE | ID: mdl-32664542

RESUMEN

Stemness and reprogramming involve transcriptional master regulators that suppress cell differentiation while promoting self-renewal. A distinguished example thereof is SOX2, a high mobility group (HMG)-box transcription factor (TF), whose subcellular localization and turnover regulation in embryonic, induced-pluripotent, and cancer stem cells (ESCs, iPSCs, and CSCs, respectively) is mediated by the PI3K/AKT/SOX2 axis, a stem cell-specific branch of the PI3K/AKT signaling pathway. Further effector functions associated with PI3K/AKT induction include cell cycle progression, cellular (mass) growth, and the suppression of apoptosis. Apoptosis, however, is a central element of DNA damage response (DDR), where it provides a default mechanism for cell clearance when DNA integrity cannot be maintained. A key player in DDR is tumor suppressor p53, which accumulates upon DNA-damage and is counter-balanced by PI3K/AKT enforced turnover. Accordingly, stemness sustaining SOX2 expression and p53-dependent DDR mechanisms show molecular-functional overlap in PI3K/AKT signaling. This constellation proves challenging for stem cells whose genomic integrity is a functional imperative for normative ontogenesis. Unresolved mutations in stem and early progenitor cells may in fact provoke transformation and cancer development. Such mechanisms are also particularly relevant for iPSCs, where genetic changes imposed through somatic cell reprogramming may promote DNA damage. The current review aims to summarize the latest advances in the understanding of PI3K/AKT/SOX2-driven stemness and its intertwined relations to p53-signaling in DDR under conditions of pluripotency, reprogramming, and transformation.


Asunto(s)
Autorrenovación de las Células/fisiología , Transformación Celular Neoplásica/genética , Reprogramación Celular/fisiología , Regulación Neoplásica de la Expresión Génica , Neoplasias/genética , Fosfatidilinositol 3-Quinasas/fisiología , Proteínas Proto-Oncogénicas c-akt/fisiología , Factores de Transcripción SOXB1/genética , Transducción de Señal/fisiología , Proteína p53 Supresora de Tumor/genética , Apoptosis , Ciclo Celular/fisiología , Daño del ADN , Reparación del ADN , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Neoplasias/enzimología , Células Madre Neoplásicas/metabolismo , Células Madre Pluripotentes/metabolismo , Factores de Transcripción SOXB1/biosíntesis , Proteína p53 Supresora de Tumor/biosíntesis
3.
Nat Immunol ; 20(10): 1311-1321, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31527833

RESUMEN

Whether screening the metabolic activity of immune cells facilitates discovery of molecular pathology remains unknown. Here we prospectively screened the extracellular acidification rate as a measure of glycolysis and the oxygen consumption rate as a measure of mitochondrial respiration in B cells from patients with primary antibody deficiency. The highest oxygen consumption rate values were detected in three study participants with persistent polyclonal B cell lymphocytosis (PPBL). Exome sequencing identified germline mutations in SDHA, which encodes succinate dehydrogenase subunit A, in all three patients with PPBL. SDHA gain-of-function led to an accumulation of fumarate in PPBL B cells, which engaged the KEAP1-Nrf2 system to drive the transcription of genes encoding inflammatory cytokines. In a single patient trial, blocking the activity of the cytokine interleukin-6 in vivo prevented systemic inflammation and ameliorated clinical disease. Overall, our study has identified pathological mitochondrial retrograde signaling as a disease modifier in primary antibody deficiency.


Asunto(s)
Linfocitos B/inmunología , Complejo II de Transporte de Electrones/genética , Inflamación/metabolismo , Linfocitosis/inmunología , Mitocondrias/metabolismo , Mutación/genética , Antiinflamatorios/farmacología , Respiración de la Célula , Células Cultivadas , Fumaratos/metabolismo , Glucólisis , Humanos , Inflamación/genética , Interleucina-6/antagonistas & inhibidores , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Consumo de Oxígeno , Estudios Prospectivos , Transducción de Señal , Secuenciación del Exoma
4.
Eur J Immunol ; 48(10): 1632-1643, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-30028501

RESUMEN

The role of mitochondrial biogenesis during naïve to effector differentiation of CD8+ T cells remains ill explored. In this study, we describe a critical role for early mitochondrial biogenesis in supporting cytokine production of nascent activated human naïve CD8+ T cells. Specifically, we found that prior to the first round of cell division activated naïve CD8+ T cells rapidly increase mitochondrial mass, mitochondrial respiration, and mitochondrial reactive oxygen species (mROS) generation, which were all inter-linked and important for CD8+ T cell effector maturation. Inhibition of early mitochondrial biogenesis diminished mROS dependent IL-2 production - as well as subsequent IL-2 dependent TNF, IFN-γ, perforin, and granzyme B production. Together, these findings point to the importance of mitochondrial biogenesis during early effector maturation of CD8+ T cells.


Asunto(s)
Linfocitos T CD8-positivos/citología , Diferenciación Celular/inmunología , Mitocondrias/fisiología , Biogénesis de Organelos , Linfocitos T CD8-positivos/inmunología , Citocinas/inmunología , Humanos , Interleucina-2/inmunología , Activación de Linfocitos , Especies Reactivas de Oxígeno/metabolismo
5.
Immunity ; 48(3): 542-555.e6, 2018 03 20.
Artículo en Inglés | MEDLINE | ID: mdl-29523440

RESUMEN

Glycolysis is linked to the rapid response of memory CD8+ T cells, but the molecular and subcellular structural elements enabling enhanced glucose metabolism in nascent activated memory CD8+ T cells are unknown. We found that rapid activation of protein kinase B (PKB or AKT) by mammalian target of rapamycin complex 2 (mTORC2) led to inhibition of glycogen synthase kinase 3ß (GSK3ß) at mitochondria-endoplasmic reticulum (ER) junctions. This enabled recruitment of hexokinase I (HK-I) to the voltage-dependent anion channel (VDAC) on mitochondria. Binding of HK-I to VDAC promoted respiration by facilitating metabolite flux into mitochondria. Glucose tracing pinpointed pyruvate oxidation in mitochondria, which was the metabolic requirement for rapid generation of interferon-γ (IFN-γ) in memory T cells. Subcellular organization of mTORC2-AKT-GSK3ß at mitochondria-ER contact sites, promoting HK-I recruitment to VDAC, thus underpins the metabolic reprogramming needed for memory CD8+ T cells to rapidly acquire effector function.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Retículo Endoplásmico/metabolismo , Metabolismo Energético , Memoria Inmunológica , Mitocondrias/metabolismo , Transducción de Señal , Respiración de la Célula , Retículo Endoplásmico/ultraestructura , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Glucólisis , Membranas Intracelulares/metabolismo , Activación de Linfocitos , Diana Mecanicista del Complejo 2 de la Rapamicina/metabolismo , Mitocondrias/ultraestructura , Modelos Biológicos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteína Asociada al mTOR Insensible a la Rapamicina/deficiencia
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