MYC and HIF in shaping immune response and immune metabolism

Gnanaprakasam, JN Rashida; Sherman, John; Wang, Ruoning

doi:10.1016/j.cytogfr.2017.03.004

Cited by 71 publications

(46 citation statements)

References 116 publications

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“…The role of MYC in growth of hepatocytes and HCC development is well known. 70 Recently, YY1 has been reported to induce MYC expression, which in turn leads to activation of the solute carrier family 2 (facilitated glucose transporter), member 1 (SLC2A1), the expression level of which positively correlates with the rate of cellular glucose metabolism. 69,71 Thus, it was theorized that YY1 can contribute to aberrant glucose uptake and lactate production at the advanced stage of tumorigenesis 69 (►Fig.…”

Section: Yy1 and Glycometabolism Reprogrammingmentioning

confidence: 99%

Multifunctional YY1 in Liver Diseases

Zhang

Yang

et al. 2017

Semin Liver Dis

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The transcription factor Yin Yang 1 (YY1) is a multifunctional protein that can activate or repress gene expression, depending on the cellular context. While YY1 is ubiquitously expressed and highly conserved between species, its role varies among the diverse cell types and includes proliferation, differentiation, and apoptosis. Upregulated YY1 expression is found in pathogenic conditions, such as human hepatocellular carcinoma and hepatitis B virus infection, and its roles in the molecular pathogenic mechanisms in liver (i.e., fibrosis, carcinogenesis, viral-induced injury) are currently being elucidated. The most recent studies have revealed that YY1 is deeply involved in such dysregulated cellular metabolisms as glycometabolism, lipid metabolism, and bile acid metabolism, which are all involved in various diseases. In this review, we will summarize the current knowledge on YY1 in liver diseases, providing a focused discussion on the characterized and probable underlying mechanisms, as well as a reasoned evaluation of the potential for YY1-mediated pathology as drug targets in liver disease therapies.

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Section: Yy1 and Glycometabolism Reprogrammingmentioning

confidence: 99%

Multifunctional YY1 in Liver Diseases

Zhang

Yang

et al. 2017

Semin Liver Dis

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“…Cell metabolism is now appreciated as a key regulator of T cell differentiation, modulating effector and memory functions (16). The transcriptional control of glycolysis in T cells mainly relies on the expression of hypoxia-inducible factor 1 (HIF-1) and the proto-oncogene MYC (17). Accumulation of HIF-1a in normoxic conditions has been observed in several cell types upon LPS stimulation (14,18,19).…”

mentioning

confidence: 99%

Toll-like Receptor 4–Induced Glycolytic Burst in Human Monocyte-Derived Dendritic Cells Results from p38-Dependent Stabilization of HIF-1α and Increased Hexokinase II Expression

Perrin-Cocon

Aublin-Gex

Diaz

et al. 2018

The Journal of Immunology

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Cell metabolism now appears as an essential regulator of immune cells activation. In particular, TLR stimulation triggers metabolic reprogramming of dendritic cells (DCs) with an increased glycolytic flux, whereas inhibition of glycolysis alters their functional activation. The molecular mechanisms involved in the control of glycolysis upon TLR stimulation are poorly understood for human DCs. TLR4 activation of human monocyte-derived DCs (MoDCs) stimulated glycolysis with an increased glucose consumption and lactate production. Global hexokinase (HK) activity, controlling the initial rate-limiting step of glycolysis, was also increased. TLR4-induced glycolytic burst correlated with a differential modulation of HK isoenzymes. LPS strongly enhanced the expression of HK2, whereas HK3 was reduced, HK1 remained unchanged, and HK4 was not expressed. Expression of the other rate-limiting glycolytic enzymes was not significantly increased. Exploring the signaling pathways involved in LPS-induced glycolysis with various specific inhibitors, we observed that only the inhibitors of p38-MAPK (SB203580) and of HIF-1α DNA binding (echinomycin) reduced both the glycolytic activity and production of cytokines triggered by TLR4 stimulation. In addition, LPS-induced HK2 expression required p38-MAPK-dependent HIF-1α accumulation and transcriptional activity. TLR1/2 and TLR2/6 stimulation increased glucose consumption by MoDCs through alternate mechanisms that are independent of p38-MAPK activation. TBK1 contributed to glycolysis regulation when DCs were stimulated via TLR2/6. Therefore, our results indicate that TLR4-dependent upregulation of glycolysis in human MoDCs involves a p38-MAPK-dependent HIF-1α accumulation, leading to an increased HK activity supported by enhanced HK2 expression.

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“…7I). Among the downstream target genes, Myc is involved in T-cell differentiation and control of glycolysis [40]. Thus, we further validated the regulation of Myc by let-7i, using western blotting.…”

Section: Let-7i Regulated the Metabolic And Functional Alterations Inmentioning

confidence: 84%

Metabolic reprogramming orchestrates CD4+ T-cell immunological status and restores cardiac dysfunction in autoimmune induced-dilated cardiomyopathy mice

Park

Chen

et al. 2019

Journal of Molecular and Cellular Cardiology

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Cellular autoimmune responses, especially those mediated by T-cells, play vital roles in the immunopathogenesis of dilated cardiomyopathy (DCM). Metabolic reprogramming directly controls T-cell function, imprinting distinct functional fates. However, its contribution to T-cell dysfunction and the immunopathogenesis of DCM is unknown. Here, we found that in DCM patients, CD4 + T-cells exhibited immune dysfunction and glycolytic metabolic reprogramming based on extracellular acidification and oxygen consumption rates. Similar results were observed in splenic and cardiac CD4 + T-cells from autoimmune-induced DCM mice. In vitro, the glycolysis inhibitor 2-deoxy-D-glucose (2-DG) reversed T-cell dysfunction; thus, heightened metabolic activity directly controls CD4 + T-cell immunological status. Adoptive transfer of CD4 + T-cells from DCM mice to normal recipients induced cardiac remodeling and cardiac T-cell dysfunction. Strikingly, these effects were abolished by preconditioning cells with 2-DG, indicating that CD4 + T-cell dysfunction partially induced by metabolic reprogramming contributes to cardiac remodeling. Moreover, the microRNA let-7i modulated the metabolism and function of T-cells from DCM mice by directly targeting Myc. Collectively, our results show that metabolic reprogramming occurs in T-cells of autoimmune-induced DCM mice and patients. Further, our findings highlight that glycolytic metabolism is a critical contributor to T-cell dysfunction and DCM immunopathogenesis. Our data position the modulation of the metabolism as a central integrator for T-cell function, representing a promising strategy against autoimmune-mediated DCM progression.

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MYC and HIF in shaping immune response and immune metabolism

Cited by 71 publications

References 116 publications

Multifunctional YY1 in Liver Diseases

Multifunctional YY1 in Liver Diseases

Toll-like Receptor 4–Induced Glycolytic Burst in Human Monocyte-Derived Dendritic Cells Results from p38-Dependent Stabilization of HIF-1α and Increased Hexokinase II Expression

Metabolic reprogramming orchestrates CD4+ T-cell immunological status and restores cardiac dysfunction in autoimmune induced-dilated cardiomyopathy mice

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