bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2020‒11‒29
23 papers selected by
Pierpaolo Ginefra
Ludwig Institute for Cancer Research


  1. EMBO Rep. 2020 Nov 27. e50500
    Cirotti C, Rizza S, Giglio P, Poerio N, Allega MF, Claps G, Pecorari C, Lee JH, Benassi B, Barilà D, Robert C, Stamler JS, Cecconi F, Fraziano M, Paull TT, Filomeni G.
      The denitrosylase S-nitrosoglutathione reductase (GSNOR) has been suggested to sustain mitochondrial removal by autophagy (mitophagy), functionally linking S-nitrosylation to cell senescence and aging. In this study, we provide evidence that GSNOR is induced at the translational level in response to hydrogen peroxide and mitochondrial ROS. The use of selective pharmacological inhibitors and siRNA demonstrates that GSNOR induction is an event downstream of the redox-mediated activation of ATM, which in turn phosphorylates and activates CHK2 and p53 as intermediate players of this signaling cascade. The modulation of ATM/GSNOR axis, or the expression of a redox-insensitive ATM mutant influences cell sensitivity to nitrosative and oxidative stress, impairs mitophagy and affects cell survival. Remarkably, this interplay modulates T-cell activation, supporting the conclusion that GSNOR is a key molecular effector of the antioxidant function of ATM and providing new clues to comprehend the pleiotropic effects of ATM in the context of immune function.
    Keywords:  ATM; GSNOR; ROS; T cell; mitophagy
    DOI:  https://doi.org/10.15252/embr.202050500
  2. Antioxidants (Basel). 2020 Nov 19. pii: E1152. [Epub ahead of print]9(11):
    Meryk A, Grasse M, Balasco L, Kapferer W, Grubeck-Loebenstein B, Pangrazzi L.
      Aging is characterized by reduced immune responses, a process known as immunosenescence. Shortly after their generation, antigen-experienced adaptive immune cells, such as CD8+ and CD4+ T cells, migrate into the bone marrow (BM), in which they can be maintained for long periods of time within survival niches. Interestingly, we recently observed how oxidative stress may negatively support the maintenance of immunological memory in the BM in old age. To assess whether the generation and maintenance of immunological memory could be improved by scavenging oxygen radicals, we vaccinated 18-months (old) and 3-weeks (young) mice with alum-OVA, in the presence/absence of antioxidants vitamin C (Vc) and/or N-acetylcysteine (NAC). To monitor the phenotype of the immune cell population, blood was withdrawn at several time-points, and BM and spleen were harvested 91 days after the first alum-OVA dose. Only in old mice, memory T cell commitment was boosted with some antioxidant treatments. In addition, oxidative stress and the expression of pro-inflammatory molecules decreased in old mice. Finally, changes in the phenotype of dendritic cells, important regulators of T cell activation, were additionally observed. Taken together, our data show that the generation and maintenance of memory T cells in old age may be improved by targeting oxidative stress.
    Keywords:  NAC; T cells; aging; antioxidants; immunosenescence; vaccination; vitamin C
    DOI:  https://doi.org/10.3390/antiox9111152
  3. Trends Immunol. 2020 Nov 24. pii: S1471-4906(20)30257-X. [Epub ahead of print]
    Blanchett S, Boal-Carvalho I, Layzell S, Seddon B.
      NF-κB signaling is required at multiple stages of T cell development and function. The NF-κB pathway integrates signals from many receptors and involves diverse adapters and kinases. Recent advances demonstrate that kinases controlling NF-κB activation, such as the IKK complex, serve dual independent functions because they also control cell death checkpoints. Survival functions previously attributed to NF-κB are in fact mediated by these upstream kinases by novel mechanisms. This new understanding has led to a refined view of how NF-κB and cell death signaling are interlinked and how they regulate cell fate. We discuss how NF-κB activation and control of cell death signaling by common upstream triggers cooperate to regulate different aspects of T cell development and function.
    Keywords:  T cells; apoptosis; necroptosis; nuclear factor κB
    DOI:  https://doi.org/10.1016/j.it.2020.10.013
  4. Cytokine. 2020 Nov 19. pii: S1043-4666(20)30383-5. [Epub ahead of print] 155367
    Özgül Özdemir RB, Özdemir AT, Kırmaz C, Eker Sarıboyacı A, Karaöz E, Erman G, Vatansever HS, Mete Gökmen N.
      Mesenchymal stem cells (MSCs) are powerful immunomodulatory cells. The effects of the aging on these abilities of MSCs have not been adequately clarified. In this study, alterations in immunomodulatory abilities of MSCs caused by aging were investigated. For this, dental pulp (DP) MSCs and peripheral blood mononuclear cells (PBMCs) of elderly and young donors were co-cultured age-matched and cross. We detected that the effects of DP-MSCs on Th1 and Th2 cells and their specific cytokines IFN-γ and IL-4 are not affected by aging. However, we observed that young and elderly DP-MSCs have different effects on Th17 and Treg cells. Th17 frequencies of young and elderly PBMCs were significantly increased only by young DP-MSCs, in contrast, Treg frequencies were significantly increased by elderly DP-MSCs. IL-6, IL-17a and HGF levels of both young and elderly PBMCs showed a significant increase only by young DP-MSCs, but TGF-β levels were significantly increased only by elderly DP-MSCs. The oral cavity is home to a rich microflora. The interactions of dental tissues with this microflora can lead them to acquire different epigenetic modifications. Aging can affect the microflora composition of the oral cavity and change this process in different directions. According to our findings, DP-MSCs are effective cells in the regulation of CD4+ T cells, and their effects on Th1 and Th2 cells were not affected by aging. However, pleiotropic molecules IL-6 and HGF expressions, which are important in dental and bone tissue regeneration, decreased significantly in elderly DP-MSCs. This situation may have indirectly made a difference in the modulation effects of young and elderly DP-MSCs on the Th17 and Treg cells.
    Keywords:  Aging; CD4 T cell; Dental pulp; Immunomodulation; Mesenchymal stem cell
    DOI:  https://doi.org/10.1016/j.cyto.2020.155367
  5. Elife. 2020 Nov 23. pii: e56612. [Epub ahead of print]9
    Saragovi A, Abramovich I, Omar I, Arbib E, Toker O, Gottlieb E, Berger M.
      Systemic oxygen restriction (SOR) is prevalent in numerous clinical conditions, including chronic obstructive pulmonary disease (COPD),and is associated with increased susceptibility to viral infections. However, the influence of SOR on T cell immunity remains uncharacterized. Here we show the detrimental effect of hypoxia on mitochondrial-biogenesis in activated mouse CD8+ T cells. We find that low oxygen level diminishes CD8+ T cell viral response in vivo. We reveal that respiratory restriction inhibits ATP-dependent matrix processes that are critical for mitochondrial biogenesis. This respiratory restriction-mediated effect could be rescued by TCA cycle re-stimulation, which yielded increased mitochondrial matrix-localized ATP via substrate-level phosphorylation. Finally, we demonstrate that the hypoxia-arrested CD8+ viral response could be rescued in vivo through brief exposure to atmospheric oxygen pressure. Overall, these findings elucidate the detrimental effect of hypoxia on mitochondrial-biogenesis in activated CD8+ T cells, and suggest a new approach for reducing viral infections in COPD.
    Keywords:  immunology; inflammation; mouse
    DOI:  https://doi.org/10.7554/eLife.56612
  6. Immunometabolism. 2020 ;pii: e200005. [Epub ahead of print]2(1):
    Taylor HE, Palmer CS.
      HIV infection is characterized by elevated glycolytic metabolism in CD4 T cells. In their recent study, Valle-Casuso et al. demonstrated that both increased glucose utilization and glutamine metabolism are essential for HIV infectivity and replication in CD4 T cells. Here, we discuss the broader implications of immunometabolism in studies of HIV persistence and their potential to inform new treatment and curative strategies.
    Keywords:  CD4 T cells; HIV; HIV cure; immune activation; immunometabolism; metabolism
    DOI:  https://doi.org/10.20900/immunometab20200005
  7. Genes Immun. 2020 Nov 23.
    Glinos DA, Soskic B, Williams C, Kennedy A, Jostins L, Sansom DM, Trynka G.
      T-cell activation is a critical driver of immune responses. The CD28 costimulation is an essential regulator of CD4 T-cell responses, however, its relative importance in naive and memory T cells is not fully understood. Using different model systems, we observe that human memory T cells are more sensitive to CD28 costimulation than naive T cells. To deconvolute how the T-cell receptor (TCR) and CD28 orchestrate activation of human T cells, we stimulate cells using varying intensities of TCR and CD28 and profiled gene expression. We show that genes involved in cell cycle progression and division are CD28-driven in memory cells, but under TCR control in naive cells. We further demonstrate that T-helper differentiation and cytokine expression are controlled by CD28. Using chromatin accessibility profiling, we observe that AP1 transcriptional regulation is enriched when both TCR and CD28 are engaged, whereas open chromatin near CD28-sensitive genes is enriched for NF-kB motifs. Lastly, we show that CD28-sensitive genes are enriched in GWAS regions associated with immune diseases, implicating a role for CD28 in disease development. Our study provides important insights into the differential role of costimulation in naive and memory T-cell responses and disease susceptibility.
    DOI:  https://doi.org/10.1038/s41435-020-00118-0
  8. Immunity. 2020 Nov 10. pii: S1074-7613(20)30461-1. [Epub ahead of print]
    Bonavita E, Bromley CP, Jonsson G, Pelly VS, Sahoo S, Walwyn-Brown K, Mensurado S, Moeini A, Flanagan E, Bell CR, Chiang SC, Chikkanna-Gowda CP, Rogers N, Silva-Santos B, Jaillon S, Mantovani A, Reis E Sousa C, Guerra N, Davis DM, Zelenay S.
      Inflammation can support or restrain cancer progression and the response to therapy. Here, we searched for primary regulators of cancer-inhibitory inflammation through deep profiling of inflammatory tumor microenvironments (TMEs) linked to immune-dependent control in mice. We found that early intratumoral accumulation of interferon gamma (IFN-γ)-producing natural killer (NK) cells induced a profound remodeling of the TME and unleashed cytotoxic T cell (CTL)-mediated tumor eradication. Mechanistically, tumor-derived prostaglandin E2 (PGE2) acted selectively on EP2 and EP4 receptors on NK cells, hampered the TME switch, and enabled immune evasion. Analysis of patient datasets across human cancers revealed distinct inflammatory TME phenotypes resembling those associated with cancer immune control versus escape in mice. This allowed us to generate a gene-expression signature that integrated opposing inflammatory factors and predicted patient survival and response to immune checkpoint blockade. Our findings identify features of the tumor inflammatory milieu associated with immune control of cancer and establish a strategy to predict immunotherapy outcomes.
    Keywords:  NK cells; cancer-related inflammation; cytotoxic T cells; immune evasion; immunotherapy; interferon-gamma; prostaglandin E2; tumor immunity; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.immuni.2020.10.020
  9. J Exp Med. 2021 Mar 01. pii: e20192283. [Epub ahead of print]218(3):
    Kuribayashi W, Oshima M, Itokawa N, Koide S, Nakajima-Takagi Y, Yamashita M, Yamazaki S, Rahmutulla B, Miura F, Ito T, Kaneda A, Iwama A.
      Hematopoietic stem cells (HSCs) exhibit functional alterations, such as reduced regenerative capacity and myeloid-biased differentiation, with age. The HSC niche, which is essential for the maintenance of HSCs, also undergoes marked changes with aging. However, it has been technically challenging to directly evaluate the contribution of niche aging to age-associated HSC alterations without niche-damaging myeloablation in HSC transplantation assays. We herein transplanted an excess of aged HSCs into young mice without preconditioning. Although aged HSCs successfully engrafted in the intact young bone marrow niche, they poorly regenerated downstream progenitors and exhibited persistent myeloid-biased differentiation, resulting in no significant functional rejuvenation. Transcriptome and methylome analyses revealed that the young niche largely restored the transcriptional profile of aged HSCs, but not their DNA methylation profiles. Therefore, the restoration of the young niche is insufficient for rejuvenating HSC functions, highlighting a key role for age-associated cell-intrinsic defects in HSC aging.
    DOI:  https://doi.org/10.1084/jem.20192283
  10. Curr Opin Biotechnol. 2020 Nov 21. pii: S0958-1669(20)30156-7. [Epub ahead of print]70 29-35
    Goncalves MD, Maddocks OD.
      Cancer cells acquire a diverse range of metabolic adaptations that support their enhanced rates of growth and proliferation. While these adaptations help tune metabolism to support higher anabolic output and bolster antioxidant defenses, they can also decrease metabolic flexibility and increase dependence on nutrient uptake versus de novo synthesis. Diet is the major source of nutrients that ultimately support tumor growth, yet the potential impact of diet is currently underutilized during the treatment of cancer. Here, we review several forms of dietary augmentation therapy including those that alter the content of food, such as energy or macronutrient restriction, and those that alter the timing of food consumption, like intermittent fasting regimens. We discuss how these dietary strategies can be combined with pharmacologic therapies to exaggerate the metabolic liabilities of different cancer types.
    DOI:  https://doi.org/10.1016/j.copbio.2020.10.007
  11. Cold Spring Harb Perspect Biol. 2020 Nov 23. pii: a037788. [Epub ahead of print]
    Jameson SC.
      With ever-improving methods of cell characterization, the field of immunology has enjoyed unprecedented opportunities to resolve distinctions between lymphocyte populations. However, this has led to a proliferation of "subset" designations that threatens to complicate and confuse clear identification of populations that share critical functional traits. This article discusses some of the challenges associated with a uniform approach to assigning subset designations to memory T-cell populations.
    DOI:  https://doi.org/10.1101/cshperspect.a037788
  12. Front Cell Dev Biol. 2020 ;8 590192
    Cozzo AJ, Coleman MF, Pearce JB, Pfeil AJ, Etigunta SK, Hursting SD.
      Cancer cells experience unique and dynamic shifts in their metabolic function in order to survive, proliferate, and evade growth inhibition in the resource-scarce tumor microenvironment. Therefore, identification of pharmacological agents with potential to reprogram cancer cell metabolism may improve clinical outcomes in cancer therapy. Cancer cells also often exhibit an increased dependence on the process known as autophagy, both for baseline survival and as a response to stressors such as chemotherapy or a decline in nutrient availability. There is evidence to suggest that this increased dependence on autophagy in cancer cells may be exploitable clinically by combining autophagy modulators with existing chemotherapies. In light of the increased metabolic rate in cancer cells, interest is growing in approaches aimed at "starving" cancer through dietary and pharmacologic interventions that reduce availability of nutrients and pro-growth hormonal signals known to promote cancer progression. Several dietary approaches, including chronic calorie restriction and multiple forms of fasting, have been investigated for their potential anti-cancer benefits, yielding promising results in animal models. Induction of autophagy in response to dietary energy restriction may underlie some of the observed benefit. However, while interventions based on dietary energy restriction have demonstrated safety in clinical trials, uncertainty remains regarding translation to humans as well as feasibility of achieving compliance due to the potential discomfort and weight loss that accompanies dietary restriction. Further induction of autophagy through dietary or pharmacologic metabolic reprogramming interventions may enhance the efficacy of autophagy inhibition in the context of adjuvant or neo-adjuvant chemotherapy. Nonetheless, it remains unclear whether therapeutic agents aimed at autophagy induction, autophagy inhibition, or both are a viable therapeutic strategy for improving cancer outcomes. This review discusses the literature available for the therapeutic potential of these approaches.
    Keywords:  autophagy; caloric restriction; cancer; cancer therapy; fasting; metabolism
    DOI:  https://doi.org/10.3389/fcell.2020.590192
  13. Nat Commun. 2020 11 23. 11(1): 5927
    Gut P, Matilainen S, Meyer JG, Pällijeff P, Richard J, Carroll CJ, Euro L, Jackson CB, Isohanni P, Minassian BA, Alkhater RA, Østergaard E, Civiletto G, Parisi A, Thevenet J, Rardin MJ, He W, Nishida Y, Newman JC, Liu X, Christen S, Moco S, Locasale JW, Schilling B, Suomalainen A, Verdin E.
      Mitochondrial acyl-coenzyme A species are emerging as important sources of protein modification and damage. Succinyl-CoA ligase (SCL) deficiency causes a mitochondrial encephalomyopathy of unknown pathomechanism. Here, we show that succinyl-CoA accumulates in cells derived from patients with recessive mutations in the tricarboxylic acid cycle (TCA) gene succinyl-CoA ligase subunit-β (SUCLA2), causing global protein hyper-succinylation. Using mass spectrometry, we quantify nearly 1,000 protein succinylation sites on 366 proteins from patient-derived fibroblasts and myotubes. Interestingly, hyper-succinylated proteins are distributed across cellular compartments, and many are known targets of the (NAD+)-dependent desuccinylase SIRT5. To test the contribution of hyper-succinylation to disease progression, we develop a zebrafish model of the SCL deficiency and find that SIRT5 gain-of-function reduces global protein succinylation and improves survival. Thus, increased succinyl-CoA levels contribute to the pathology of SCL deficiency through post-translational modifications.
    DOI:  https://doi.org/10.1038/s41467-020-19743-4
  14. Nat Immunol. 2020 Nov 23.
    Verma V, Jafarzadeh N, Boi S, Kundu S, Jiang Z, Fan Y, Lopez J, Nandre R, Zeng P, Alolaqi F, Ahmad S, Gaur P, Barry ST, Valge-Archer VE, Smith PD, Banchereau J, Mkrtichyan M, Youngblood B, Rodriguez PC, Gupta S, Khleif SN.
      Regenerative stem cell-like memory (TSCM) CD8+ T cells persist longer and produce stronger effector functions. We found that MEK1/2 inhibition (MEKi) induces TSCM that have naive phenotype with self-renewability, enhanced multipotency and proliferative capacity. This is achieved by delaying cell division and enhancing mitochondrial biogenesis and fatty acid oxidation, without affecting T cell receptor-mediated activation. DNA methylation profiling revealed that MEKi-induced TSCM cells exhibited plasticity and loci-specific profiles similar to bona fide TSCM isolated from healthy donors, with intermediate characteristics compared to naive and central memory T cells. Ex vivo, antigenic rechallenge of MEKi-treated CD8+ T cells showed stronger recall responses. This strategy generated T cells with higher efficacy for adoptive cell therapy. Moreover, MEKi treatment of tumor-bearing mice also showed strong immune-mediated antitumor effects. In conclusion, we show that MEKi leads to CD8+ T cell reprogramming into TSCM that acts as a reservoir for effector T cells with potent therapeutic characteristics.
    DOI:  https://doi.org/10.1038/s41590-020-00818-9
  15. Immunity. 2020 Nov 17. pii: S1074-7613(20)30466-0. [Epub ahead of print]
    Almeida L, Dhillon-LaBrooy A, Castro CN, Adossa N, Carriche GM, Guderian M, Lippens S, Dennerlein S, Hesse C, Lambrecht BN, Berod L, Schauser L, Blazar BR, Kalesse M, Müller R, Moita LF, Sparwasser T.
      While antibiotics are intended to specifically target bacteria, most are known to affect host cell physiology. In addition, some antibiotic classes are reported as immunosuppressive for reasons that remain unclear. Here, we show that Linezolid, a ribosomal-targeting antibiotic (RAbo), effectively blocked the course of a T cell-mediated autoimmune disease. Linezolid and other RAbos were strong inhibitors of T helper-17 cell effector function in vitro, showing that this effect was independent of their antibiotic activity. Perturbing mitochondrial translation in differentiating T cells, either with RAbos or through the inhibition of mitochondrial elongation factor G1 (mEF-G1) progressively compromised the integrity of the electron transport chain. Ultimately, this led to deficient oxidative phosphorylation, diminishing nicotinamide adenine dinucleotide concentrations and impairing cytokine production in differentiating T cells. In accordance, mice lacking mEF-G1 in T cells were protected from experimental autoimmune encephalomyelitis, demonstrating that this pathway is crucial in maintaining T cell function and pathogenicity.
    Keywords:  Argyrin; Linezolid; NAD+; T cells; antibiotics; autoimmunity; elongation factor G1; mitochondrial translation; ribosome-targeting mitochondria
    DOI:  https://doi.org/10.1016/j.immuni.2020.11.001
  16. Br J Haematol. 2020 Nov 22.
    Wu L, Li X, Lin Q, Chowdhury F, Mazumder MH, Du W.
      The Fanconi anaemia protein FANCD2 suppresses PPARƔ to maintain haematopoietic stem cell's (HSC) function; however, the underlying mechanism is not known. Here we show that FANCD2 acts in concert with the Notch target HES1 to suppress inflammation-induced PPARƔ in HSC maintenance. Loss of HES1 exacerbates FANCD2-KO HSC defects. However, deletion of HES1 does not cause more severe inflammation-mediated HSC defects in FANCD2-KO mice, indicating that both FANCD2 and HES1 are required for limiting detrimental effects of inflammation on HSCs. Further analysis shows that both FANCD2 and HES1 are required for transcriptional repression of inflammation-activated PPARg promoter. Inflammation orchestrates an overlapping transcriptional programme in HSPCs deficient for FANCD2 and HES1, featuring upregulation of genes in fatty acid oxidation (FAO) and oxidative phosphorylation. Loss of FANCD2 or HES1 augments both basal and inflammation-primed FAO. Targeted inhibition of PPARƔ or the mitochondrial carnitine palmitoyltransferase-1 (CPT1) reduces FAO and ameliorates HSC defects in inflammation-primed HSPCs deleted for FANCD2 or HES1 or both. Finally, depletion of PPARg or CPT1 restores quiescence in these mutant HSCs under inflammatory stress. Our results suggest that this novel FANCD2/HES1/PPARƔ axis may constitute a key component of immunometabolic regulation, connecting inflammation, cellular metabolism and HSC function.
    Keywords:  PPARƔ; bone marrow transplant; fatty acid oxidation; haematopoietic stem and progenitor cells; inflammation; stem cell quiescence
    DOI:  https://doi.org/10.1111/bjh.17230
  17. Nat Commun. 2020 11 24. 11(1): 5959
    Li Y, Ding W, Li CY, Liu Y.
      The ability of organisms to sense nutrient availability and tailor their metabolic states to withstand nutrient deficiency is critical for survival. To identify previously unknown regulators that couple nutrient deficiency to body fat utilization, we performed a cherry-picked RNAi screen in C. elegans and found that the transcription factor HLH-11 regulates lipid metabolism in response to food availability. In well-fed worms, HLH-11 suppresses transcription of lipid catabolism genes. Upon fasting, the HLH-11 protein level is reduced through lysosome- and proteasome-mediated degradation, thus alleviating the inhibitory effect of HLH-11, activating the transcription of lipid catabolism genes, and utilizing fat. Additionally, lipid profiling revealed that reduction in the HLH-11 protein level remodels the lipid landscape in C. elegans. Moreover, TFAP4, the mammalian homolog of HLH-11, plays an evolutionarily conserved role in regulating lipid metabolism in response to starvation. Thus, TFAP4 may represent a potential therapeutic target for lipid storage disorders.
    DOI:  https://doi.org/10.1038/s41467-020-19754-1
  18. Cells. 2020 Nov 21. pii: E2519. [Epub ahead of print]9(11):
    Audano M, Pedretti S, Ligorio S, Crestani M, Caruso D, De Fabiani E, Mitro N.
      Mitochondria represent the energy hub of cells and their function is under the constant influence of their tethering with other subcellular organelles. Mitochondria interact with the endoplasmic reticulum, lysosomes, cytoskeleton, peroxisomes, and nucleus in several ways, ranging from signal transduction, vesicle transport, and membrane contact sites, to regulate energy metabolism, biosynthetic processes, apoptosis, and cell turnover. Tumorigenesis is often associated with mitochondrial dysfunction, which could likely be the result of an altered interaction with different cell organelles or structures. The purpose of the present review is to provide an updated overview of the links between inter-organellar communications and interactions and metabolism in cancer cells, with a focus on mitochondria. The very recent publication of several reviews on these aspects testifies the great interest in the area. Here, we aim at (1) summarizing recent evidence supporting that the metabolic rewiring and adaptation observed in tumors deeply affect organelle dynamics and cellular functions and vice versa; (2) discussing insights on the underlying mechanisms, when available; and (3) critically presenting the gaps in the field that need to be filled, for a comprehensive understanding of tumor cells' biology. Chemo-resistance and druggable vulnerabilities of cancer cells related to the aspects mentioned above is also outlined.
    Keywords:  cancer; metabolism; mitochondria; subcellular organelles
    DOI:  https://doi.org/10.3390/cells9112519
  19. Nat Metab. 2020 Nov 23.
    Raho S, Capobianco L, Malivindi R, Vozza A, Piazzolla C, De Leonardis F, Gorgoglione R, Scarcia P, Pezzuto F, Agrimi G, Barile SN, Pisano I, Reshkin SJ, Greco MR, Cardone RA, Rago V, Li Y, Marobbio CMT, Sommergruber W, Riley CL, Lasorsa FM, Mills E, Vegliante MC, De Benedetto GE, Fratantonio D, Palmieri L, Dolce V, Fiermonte G.
      The oncogenic KRAS mutation has a critical role in the initiation of human pancreatic ductal adenocarcinoma (PDAC) since it rewires glutamine metabolism to increase reduced nicotinamide adenine dinucleotide phosphate (NADPH) production, balancing cellular redox homeostasis with macromolecular synthesis1,2. Mitochondrial glutamine-derived aspartate must be transported into the cytosol to generate metabolic precursors for NADPH production2. The mitochondrial transporter responsible for this aspartate efflux has remained elusive. Here, we show that mitochondrial uncoupling protein 2 (UCP2) catalyses this transport and promotes tumour growth. UCP2-silenced KRASmut cell lines display decreased glutaminolysis, lower NADPH/NADP+ and glutathione/glutathione disulfide ratios and higher reactive oxygen species levels compared to wild-type counterparts. UCP2 silencing reduces glutaminolysis also in KRASWT PDAC cells but does not affect their redox homeostasis or proliferation rates. In vitro and in vivo, UCP2 silencing strongly suppresses KRASmut PDAC cell growth. Collectively, these results demonstrate that UCP2 plays a vital role in PDAC, since its aspartate transport activity connects the mitochondrial and cytosolic reactions necessary for KRASmut rewired glutamine metabolism2, and thus it should be considered a key metabolic target for the treatment of this refractory tumour.
    DOI:  https://doi.org/10.1038/s42255-020-00315-1
  20. Nat Cell Biol. 2020 Nov 23.
    Espanola SG, Song H, Ryu E, Saxena A, Kim ES, Manegold JE, Nasamran CA, Sahoo D, Oh CK, Bickers C, Shin U, Grainger S, Park YH, Pandolfo L, Kang MS, Kang S, Myung K, Cooper KL, Yelon D, Traver D, Lee Y.
      Haematopoietic stem and progenitor cells (HSPCs) have been the focus of developmental and regenerative studies, yet our understanding of the signalling events regulating their specification remains incomplete. We demonstrate that supt16h, a component of the Facilitates chromatin transcription (FACT) complex, is required for HSPC formation. Zebrafish supt16h mutants express reduced levels of Notch-signalling components, genes essential for HSPC development, due to abrogated transcription. Whereas global chromatin accessibility in supt16h mutants is not substantially altered, we observe a specific increase in p53 accessibility, causing an accumulation of p53. We further demonstrate that p53 influences expression of the Polycomb-group protein PHC1, which functions as a transcriptional repressor of Notch genes. Suppression of phc1 or its upstream regulator, p53, rescues the loss of both Notch and HSPC phenotypes in supt16h mutants. Our results highlight a relationship between supt16h, p53 and phc1 to specify HSPCs via modulation of Notch signalling.
    DOI:  https://doi.org/10.1038/s41556-020-00604-7
  21. Semin Cell Dev Biol. 2020 Nov 18. pii: S1084-9521(20)30171-3. [Epub ahead of print]
    Maier JA, Castiglioni S, Locatelli L, Zocchi M, Mazur A.
      Magnesium is an essential element of life, involved in the regulation of metabolism and homeostasis of all the tissues. It also regulates immunological functions, acting on the cells of innate and adaptive immune systems. Magnesium deficiency primes phagocytes, enhances granulocyte oxidative burst, activates endothelial cells and increases the levels of cytokines, thus promoting inflammation. Consequently, a low magnesium status, which is often underdiagnosed, potentiates the reactivity to various immune challenges and is implicated in the pathophysiology of many common chronic diseases. Here we summarize recent advances supporting the link between magnesium deficiency, inflammatory responses and diseases, and offer new hints towards a better understanding of the underlying mechanisms.
    Keywords:  COVID-19; Inflammation; MagT1; Magnesium; Non-communicable diseases; TRPM7
    DOI:  https://doi.org/10.1016/j.semcdb.2020.11.002
  22. J Immunol. 2020 Nov 23. pii: ji2000216. [Epub ahead of print]
    Hills LB, Abdullah L, Lust HE, Degefu H, Huang YH.
      Foxo1 is an essential transcription factor required for the survival and differentiation of memory CD8 T cells, yet it is unclear whether these Foxo1-dependent functions are inherently coupled. To address this question, we examined the effects of different Foxo1 posttranslational modifications. Phosphorylation of Foxo1 by Akt kinases at three distinct residues is well characterized to inhibit Foxo1 transcriptional activity. However, the effect of Foxo1 phosphorylation within its DNA-binding domain at serine 209 by Mst1 kinase is not fully understood. In this study, we show that an S209A phospho-null Foxo1 exhibited Akt-dependent nuclear trafficking in mouse CD8 T cells and augmented the expression of canonical Foxo1 target genes such as Il7r and Sell In contrast, an S209D phosphomimetic Foxo1 (SD-Foxo1) was largely excluded from the nucleus of CD8 T cells and failed to transactivate these genes. RNA sequencing analysis revealed that SD-Foxo1 was associated with a distinct Foxo1-dependent transcriptional profile, including genes mediating CD8 effector function and cell survival. Despite defective transactivation of canonical target genes, SD-Foxo1 promoted IL-15-mediated CD8 T cell survival in vitro and survival of short-lived effector cells in vivo in response to Listeria monocytogenes infection. However, SD-Foxo1 actively repressed CD127 expression and failed to generate memory precursors and long-lived memory T cells. Together, these data indicate that S209 is a critical residue for the regulation of Foxo1 subcellular localization and for balancing CD8 T cell differentiation and survival.
    DOI:  https://doi.org/10.4049/jimmunol.2000216