bims-mepmim Biomed News
on Metabolites in pathological microenvironments and immunometabolism
Issue of 2024‒04‒14
twenty-six papers selected by
Erika Mariana Palmieri, NIH/NCI Laboratory of Cancer ImmunoMetabolism
  1. Adipose tissue macrophages secrete small extracellular vesicles that mediate rosiglitazone-induced insulin sensitization.
  2. HIF1α-dependent uncoupling of glycolysis suppresses tumor cell proliferation.
  3. A CRISPRi/a screening platform to study cellular nutrient transport in diverse microenvironments.
  4. A lipid atlas of human and mouse immune cells provides insights into ferroptosis susceptibility.
  5. A call for accessible tools to unlock single-cell immunometabolism research.
  6. LDL receptor-related protein 5 selectively transports unesterified polyunsaturated fatty acids to intracellular compartments.
  7. Statin-mediated reduction in mitochondrial cholesterol primes an anti-inflammatory response in macrophages by upregulating Jmjd3.
  8. Coenzyme Q4 is a functional substitute for coenzyme Q10 and can be targeted to the mitochondria.
  9. Metabolic rewiring promotes anti-inflammatory effects of glucocorticoids.
  10. ALOX15B controls macrophage cholesterol homeostasis via lipid peroxidation, ERK1/2 and SREBP2.
  11. NLRP3 Cys126 palmitoylation by ZDHHC7 promotes inflammasome activation.
  12. Fatty acyl-coenzyme A activates mitochondrial division through oligomerization of MiD49 and MiD51.
  13. The helminth-derived peptide, FhHDM-1, reverses the trained phenotype of NOD bone-marrow-derived macrophages and regulates proinflammatory responses.
  14. Tim4 enables large peritoneal macrophages to cross-present tumor antigens at early stages of tumorigenesis.
  15. Enhanced mitochondrial fusion during a critical period of synaptic plasticity in adult-born neurons.
  16. A glycolytic metabolite bypasses "two-hit" tumor suppression by BRCA2.
  17. TFE3-SLC36A1 axis promotes resistance to glucose starvation in kidney cancer cells.
  18. Metabolic plasticity, essentiality and therapeutic potential of ribose-5-phosphate synthesis in Toxoplasma gondii.
  19. The crosstalk between macrophages and cancer cells potentiates pancreatic cancer cachexia.
  20. FOXO1 is a master regulator of memory programming in CAR T cells.
  21. USP8-governed GPX4 homeostasis orchestrates ferroptosis and cancer immunotherapy.
  22. Respiratory complex I regulates dendritic cell maturation in explant model of human tumor immune microenvironment.
  23. Phosphoglycerate mutase 5 exacerbates liver ischemia-reperfusion injury by activating mitochondrial fission.
  24. Selenoprotein I is indispensable for ether lipid homeostasis and proper myelination.
  25. Structure and mechanisms of transport of human Asc1/CD98hc amino acid transporter.
  26. Hostile bile limits anti-cancer immunity.
  1. Nat Metab. 2024 Apr 11.
    Adipose tissue macrophages secrete small extracellular vesicles that mediate rosiglitazone-induced insulin sensitization.
    Theresa V Rohm, Felipe Castellani Gomes Dos Reis, Roi Isaac, Cairo Murphy, Karina Cunha E Rocha, Gautam Bandyopadhyay, Hong Gao, Avraham M Libster, Rizaldy C Zapata, Yun Sok Lee, Wei Ying, Charlene Miciano, Allen Wang, Jerrold M Olefsky.
      The obesity epidemic continues to worsen worldwide, driving metabolic and chronic inflammatory diseases. Thiazolidinediones, such as rosiglitazone (Rosi), are PPARγ agonists that promote 'M2-like' adipose tissue macrophage (ATM) polarization and cause insulin sensitization. As ATM-derived small extracellular vesicles (ATM-sEVs) from lean mice are known to increase insulin sensitivity, we assessed the metabolic effects of ATM-sEVs from Rosi-treated obese male mice (Rosi-ATM-sEVs). Here we show that Rosi leads to improved glucose and insulin tolerance, transcriptional repolarization of ATMs and increased sEV secretion. Administration of Rosi-ATM-sEVs rescues obesity-induced glucose intolerance and insulin sensitivity in vivo without the known thiazolidinedione-induced adverse effects of weight gain or haemodilution. Rosi-ATM-sEVs directly increase insulin sensitivity in adipocytes, myotubes and primary mouse and human hepatocytes. Additionally, we demonstrate that the miRNAs within Rosi-ATM-sEVs, primarily miR-690, are responsible for these beneficial metabolic effects. Thus, using ATM-sEVs with specific miRNAs may provide a therapeutic path to induce insulin sensitization.
    DOI:  https://doi.org/10.1038/s42255-024-01023-w
  2. Cell Rep. 2024 Apr 11. pii: S2211-1247(24)00431-5. [Epub ahead of print]43(4): 114103
    HIF1α-dependent uncoupling of glycolysis suppresses tumor cell proliferation.
    Andrés A Urrutia, Claudia Mesa-Ciller, Andrea Guajardo-Grence, H Furkan Alkan, Inés Soro-Arnáiz, Anke Vandekeere, Ana Margarida Ferreira Campos, Sebastian Igelmann, Lucía Fernández-Arroyo, Gianmarco Rinaldi, Doriane Lorendeau, Katrien De Bock, Sarah-Maria Fendt, Julián Aragonés.
      Hypoxia-inducible factor-1α (HIF1α) attenuates mitochondrial activity while promoting glycolysis. However, lower glycolysis is compromised in human clear cell renal cell carcinomas, in which HIF1α acts as a tumor suppressor by inhibiting cell-autonomous proliferation. Here, we find that, unexpectedly, HIF1α suppresses lower glycolysis after the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) step, leading to reduced lactate secretion in different tumor cell types when cells encounter a limited pyruvate supply such as that typically found in the tumor microenvironment in vivo. This is because HIF1α-dependent attenuation of mitochondrial oxygen consumption increases the NADH/NAD+ ratio that suppresses the activity of the NADH-sensitive GAPDH glycolytic enzyme. This is manifested when pyruvate supply is limited, since pyruvate acts as an electron acceptor that prevents the increment of the NADH/NAD+ ratio. Furthermore, this anti-glycolytic function provides a molecular basis to explain how HIF1α can suppress tumor cell proliferation by increasing the NADH/NAD+ ratio.
    Keywords:  CP: Cancer; CP: Metabolism; HIF1α; NADH; glycolysis; hypoxia; mitochondria; oxygen; renal cell carcinoma; tumor
    DOI:  https://doi.org/10.1016/j.celrep.2024.114103
  3. Nat Cell Biol. 2024 Apr 11.
    A CRISPRi/a screening platform to study cellular nutrient transport in diverse microenvironments.
    Christopher Chidley, Alicia M Darnell, Benjamin L Gaudio, Evan C Lien, Anna M Barbeau, Matthew G Vander Heiden, Peter K Sorger.
      Blocking the import of nutrients essential for cancer cell proliferation represents a therapeutic opportunity, but it is unclear which transporters to target. Here we report a CRISPR interference/activation screening platform to systematically interrogate the contribution of nutrient transporters to support cancer cell proliferation in environments ranging from standard culture media to tumours. We applied this platform to identify the transporters of amino acids in leukaemia cells and found that amino acid transport involves high bidirectional flux dependent on the microenvironment composition. While investigating the role of transporters in cystine starved cells, we uncovered a role for serotonin uptake in preventing ferroptosis. Finally, we identified transporters essential for cell proliferation in subcutaneous tumours and found that levels of glucose and amino acids can restrain proliferation in that environment. This study establishes a framework for systematically identifying critical cellular nutrient transporters, characterizing their function and exploring how the tumour microenvironment impacts cancer metabolism.
    DOI:  https://doi.org/10.1038/s41556-024-01402-1
  4. Nat Cell Biol. 2024 Apr 08.
    A lipid atlas of human and mouse immune cells provides insights into ferroptosis susceptibility.
    Pooranee K Morgan, Gerard Pernes, Kevin Huynh, Corey Giles, Sudip Paul, Adam Alexander T Smith, Natalie A Mellett, Amy Liang, Tilly van Buuren-Milne, Camilla Bertuzzo Veiga, Thomas J C Collins, Yangsong Xu, Man K S Lee, T Michael De Silva, Peter J Meikle, Graeme I Lancaster, Andrew J Murphy.
      The cellular lipidome comprises thousands of unique lipid species. Here, using mass spectrometry-based targeted lipidomics, we characterize the lipid landscape of human and mouse immune cells ( www.cellularlipidatlas.com ). Using this resource, we show that immune cells have unique lipidomic signatures and that processes such as activation, maturation and development impact immune cell lipid composition. To demonstrate the potential of this resource to provide insights into immune cell biology, we determine how a cell-specific lipid trait-differences in the abundance of polyunsaturated fatty acid-containing glycerophospholipids (PUFA-PLs)-influences immune cell biology. First, we show that differences in PUFA-PL content underpin the differential susceptibility of immune cells to ferroptosis. Second, we show that low PUFA-PL content promotes resistance to ferroptosis in activated neutrophils. In summary, we show that the lipid landscape is a defining feature of immune cell identity and that cell-specific lipid phenotypes underpin aspects of immune cell physiology.
    DOI:  https://doi.org/10.1038/s41556-024-01377-z
  5. Nat Metab. 2024 Apr 11.
    A call for accessible tools to unlock single-cell immunometabolism research.
    Jason Cosgrove, Antoine Marçais, Felix J Hartmann, Andreas Bergthaler, Ivan Zanoni, Mauro Corrado, Leïla Perié, Nina Cabezas-Wallscheid, Philippe Bousso, Theodore Alexandrov, Tammy Kielian, Nuria Martínez-Martín, Christiane A Opitz, Costas A Lyssiotis, Rafael J Argüello, Jan Van den Bossche.
      
    DOI:  https://doi.org/10.1038/s42255-024-01031-w
  6. Nat Commun. 2024 Apr 09. 15(1): 3068
    LDL receptor-related protein 5 selectively transports unesterified polyunsaturated fatty acids to intracellular compartments.
    Wenwen Tang, Yi Luan, Qianying Yuan, Ao Li, Song Chen, Stanley Menacherry, Lawrence Young, Dianqing Wu.
      Polyunsaturated fatty acids (PUFAs), which cannot be synthesized by animals and must be supplied from the diet, have been strongly associated with human health. However, the mechanisms for their accretion remain poorly understood. Here, we show that LDL receptor-related protein 5 (LRP5), but not its homolog LRP6, selectively transports unesterified PUFAs into a number of cell types. The LDLa ligand-binding repeats of LRP5 directly bind to PUFAs and are required and sufficient for PUFA transport. In contrast to the known PUFA transporters Mfsd2a, CD36 and FATP2, LRP5 transports unesterified PUFAs via internalization to intracellular compartments including lysosomes, and n-3 PUFAs depend on this transport mechanism to inhibit mTORC1. This LRP5-mediated PUFA transport mechanism suppresses extracellular trap formation in neutrophils and protects mice from myocardial injury during ischemia-reperfusion. Thus, this study reveals a biologically important mechanism for unesterified PUFA transport to intracellular compartments.
    DOI:  https://doi.org/10.1038/s41467-024-47262-z
  7. Elife. 2024 Apr 11. pii: e85964. [Epub ahead of print]13
    Statin-mediated reduction in mitochondrial cholesterol primes an anti-inflammatory response in macrophages by upregulating Jmjd3.
    Zeina Salloum, Kristin Dauner, Yun-Fang Li, Neha Verma, David Valdivieso-González, Víctor G Almendro-Vedia, John D Zhang, Kiran Nakka, Mei Xi Chen, Jeffrey G McDonald, Chase D Corley, Alexander Sorisky, Bao-Liang Song, Iván López-Montero, Jie Luo, Jeffrey F Dilworth, Xiaohui Zha.
      Stains are known to be anti-inflammatory, but the mechanism remains poorly understood. Here we show that macrophages, either treated with statin in vitro or from statin-treated mice, have reduced cholesterol levels and higher expression of Jmjd3, a H3K27me3 demethylase. We provide evidence that lowering cholesterol levels in macrophages suppresses the ATP synthase in the inner mitochondrial membrane (IMM) and changes the proton gradient in the mitochondria. This activates NFkB and Jmjd3 expression to remove the repressive marker H3K27me3. Accordingly, the epigenome is altered by the cholesterol reduction. When subsequently challenged by the inflammatory stimulus LPS (M1), both macrophages treated with statins in vitro or isolated from statin-treated mice in vivo, express lower levels pro-inflammatory cytokines than controls, while augmenting anti-inflammatory Il10 expression. On the other hand, when macrophages are alternatively activated by IL4 (M2), statins promote the expression of Arg1, Ym1, and Mrc1. The enhanced expression is correlated with the statin-induced removal of H3K27me3 from these genes prior to activation. In addition, Jmjd3 and its demethylase activity are necessary for cholesterol to modulate both M1 and M2 activation. We conclude that upregulation of Jmjd3 is a key event for the anti-inflammatory function of statins on macrophages.
    Keywords:  cell biology; mouse
    DOI:  https://doi.org/10.7554/eLife.85964
  8. J Biol Chem. 2024 Apr 06. pii: S0021-9258(24)01770-8. [Epub ahead of print] 107269
    Coenzyme Q4 is a functional substitute for coenzyme Q10 and can be targeted to the mitochondria.
    Laura H Steenberge, Sean Rogers, Andrew Y Sung, Jing Fan, David J Pagliarini.
      Coenzyme Q10 (CoQ10) is an important cofactor and antioxidant for numerous cellular processes, and its deficiency has been linked to human disorders including mitochondrial disease, heart failure, Parkinson's disease, and hypertension. Unfortunately, treatment with exogenous CoQ10 is often ineffective, likely due to the extreme hydrophobicity and high molecular weight of CoQ10. Here, we show that less hydrophobic CoQ species with shorter isoprenoid tails can serve as viable substitutes for CoQ10 in human cells. We demonstrate that CoQ4 can perform multiple functions of CoQ10 in CoQ-deficient cells at markedly lower treatment concentrations, motivating further investigation of CoQ4 as a supplement for CoQ10 deficiencies. In addition, we describe the synthesis and evaluation of an initial set of compounds designed to target CoQ4 selectively to mitochondria using triphenylphosphonium (TPP). Our results indicate that select versions of these compounds can successfully be delivered to mitochondria in a cell model and be cleaved to produce CoQ4, laying the groundwork for further development.
    Keywords:  Antioxidant; Bioenergetics; Coenzyme Q10 (CoQ10); Ferroptosis; Membrane lipid; Mitochondrial respiratory chain complex; Mitochondrial therapeutics; Pyrimidine biosynthesis; Ubiquinone
    DOI:  https://doi.org/10.1016/j.jbc.2024.107269
  9. Nature. 2024 Apr 10.
    Metabolic rewiring promotes anti-inflammatory effects of glucocorticoids.
    Jean-Philippe Auger, Max Zimmermann, Maria Faas, Ulrich Stifel, David Chambers, Brenda Krishnacoumar, R Verena Taudte, Charlotte Grund, Gitta Erdmann, Carina Scholtysek, Stefan Uderhardt, Oumaima Ben Brahim, Mónica Pascual Maté, Cornelia Stoll, Martin Böttcher, Katrin Palumbo-Zerr, Matthew S J Mangan, Maria Dzamukova, Markus Kieler, Melanie Hofmann, Stephan Blüml, Gernot Schabbauer, Dimitrios Mougiakakos, Uwe Sonnewald, Fabian Hartmann, David Simon, Arnd Kleyer, Anika Grüneboom, Susetta Finotto, Eicke Latz, Jörg Hofmann, Georg Schett, Jan Tuckermann, Gerhard Krönke.
      Glucocorticoids represent the mainstay of therapy for a broad spectrum of immune-mediated inflammatory diseases. However, the molecular mechanisms underlying their anti-inflammatory mode of action have remained incompletely understood1. Here we show that the anti-inflammatory properties of glucocorticoids involve reprogramming of the mitochondrial metabolism of macrophages, resulting in increased and sustained production of the anti-inflammatory metabolite itaconate and consequent inhibition of the inflammatory response. The glucocorticoid receptor interacts with parts of the pyruvate dehydrogenase complex whereby glucocorticoids provoke an increase in activity and enable an accelerated and paradoxical flux of the tricarboxylic acid (TCA) cycle in otherwise pro-inflammatory macrophages. This glucocorticoid-mediated rewiring of mitochondrial metabolism potentiates TCA-cycle-dependent production of itaconate throughout the inflammatory response, thereby interfering with the production of pro-inflammatory cytokines. By contrast, artificial blocking of the TCA cycle or genetic deficiency in aconitate decarboxylase 1, the rate-limiting enzyme of itaconate synthesis, interferes with the anti-inflammatory effects of glucocorticoids and, accordingly, abrogates their beneficial effects during a diverse range of preclinical models of immune-mediated inflammatory diseases. Our findings provide important insights into the anti-inflammatory properties of glucocorticoids and have substantial implications for the design of new classes of anti-inflammatory drugs.
    DOI:  https://doi.org/10.1038/s41586-024-07282-7
  10. Redox Biol. 2024 Apr 03. pii: S2213-2317(24)00125-3. [Epub ahead of print]72 103149
    ALOX15B controls macrophage cholesterol homeostasis via lipid peroxidation, ERK1/2 and SREBP2.
    Yvonne Benatzy, Megan A Palmer, Dieter Lütjohann, Rei-Ichi Ohno, Nadja Kampschulte, Nils Helge Schebb, Dominik C Fuhrmann, Ryan G Snodgrass, Bernhard Brüne.
      Macrophage cholesterol homeostasis is crucial for health and disease and has been linked to the lipid-peroxidizing enzyme arachidonate 15-lipoxygenase type B (ALOX15B), albeit molecular mechanisms remain obscure. We performed global transcriptome and immunofluorescence analysis in ALOX15B-silenced primary human macrophages and observed a reduction of nuclear sterol regulatory element-binding protein (SREBP) 2, the master transcription factor of cellular cholesterol biosynthesis. Consequently, SREBP2-target gene expression was reduced as were the sterol biosynthetic intermediates desmosterol and lathosterol as well as 25- and 27-hydroxycholesterol. Mechanistically, suppression of ALOX15B reduced lipid peroxidation in primary human macrophages and thereby attenuated activation of mitogen-activated protein kinase ERK1/2, which lowered SREBP2 abundance and activity. Low nuclear SREBP2 rendered both, ALOX15B-silenced and ERK1/2-inhibited macrophages refractory to SREBP2 activation upon blocking the NPC intracellular cholesterol transporter 1. These studies suggest a regulatory mechanism controlling macrophage cholesterol homeostasis based on ALOX15B-mediated lipid peroxidation and concomitant ERK1/2 activation.
    Keywords:  15-LO2; Arachidonate 15-lipoxygenase type B; Lipid peroxidation; MAPK; Reactive oxygen species; Sterol regulatory element-binding protein 2
    DOI:  https://doi.org/10.1016/j.redox.2024.103149
  11. Cell Rep. 2024 Apr 06. pii: S2211-1247(24)00398-X. [Epub ahead of print]43(4): 114070
    NLRP3 Cys126 palmitoylation by ZDHHC7 promotes inflammasome activation.
    Tao Yu, Dan Hou, Jiaqi Zhao, Xuan Lu, Wendy K Greentree, Qian Zhao, Min Yang, Don-Gerard Conde, Maurine E Linder, Hening Lin.
      Nucleotide oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome hyperactivation contributes to many human chronic inflammatory diseases, and understanding how NLRP3 inflammasome is regulated can provide strategies to treat inflammatory diseases. Here, we demonstrate that NLRP3 Cys126 is palmitoylated by zinc finger DHHC-type palmitoyl transferase 7 (ZDHHC7), which is critical for NLRP3-mediated inflammasome activation. Perturbing NLRP3 Cys126 palmitoylation by ZDHHC7 knockout, pharmacological inhibition, or modification site mutation diminishes NLRP3 activation in macrophages. Furthermore, Cys126 palmitoylation is vital for inflammasome activation in vivo. Mechanistically, ZDHHC7-mediated NLRP3 Cys126 palmitoylation promotes resting NLRP3 localizing on the trans-Golgi network (TGN) and activated NLRP3 on the dispersed TGN, which is indispensable for recruitment and oligomerization of the adaptor ASC (apoptosis-associated speck-like protein containing a CARD). The activation of NLRP3 by ZDHHC7 is different from the termination effect mediated by ZDHHC12, highlighting versatile regulatory roles of S-palmitoylation. Our study identifies an important regulatory mechanism of NLRP3 activation that suggests targeting ZDHHC7 or the NLRP3 Cys126 residue as a potential therapeutic strategy to treat NLRP3-related human disorders.
    Keywords:  CP: Immunology; NLRP3; ZDHHC7; endotoxic shock; inflammasome; palmitoylation; peritonitis; trans-Golgi network localization
    DOI:  https://doi.org/10.1016/j.celrep.2024.114070
  12. Nat Cell Biol. 2024 Apr 09.
    Fatty acyl-coenzyme A activates mitochondrial division through oligomerization of MiD49 and MiD51.
    Ao Liu, Frieda Kage, Asan F Abdulkareem, Mac Pholo Aguirre-Huamani, Gracie Sapp, Halil Aydin, Henry N Higgs.
      Mitochondrial fission occurs in many cellular processes, but the regulation of fission is poorly understood. We show that long-chain acyl-coenzyme A (LCACA) activates two related mitochondrial fission proteins, MiD49 and MiD51, by inducing their oligomerization, which activates their ability to stimulate the DRP1 GTPase. The 1:1 stoichiometry of LCACA:MiD in the oligomer suggests interaction in the previously identified nucleotide-binding pocket, and a point mutation in this pocket reduces LCACA binding and LCACA-induced oligomerization for MiD51. In cells, this LCACA binding mutant does not assemble into puncta on mitochondria or rescue MiD49/51 knockdown effects on mitochondrial length and DRP1 recruitment. Furthermore, cellular treatment with BSA-bound oleic acid, which causes increased LCACA, promotes mitochondrial fission in an MiD49/51-dependent manner. These results suggest that LCACA is an endogenous ligand for MiDs, inducing mitochondrial fission and providing a potential mechanism for fatty-acid-induced mitochondrial division. Finally, MiD49 or MiD51 oligomers synergize with Mff, but not with actin filaments, in DRP1 activation, suggesting distinct pathways for DRP1 activation.
    DOI:  https://doi.org/10.1038/s41556-024-01400-3
  13. Eur J Immunol. 2024 Apr 05. e2350643
    The helminth-derived peptide, FhHDM-1, reverses the trained phenotype of NOD bone-marrow-derived macrophages and regulates proinflammatory responses.
    Susel Loli Quinteros, Nathaniel W Snyder, Adam Chatoff, Fiona Ryan, Bronwyn O'Brien, Sheila Donnelly.
      We implicate a phenotype of trained immunity in bone-marrow-derived macrophages in the onset and progression of type 1 diabetes in nonobese diabetic mice. Treatment with FhHDM-1 reversed immune training, reducing histone methylation and glycolysis, and decreasing proinflammatory cytokine production to the same level as macrophages from nondiabetic immune-competent BALB/c mice.
    Keywords:  FhHDM‐1; Helminth therapy; Macrophage; Trained immunity; Type 1 diabetes
    DOI:  https://doi.org/10.1002/eji.202350643
  14. Cell Rep. 2024 Apr 11. pii: S2211-1247(24)00424-8. [Epub ahead of print]43(4): 114096
    Tim4 enables large peritoneal macrophages to cross-present tumor antigens at early stages of tumorigenesis.
    Sonal Joshi, Lucía López, Luciano Gastón Morosi, Roberto Amadio, Manendra Pachauri, Marco Bestagno, Ironya Paul Ogar, Mauro Giacca, Giulia Maria Piperno, Daan Vorselen, Federica Benvenuti.
      Receptors controlling the cross-presentation of tumor antigens by macrophage subsets in cancer tissues are poorly explored. Here, we show that TIM4+ large peritoneal macrophages efficiently capture and cross-present tumor-associated antigens at early stages of peritoneal infiltration by ovarian cancer cells. The phosphatidylserine (PS) receptor TIM4 promotes maximal uptake of dead cells or PS-coated artificial targets and triggers inflammatory and metabolic gene programs in combination with cytoskeletal remodeling and upregulation of transcriptional signatures related to antigen processing. At the cellular level, TIM4-mediated engulfment induces nucleation of F-actin around nascent phagosomes, delaying the recruitment of vacuolar ATPase, acidification, and cargo degradation. In vivo, TIM4 deletion blunts induction of early anti-tumoral effector CD8 T cells and accelerates the progression of ovarian tumors. We conclude that TIM4-mediated uptake drives the formation of specialized phagosomes that prolong the integrity of ingested antigens and facilitate cross-presentation, contributing to immune surveillance of the peritoneum.
    Keywords:  CP: Cancer; CP: Immunology; Tim4; cross-presentation; large peritoneal macrophages; ovarian cancer; phagocytosis; tissue resident macrophages; tumor antigens; tumor specific CD8 T cells
    DOI:  https://doi.org/10.1016/j.celrep.2024.114096
  15. Neuron. 2024 Mar 26. pii: S0896-6273(24)00167-3. [Epub ahead of print]
    Enhanced mitochondrial fusion during a critical period of synaptic plasticity in adult-born neurons.
    Sandra M V Kochan, Meret Cepero Malo, Milica Jevtic, Hannah M Jahn-Kelleter, Gulzar A Wani, Kristiano Ndoci, Laura Pérez-Revuelta, Felix Gaedke, Iris Schäffner, Dieter Chichung Lie, Astrid Schauss, Matteo Bergami.
      Integration of new neurons into adult hippocampal circuits is a process coordinated by local and long-range synaptic inputs. To achieve stable integration and uniquely contribute to hippocampal function, immature neurons are endowed with a critical period of heightened synaptic plasticity, yet it remains unclear which mechanisms sustain this form of plasticity during neuronal maturation. We found that as new neurons enter their critical period, a transient surge in fusion dynamics stabilizes elongated mitochondrial morphologies in dendrites to fuel synaptic plasticity. Conditional ablation of fusion dynamics to prevent mitochondrial elongation selectively impaired spine plasticity and synaptic potentiation, disrupting neuronal competition for stable circuit integration, ultimately leading to decreased survival. Despite profuse mitochondrial fragmentation, manipulation of competition dynamics was sufficient to restore neuronal survival but left neurons poorly responsive to experience at the circuit level. Thus, by enabling synaptic plasticity during the critical period, mitochondrial fusion facilitates circuit remodeling by adult-born neurons.
    Keywords:  LTP; Mfn2; adult neurogenesis; competition; experience; hippocampus; mitochondria; mitochondrial fusion; neural stem cell; synaptic plasticity
    DOI:  https://doi.org/10.1016/j.neuron.2024.03.013
  16. Cell. 2024 Apr 08. pii: S0092-8674(24)00255-1. [Epub ahead of print]
    A glycolytic metabolite bypasses "two-hit" tumor suppression by BRCA2.
    Li Ren Kong, Komal Gupta, Andy Jialun Wu, David Perera, Roland Ivanyi-Nagy, Syed Moiz Ahmed, Tuan Zea Tan, Shawn Lu-Wen Tan, Alessandra Fuddin, Elayanambi Sundaramoorthy, Grace Shiqing Goh, Regina Tong Xin Wong, Ana S H Costa, Callum Oddy, Hannan Wong, C Pawan K Patro, Yun Suen Kho, Xiao Zi Huang, Joan Choo, Mona Shehata, Soo Chin Lee, Boon Cher Goh, Christian Frezza, Jason J Pitt, Ashok R Venkitaraman.
      Knudson's "two-hit" paradigm posits that carcinogenesis requires inactivation of both copies of an autosomal tumor suppressor gene. Here, we report that the glycolytic metabolite methylglyoxal (MGO) transiently bypasses Knudson's paradigm by inactivating the breast cancer suppressor protein BRCA2 to elicit a cancer-associated, mutational single-base substitution (SBS) signature in nonmalignant mammary cells or patient-derived organoids. Germline monoallelic BRCA2 mutations predispose to these changes. An analogous SBS signature, again without biallelic BRCA2 inactivation, accompanies MGO accumulation and DNA damage in Kras-driven, Brca2-mutant murine pancreatic cancers and human breast cancers. MGO triggers BRCA2 proteolysis, temporarily disabling BRCA2's tumor suppressive functions in DNA repair and replication, causing functional haploinsufficiency. Intermittent MGO exposure incites episodic SBS mutations without permanent BRCA2 inactivation. Thus, a metabolic mechanism wherein MGO-induced BRCA2 haploinsufficiency transiently bypasses Knudson's two-hit requirement could link glycolysis activation by oncogenes, metabolic disorders, or dietary challenges to mutational signatures implicated in cancer evolution.
    Keywords:  DNA repair and replication; breast cancer gene BRCA2; cancer genome; cancer metabolism; environmental carcinogenesis; gene-environment interaction; glycolysis; methylglyoxal; mutational signature; tumor suppression
    DOI:  https://doi.org/10.1016/j.cell.2024.03.006
  17. J Biol Chem. 2024 Apr 08. pii: S0021-9258(24)01771-X. [Epub ahead of print] 107270
    TFE3-SLC36A1 axis promotes resistance to glucose starvation in kidney cancer cells.
    Suli Lv, Zongbiao Zhang, Zhenyong Li, Qian Ke, Xianyun Ma, Neng Li, Xuefeng Zhao, Qingli Zou, Lidong Sun, Tanjing Song.
      Higher demand for nutrients including glucose is characteristic of cancer. "Starving cancer" has been pursued to curb tumor progression. An ,intriguing regime is to inhibit glucose transporter GLUT1 in cancer cells. In addition, during cancer progression, cancer cells may suffer from insufficient glucose supply. Yet cancer cells can somehow tolerate glucose starvation. Uncovering the underlying mechanisms shall not only shed insight into cancer progression but also benefit cancer therapy. TFE3 is a transcription factor known to activate autophagic genes. Physiological TFE3 activity is regulated by phosphorylation-triggered translocation responsive to nutrient status. We recently reported TFE3 constitutively localizes to the cell nucleus and promotes cell proliferation in kidney cancer even under nutrient replete condition. Whether and how TFE3 responds to glucose starvation remain unclear. In this study, we show TFE3 promotes kidney cancer cell resistance to glucose starvation by exposing cells to physiologically relevant glucose concentration. We find glucose starvation triggers TFE3 protein stabilization through increasing its O-GlcNAcylation. Furthermore, through an unbiased functional genomic study, we identify SLC36A1, a lysosomal amino acid transporter, as a TFE3 target gene sensitive to TFE3 protein level. We find SLC36A1 is overexpressed in kidney cancer, which promotes mTOR activity and kidney cancer cell proliferation. Importantly, SLC36A1 level is induced by glucose starvation through TFE3, which enhances cellular resistance to glucose starvation. Suppressing TFE3 or SLC36A1 significantly increases cellular sensitivity to GLUT1 inhibitor in kidney cancer cells. Collectively, we uncover a functional TFE3-SLC36A1 axis that responds to glucose starvation and enhances starvation tolerance in kidney cancer.
    Keywords:  O-GlcNAcylation; amino acid transporter; kidney cancer; transcription factor
    DOI:  https://doi.org/10.1016/j.jbc.2024.107270
  18. Nat Commun. 2024 Apr 08. 15(1): 2999
    Metabolic plasticity, essentiality and therapeutic potential of ribose-5-phosphate synthesis in Toxoplasma gondii.
    Xuefang Guo, Nuo Ji, Qinghong Guo, Mengting Wang, Huiyu Du, Jiajia Pan, Lihua Xiao, Nishith Gupta, Yaoyu Feng, Ningbo Xia.
      Ribose-5-phosphate (R5P) is a precursor for nucleic acid biogenesis; however, the importance and homeostasis of R5P in the intracellular parasite Toxoplasma gondii remain enigmatic. Here, we show that the cytoplasmic sedoheptulose-1,7-bisphosphatase (SBPase) is dispensable. Still, its co-deletion with transaldolase (TAL) impairs the double mutant's growth and increases 13C-glucose-derived flux into pentose sugars via the transketolase (TKT) enzyme. Deletion of the latter protein affects the parasite's fitness but is not lethal and is correlated with an increased carbon flux via the oxidative pentose phosphate pathway. Further, loss of TKT leads to a decline in 13C incorporation into glycolysis and the TCA cycle, resulting in a decrease in ATP levels and the inability of phosphoribosyl-pyrophosphate synthetase (PRPS) to convert R5P into 5'-phosphoribosyl-pyrophosphate and thereby contribute to the production of AMP and IMP. Likewise, PRPS is essential for the lytic cycle. Not least, we show that RuPE-mediated metabolic compensation is imperative for the survival of the ΔsbpaseΔtal strain. In conclusion, we demonstrate that multiple routes can flexibly supply R5P to enable parasite growth and identify catalysis by TKT and PRPS as critical enzymatic steps. Our work provides novel biological and therapeutic insights into the network design principles of intracellular parasitism in a clinically-relevant pathogen.
    DOI:  https://doi.org/10.1038/s41467-024-47097-8
  19. Cancer Cell. 2024 Mar 29. pii: S1535-6108(24)00094-1. [Epub ahead of print]
    The crosstalk between macrophages and cancer cells potentiates pancreatic cancer cachexia.
    Mingyang Liu, Yu Ren, Zhijun Zhou, Jingxuan Yang, Xiuhui Shi, Yang Cai, Alex X Arreola, Wenyi Luo, Kar-Ming Fung, Chao Xu, Ryan D Nipp, Michael S Bronze, Lei Zheng, Yi-Ping Li, Courtney W Houchen, Yuqing Zhang, Min Li.
      With limited treatment options, cachexia remains a major challenge for patients with cancer. Characterizing the interplay between tumor cells and the immune microenvironment may help identify potential therapeutic targets for cancer cachexia. Herein, we investigate the critical role of macrophages in potentiating pancreatic cancer induced muscle wasting via promoting TWEAK (TNF-like weak inducer of apoptosis) secretion from the tumor. Specifically, depletion of macrophages reverses muscle degradation induced by tumor cells. Macrophages induce non-autonomous secretion of TWEAK through CCL5/TRAF6/NF-κB pathway. TWEAK promotes muscle atrophy by activating MuRF1 initiated muscle remodeling. Notably, tumor cells recruit and reprogram macrophages via the CCL2/CCR2 axis and disrupting the interplay between macrophages and tumor cells attenuates muscle wasting. Collectively, this study identifies a feedforward loop between pancreatic cancer cells and macrophages, underlying the non-autonomous activation of TWEAK secretion from tumor cells thereby providing promising therapeutic targets for pancreatic cancer cachexia.
    Keywords:  CCL2; CCL5; RELB; TWEAK; cancer cachexia; macrophages; metabolic reprogramming; muscle wasting; p65; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.ccell.2024.03.009
  20. Nature. 2024 Apr 10.
    FOXO1 is a master regulator of memory programming in CAR T cells.
    Alexander E Doan, Katherine P Mueller, Andy Y Chen, Geoffrey T Rouin, Yingshi Chen, Bence Daniel, John Lattin, Martina Markovska, Brett Mozarsky, Jose Arias-Umana, Robert Hapke, In-Young Jung, Alice Wang, Peng Xu, Dorota Klysz, Gabrielle Zuern, Malek Bashti, Patrick J Quinn, Zhuang Miao, Katalin Sandor, Wenxi Zhang, Gregory M Chen, Faith Ryu, Meghan Logun, Junior Hall, Kai Tan, Stephan A Grupp, Susan E McClory, Caleb A Lareau, Joseph A Fraietta, Elena Sotillo, Ansuman T Satpathy, Crystal L Mackall, Evan W Weber.
      A major limitation of chimeric antigen receptor (CAR) T cell therapies is the poor persistence of these cells in vivo1. The expression of memory-associated genes in CAR T cells is linked to their long-term persistence in patients and clinical efficacy2-6, suggesting that memory programs may underpin durable CAR T cell function. Here we show that the transcription factor FOXO1 is responsible for promoting memory and restraining exhaustion in human CAR T cells. Pharmacological inhibition or gene editing of endogenous FOXO1 diminished the expression of memory-associated genes, promoted an exhaustion-like phenotype and impaired the antitumour activity of CAR T cells. Overexpression of FOXO1 induced a gene-expression program consistent with T cell memory and increased chromatin accessibility at FOXO1-binding motifs. CAR T cells that overexpressed FOXO1 retained their function, memory potential and metabolic fitness in settings of chronic stimulation, and exhibited enhanced persistence and tumour control in vivo. By contrast, overexpression of TCF1 (encoded by TCF7) did not enforce canonical memory programs or enhance the potency of CAR T cells. Notably, FOXO1 activity correlated with positive clinical outcomes of patients treated with CAR T cells or tumour-infiltrating lymphocytes, underscoring the clinical relevance of FOXO1 in cancer immunotherapy. Our results show that overexpressing FOXO1 can increase the antitumour activity of human CAR T cells, and highlight memory reprogramming as a broadly applicable approach for optimizing therapeutic T cell states.
    DOI:  https://doi.org/10.1038/s41586-024-07300-8
  21. Proc Natl Acad Sci U S A. 2024 Apr 16. 121(16): e2315541121
    USP8-governed GPX4 homeostasis orchestrates ferroptosis and cancer immunotherapy.
    Haiou Li, Yishuang Sun, Yingmeng Yao, Shanwen Ke, Nannan Zhang, Wenjun Xiong, Jie Shi, Chuan He, Xiangling Xiao, Haisheng Yu, Panpan Dai, Bolin Xiang, Xixin Xing, Gaoshan Xu, Wenjing Song, Jiquan Song, Jinfang Zhang.
      Ferroptosis is an iron-dependent type of regulated cell death resulting from extensive lipid peroxidation and plays a critical role in various physiological and pathological processes. However, the regulatory mechanisms for ferroptosis sensitivity remain incompletely understood. Here, we report that homozygous deletion of Usp8 (ubiquitin-specific protease 8) in intestinal epithelial cells (IECs) leads to architectural changes in the colonic epithelium and shortens mouse lifespan accompanied by increased IEC death and signs of lipid peroxidation. However, mice with heterozygous deletion of Usp8 in IECs display normal phenotype and become resistant to azoxymethane/dextran sodium sulfate-induced colorectal tumorigenesis. Mechanistically, USP8 interacts with and deubiquitinates glutathione peroxidase 4 (GPX4), leading to GPX4 stabilization. Thus, USP8 inhibition destabilizes GPX4 and sensitizes cancer cells to ferroptosis in vitro. Notably, USP8 inhibition in combination with ferroptosis inducers retards tumor growth and enhances CD8+ T cell infiltration, which potentiates tumor response to anti-PD-1 immunotherapy in vivo. These findings uncover that USP8 counteracts ferroptosis by stabilizing GPX4 and highlight targeting USP8 as a potential therapeutic strategy to boost ferroptosis for enhancing cancer immunotherapy.
    Keywords:  GPX4; USP8; ferroptosis; immunotherapy; ubiquitination
    DOI:  https://doi.org/10.1073/pnas.2315541121
  22. J Immunother Cancer. 2024 Apr 11. pii: e008053. [Epub ahead of print]12(4):
    Respiratory complex I regulates dendritic cell maturation in explant model of human tumor immune microenvironment.
    Rita Turpin, Ruixian Liu, Pauliina M Munne, Aino Peura, Jenna H Rannikko, Gino Philips, Bram Boeckx, Natasha Salmelin, Elina Hurskainen, Ilida Suleymanova, July Aung, Elisa M Vuorinen, Laura Lehtinen, Minna Mutka, Panu E Kovanen, Laura Niinikoski, Tuomo J Meretoja, Johanna Mattson, Satu Mustjoki, Päivi Saavalainen, Andrei Goga, Diether Lambrechts, Jeroen Pouwels, Maija Hollmén, Juha Klefström.
      BACKGROUND: Combining cytotoxic chemotherapy or novel anticancer drugs with T-cell modulators holds great promise in treating advanced cancers. However, the response varies depending on the tumor immune microenvironment (TIME). Therefore, there is a clear need for pharmacologically tractable models of the TIME to dissect its influence on mono- and combination treatment response at the individual level.METHODS: Here we establish a patient-derived explant culture (PDEC) model of breast cancer, which retains the immune contexture of the primary tumor, recapitulating cytokine profiles and CD8+T cell cytotoxic activity.
    RESULTS: We explored the immunomodulatory action of a synthetic lethal BCL2 inhibitor venetoclax+metformin drug combination ex vivo, discovering metformin cannot overcome the lymphocyte-depleting action of venetoclax. Instead, metformin promotes dendritic cell maturation through inhibition of mitochondrial complex I, increasing their capacity to co-stimulate CD4+T cells and thus facilitating antitumor immunity.
    CONCLUSIONS: Our results establish PDECs as a feasible model to identify immunomodulatory functions of anticancer drugs in the context of patient-specific TIME.
    Keywords:  Breast Neoplasms; Dendritic Cells; Drug Evaluation, Preclinical; Immunity, Innate; Immunomodulation
    DOI:  https://doi.org/10.1136/jitc-2023-008053
  23. Sci Rep. 2024 Apr 12. 14(1): 8535
    Phosphoglycerate mutase 5 exacerbates liver ischemia-reperfusion injury by activating mitochondrial fission.
    Hongwei Tang, Qiwen Yu, Xu Chen, Jiakai Zhang, Danfeng Guo, Wenzhi Guo, Shuijun Zhang, Xiaoyi Shi.
      Although the death of hepatocytes is a crucial trigger of liver ischemia-reperfusion (I/R) injury, the regulation of liver I/R-induced hepatocyte death is still poorly understood. Phosphoglycerate mutase 5 (PGAM5), a mitochondrial Serine/Threonine protein phosphatase, regulates mitochondrial dynamics and is involved in the process of both apoptosis and necrotic. However, it is still unclear what role PGAM5 plays in the death of hepatocytes induced by I/R. Using a PGAM5-silence mice model, we investigated the role of PGAM5 in liver I/R injury and its relevant molecular mechanisms. Our data showed that PGAM5 was highly expressed in mice with liver I/R injury. Silence of PGAM5 could decrease I/R-induced hepatocyte death in mice. In subcellular levels, the silence of PGAM5 could restore mitochondrial membrane potential, increase mitochondrial DNA copy number and transcription levels, inhibit ROS generation, and prevent I/R-induced opening of abnormal mPTP. As for the molecular mechanisms, we indicated that the silence of PGAM5 could inhibit Drp1(S616) phosphorylation, leading to a partial reduction of mitochondrial fission. In addition, Mdivi-1 could inhibit mitochondrial fission, decrease hepatocyte death, and attenuate liver I/R injury in mice. In conclusion, our data reveal the molecular mechanism of PGAM5 in driving hepatocyte death through activating mitochondrial fission in liver I/R injury.
    Keywords:  Liver I/R injury; Mitochondrial fission; Mitochondrial quality control; PGAM5
    DOI:  https://doi.org/10.1038/s41598-024-58748-7
  24. J Biol Chem. 2024 Apr 04. pii: S0021-9258(24)01760-5. [Epub ahead of print] 107259
    Selenoprotein I is indispensable for ether lipid homeostasis and proper myelination.
    Lance G A Nunes, Chi Ma, FuKun W Hoffmann, Ashley E Shay, Matthew W Pitts, Peter R Hoffmann.
      Selenoprotein I (SELENOI) catalyzes the final reaction of the CDP-ethanolamine branch of the Kennedy pathway, generating the phospholipids phosphatidylethanolamine (PE) and plasmenyl-PE. Plasmenyl-PE is a key component of myelin and is characterized by a vinyl ether bond that preferentially reacts with oxidants, thus serves as a sacrificial antioxidant. In humans, multiple loss-of-function mutations in genes affecting plasmenyl-PE metabolism have been implicated in hereditary spastic paraplegia (HSP), including SELENOI. Herein, we developed a mouse model of nervous system-restricted SELENOI deficiency that circumvents embryonic lethality caused by constitutive deletion and recapitulates phenotypic features of HSP. Resulting mice exhibited pronounced alterations in brain lipid composition, which coincided with motor deficits and neuropathology including hypomyelination, elevated reactive gliosis, and microcephaly. Further studies revealed increased lipid peroxidation in oligodendrocyte lineage cells and disrupted oligodendrocyte maturation both in vivo and in vitro. Altogether, these findings detail a critical role for SELENOI-derived plasmenyl-PE in myelination that is of paramount importance for neurodevelopment.
    Keywords:  Selenoprotein; corticospinal tract; ether lipid; hereditary spastic paraplegia; lipid peroxidation; myelin; oligodendrocyte
    DOI:  https://doi.org/10.1016/j.jbc.2024.107259
  25. Nat Commun. 2024 Apr 06. 15(1): 2986
    Structure and mechanisms of transport of human Asc1/CD98hc amino acid transporter.
    Josep Rullo-Tubau, Maria Martinez-Molledo, Paola Bartoccioni, Ignasi Puch-Giner, Ángela Arias, Suwipa Saen-Oon, Camille Stephan-Otto Attolini, Rafael Artuch, Lucía Díaz, Víctor Guallar, Ekaitz Errasti-Murugarren, Manuel Palacín, Oscar Llorca.
      Recent cryoEM studies elucidated details of the structural basis for the substrate selectivity and translocation of heteromeric amino acid transporters. However, Asc1/CD98hc is the only neutral heteromeric amino acid transporter that can function through facilitated diffusion, and the only one that efficiently transports glycine and D-serine, and thus has a regulatory role in the central nervous system. Here we use cryoEM, ligand-binding simulations, mutagenesis, transport assays, and molecular dynamics to define human Asc1/CD98hc determinants for substrate specificity and gain insights into the mechanisms that govern substrate translocation by exchange and facilitated diffusion. The cryoEM structure of Asc1/CD98hc is determined at 3.4-3.8 Å resolution, revealing an inward-facing semi-occluded conformation. We find that Ser 246 and Tyr 333 are essential for Asc1/CD98hc substrate selectivity and for the exchange and facilitated diffusion modes of transport. Taken together, these results reveal the structural bases for ligand binding and transport features specific to human Asc1.
    DOI:  https://doi.org/10.1038/s41467-024-47385-3
  26. Immunity. 2024 Apr 09. pii: S1074-7613(24)00127-4. [Epub ahead of print]57(4): 834-836
    Hostile bile limits anti-cancer immunity.
    Pavitha Parathan, Lisa A Mielke.
      Various microbial metabolites promote cell transformation. In this issue of Immunity, Cong et al. show that deoxycholic acid (DCA), a microbial metabolite of bile, promotes tumor growth by suppressing antitumor CD8+ T cell responses via dysregulation of calcium efflux.
    DOI:  https://doi.org/10.1016/j.immuni.2024.03.006
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